Hemoglobin F% and Complete Blood Count Patterns in Two Independent Sickle Cell Anemia Cohorts from India & the US
Authors: Pendharkar Dinesh , Nirmal Garima , Pande Manoj , Han Jin , Gordeuk Victor R. , Saraf Santosh L. 
Published: December 2024

Sickle cell anemia (SCA) is among the most common monogenetic diseases affecting approximately 8 million people and 300,000 newborns per year worldwide. In certain regions of India, the hemoglobin (Hb) S mutation is observed in up to 40% of the population with 2% being homozygous (Hb SS). Despite the high prevalence of SCA in India, the characteristics of SCA in this population and the impact of Hb F% on the SCA phenotype are not well understood.
We conducted a prospective, observational study to better understand the Hb F% patterns and relationship to complete blood count (CBC) parameters in a tribal region of central India. 575 patients with SCA were recruited between 11/2021 and 4/2024 and blood was collected to determine Hb F%, Hb concentrations, and white blood cell (WBC) counts. We compared our findings to a separate cohort of 240 SCA patients enrolled in a registry from a large urban academic center in the US. The Hb F% from the US cohort were obtained either before initiating hydroxyurea therapy or at the time of recruitment if not on hydroxyurea therapy.
The median age of the SCA cohort from India was 16 (interquartile range [IQR], 9 - 25) years old and 284 (49%) were female. The median Hb F% was 26.8% (IQR, 22.3% - 31.2%) and the median Hb concentration was 8.5 g/dL (IQR, 7.3 - 9.6 g/dL). Females had significantly higher Hb F% versus males (25.7% vs. 23.4%, respectively; P = 0.001) while older age was associated with a trend for lower Hb F% (β -0.032 ± 0.027; P = 0.1). A higher Hb F% was associated with improved Hb concentrations (β 0.083 ± 0.012; P &lt; 0.0001) and lower WBC counts (β -0.129 ± 0.035; P &lt; 0.0001).
In the US cohort, the median age was 31 (IQR, 23 - 42) years old and 143 (59%) were female. The median Hb F% was 4.4% (IQR, 2.4 - 7.9%) and significantly lower compared to the Hb F% observed in SCA patients from India (age-adjusted P &lt; 0.0001). The median Hb concentration was 8.6 g/dL (IQR, 7.7 - 9.4 g/dL), similar to the Hb concentrations observed in SCA patients from India (P = 0.6). Consistent with the Indian cohort, females had significantly higher Hb F% versus males (5.0% vs. 3.4%, respectively; P = 0.002) while there was no association between age and Hb F% (P = 0.7) in the US SCA cohort. Also similar to the Indian cohort, a higher Hb F% was associated with improved Hb concentrations (β 0.084 ± 0.019; P &lt; 0.0001) and lower WBC counts (β -0.125 ± 0.047; P = 0.008).
In conclusion, we demonstrate laboratory phenotyping of a large cohort of patients with SCA from a tribal region in central India. Hb F% were significantly higher in this cohort compared to a cohort of SCA patients from the US. We observed parallel findings between the two cohorts for higher Hb F% in women versus men as well as the protective effects of Hb F% on improved hemoglobin concentrations and reduced WBC counts, a biomarker that predicts vaso-occlusive episodes. Interestingly, although Hb F% were higher in SCA patients from the cohort in India vs. US, the Hb concentrations were similar. This suggests other factors, such as nutritional deficiencies, may be contributing to the anemia in SCA patients from India. Continued research is needed to better understand the phenotype of SCA in India as well as the impact of therapies that augment Hb F%, including gene therapy, in this patient population.