Hindsight 20/20: The Role of Hemoglobin F in Sickle Cell Retinopathy

Introduction:

Sickle cell disease (SCD) is a highly prevalent inheritable hematological disorder which is characterized by variable, multisystem clinical manifestations. Hemoglobin F (HbF) has been shown to demonstrate a protective effect in patients with SCD primarily through the reduction of hemoglobin polymerization. However, the effect of HbF is inconsistent, varying on the subtype of SCD complication. A common ocular manifestation of SCD, sickle cell retinopathy (SCR), occurs due to series of changing initiated by microvascular occlusions from rigged hemoglobin aggregations. SCR is classified as non-proliferative and proliferative, with the latter being the most vision-threatening. However, due to peripheral involvement, it may present silently, emphasizing the importance of regular ophthalmic examinations. The published prevalence of SCR is notably variable indicating a need for updated epidemiological data. Moreover, recent evidence suggests a potential correlation between decreased hemoglobin F (HbF) levels and increased SCR prevalence; however, results are mixed. Lower HbF levels have also been indicated as a significant predictor for proliferative SCR, the more severe subtype. Given these observations, we aimed to investigate the correlation between HbF levels and the prevalence of SCR.

Methods:

This study uses a descriptive and cross-sectional design to analyze existing, secondary medical record data of 496 SCD patients that received care from the Center for Blood Disorders at the Medical College of Georgia in Augusta, Georgia. Data utilized ranged from 1976 to 2023. Data abstraction included the most recent HbF values, along with, the presence of SCD clinical complications including SCR. The diagnosis of SCR was determined by a previous ophthalmological examination indicating the diagnosis or a previous history mentioned in the medical record.

To test the association of HbF with a categorical variable such as medical history of sickle cell retinopathy, we used a two-sample t-test to compare the mean HbF in each group. We also used the non-parametric Wilcoxon rank-sum test to compare the median HbF in each group. To test the association of HbF with a continuous variable such as D-dimer, we computed Pearson's correlation coefficient r and Spearman's correlation coefficient rho, and used Fisher's z-test. We also performed the non-parametric Kruskal-Wallis test to compare the age. All analyses were performed using R version 4.2.3.

Results:

Among the 496 included participants, 121 were reported to have SCR, with 117 having confirmatory ophthalmological documentation. The prevalence of SCR was 24% within our study. The mean HbF for individuals with SCR was 8.44 with a SD of 7.84 while individuals without SCR had a mean HbF of 9.57 with a SD of 10.8. Our study did not find a significant association between mean HbF levels and SCR ( p = 0.2056). When utilizing median HbF, to account for outliers, there was practically no difference between patients with SCD with SCR (median HbF = 6.3) and patients with SCD with SCR (median HbF = 6.2). However, there was a significant association between SCR and age (p = 0.0003) while no significant association was found with sex (p = 0.8293).

Conclusion:

In this cohort of patients, there was not a significant association between HbF levels and the presence of SCR. To our knowledge, this study evaluating association between HbF level and the development of SCR in patients with SCD is the first of its kind. Therefore, it may require a larger sample size in order to understand a role of HbF in this particular complication. Furthermore, the prevalence of SCR within this study was also lower than historical data, which begs the question, is there some protective factor against developing SCR in this population. As new disease-modifying therapies are being studied and prescribed, the rates of SCR should be compared to patients receiving standard of care therapies such as Hydroxyurea. Follow-up research separating sub-types of SCR may reveal different outcomes. Additionally, a prospective study observing patients with SCD receiving new therapy should be considered to better understand preventative treatment of SCR.