Retinal Measures Potential Biomarkers for Sickle Cell Disease Progression

Results of a longitudinal prospective case-control study found rates of retinal thinning were higher among individuals with sickle cell retinopathy compared with individuals without the condition.

Retinal thickness and rates of retinal thinning, detected using spectral-domain optical coherence tomography (OCT), may serve as potential biomarkers for the progression of sickle cells disease, according to research published in JAMA Ophthalmology. Results of a longitudinal prospective case-control study found rates of retinal thinning were higher among individuals with sickle cell retinopathy compared with individuals without the condition, and thinning rates increased as participants aged, and stages of retinopathy progressed.

“Sickle cell retinopathy is characterized by occlusion of the retinal vasculature, which may produce ischemia and infarction of the retina,” the researchers wrote. Previous studies have shown retinal macular thinning from sickle cell retinopathy is associated with age, sickle cell hemoglobin subtype, and proliferative sickle retinopathy stage.

To calculate and compare rates of retinal thinning among eyes with and without sickle cell retinopathy, investigators analyzed data of participants enrolled in a prospective longitudinal observational study that began in 2009. All participants presented to a university-based retinal subspecialty clinic between February 11, 2009, and July 3, 2019. Those with sickle cell retinopathy were matched by age and race to individuals without the condition (control group). In the United States, approximately 1 in 365 Black individuals is born with sickle cell disease.

Study participants underwent full ophthalmic examinations including best-corrected Snellen visual acuity testing, slitlamp examination, and dilate ophthalmoscopy. Electronic medical records were also reviewed to obtain past and current medical conditions at baseline, while interim medical history was obtained at follow-up visits.

Mean (SD) follow-up for the sickle cell group (n = 175; 344 eyes) was 53.7 (32.6) months compared with 54.6 (34.9) months for the control group (n = 31; 46 eyes). Those in the sickle cell group had a mean age of 37.8 (12.8) years compared with 59 (15.4) years in the control group. Data showed rates of macular thinning in the sickle cell group were significantly higher than those in the control group for the following quadrants:

  • Inner nasal (difference, −1.18 mcm per year; 95% CI, −1.71 to −0.65 mcm per year)
  • Inner superior (difference, −1.03 mcm per year; 95% CI, −1.78 to −0.29 mcm per year)
  • Inner temporal (difference, −0.61 mcm per year; 95% CI, −1.16 to −0.07 mcm per year)
  • Outer nasal (difference, −0.41 mcm per year; 95% CI, −0.80 to −0.03 mcm per year)

For most patients in each group, sickle cells stage and visual acuity remained stable.

When compared with sickle cell hemoglobin SS (HbSS) subtype, those with sickle cell hemoglobin SC (HbSC) and sickle cell hemoglobin β-thalassemia (HbS-β-thalassemia) subtypes had higher rates of retinal thinning. Participant age, stage of retinopathy, previous stroke, and presence of hypertension, acute chest syndrome, or diabetes were also associated with greater rates of retinal thinning.

In addition, hydroxyurea therapy was associated with decreased rates of thinning, suggesting the treatment may be a protective factor. “Hydroxyurea therapy is associated with increases in fetal hemoglobin, which decreases vaso-occlusive crises and could be associated with decreased retinal ischemia and less retinal thinning over time,” the authors noted.

The extent of central subfield thinning observed in the current study among the sickle cell group was much higher compared with historical control groups. To account for this, the researchers hypothesized, “Because participants in our control group were slightly older and therefore had thinner retinas, it is possible that we may have underestimated the difference between eyes with and without sickle cell retinopathy; that is, the inclusion of younger participants in the control group may have produced even greater differences.”

Furthermore, patients with the HbSS subtype have thinner retinas at baseline and therefore have less retinal tissue to lose, which may account for the greater rates of thinning seen in patients with HbSC and HbS-β-thalassemia.

The absence of analyses on the association between retinal thinning and disease-modifying therapies, including chronic exchange infusions, marks a limitation to the study, as these treatments could have slowed retinal thinning, rendering the rates reported an underestimation.

Overall, the findings suggest spectral-domain OCT is a more sensitive biomarker for the progression of sickle cell retinopathy than clinical staging and should be considered in studies investigating the effectiveness of drugs for the treatment of sickle cell disease.

“Spectral-domain OCT could be used to detect eyes with sickle cell retinopathy that exhibit greater rates of retinal thinning and that may benefit from more frequent monitoring and receipt of hydroxyurea therapy or other therapies to decrease sickling episodes,” the authors concluded.


Lim JI, Niec M, Sun J, Cao D. Longitudinal assessment of retinal thinning in adults with and without sickle cell retinopathy using spectral-domain optical coherence tomography. JAMA Ophthalmol. Published online February 4, 2021. doi:10.1001/jamaophthalmol.2020.6525