Abstract Background: Hemoglobin (Hb) SC disease is a compound sickle cell variant that affects about 25% of patients with sickle cell disease (SCD) but remains understudied compared to HbSS disease. Although considered a “mild” variant, it is characterized by cellular dehydration, increased red cell density and distinct complications including high retinopathy rates, avascular necrosis (AVN), sensorineural hearing loss (SNHL), acute chest syndrome (ACS) and venous thromboembolism (VTE). Despite known complications, there are no clear guidelines for management of HbSC and management is often extrapolated from wider SCD studies that exclude these patients. Objective: Evaluate clinical manifestations, treatment response, and complications in adults with HbSC, with focus on hydroxyurea (HU) effects and age-related complications. Methods: IRB-approved retrospective study at the Georgia Comprehensive Sickle Cell Center at Grady Memorial Hospital, of adults (≥18 years) with HbSC confirmed by electrophoresis and seen in our center from 2015-2025. Variables included demographics, comorbidities, steady-state laboratory values, morphine milliequivalent/day (MME/day) use and SCD-related hospitalization/acute visits. SCD-related complications (ACS, VTE, AVN, retinopathy, SNHL, pulmonary hypertension PH, chronic kidney disease CKD) was also obtained. Statistical analysis was performed using t-tests, chi-square, and multivariate regression (significant: p0.05). Abbreviations used: IQR (interquartile range), OR (odds ratio), CI (confidence interval). Results: Our cohort comprised 303 patients (57.4% female, 42.6% male, median age 36 IQR 29-49 years) with a median Hb of 11.5 IQR 10.5-12.1 g/dL, HbF 1.5 IQR 1-2.7 %, LDH 237 IQR 197.8-278.5 U/L, absolute reticulocyte counts 134.7 IQR 105.9-170 ×10⁹/L. Comorbid conditions included 20.5% hypertension,19.2% chronic pain, 18.8% with concomitant psychiatric diagnosis, 5.3% diabetes and 5.3% obesity. Of our cohort, 55.8% had ≥ 1 hospitalization (median of 1 IQR 1-2 visits/24 months) and 76.9% had ≥1 acute visits (median of 2 IQR 1-6 visits/24 months). Chronic opioid therapy was noted in 43.9% of patients (median MME 12.5 IQR 0-49/day over 12 months). Major complications included AVN in 40.9%, CKD in 24.8%, ACS/multi-organ failure (MOF) in 21.1%, with median LDH/platelet ratio of 3.6 IQR 1.5-5.1 at initial presentation. Retinopathy occurred in 40.3% (N=95) of examined patients with a median age at diagnosis of 31 IQR 26-42 years and an OR of early diagnosis (35 years) of 1.64 (p0.01). VTE occurred in 20.5% with 78% occurring during VOC episodes. OR of VTE in patients with history of ACS was 3.57 (95% CI 1.71-7.45, p0.001). Additionally, SNHL was noted in 8.9% of patients with median age of 49.5 IQR 41.3-57.5 years and an OR of late diagnosis (45 years) of 3.20 (95% CI 1.26-8.12, p0.01). Stroke occurred in 7.3% and PH in 6% (N=11) of screened patients. HU was utilized in 19.1% of patients (mean dose 15.6±8.5 mg/kg) and resulted in mild increase HbF (2.9% vs 1.8%, p0.05), and decrease in absolute neutrophil count (4.1 vs 6.2×10⁹/L, p0.01) and Hb (10.8 vs 11.4 g/dL, p0.05) when compared to those not on HU but did not significantly impact healthcare utilization or opioid requirements. Of patients with documented ferritin, 24.7% (N=64) had ferritin 50 ng/mL while 75.3% (N=195) had ferritin of ≥50 ng/mL. Patients with ferritin 50 ng/mL had a 17% lower risk of retinopathy, 16% lower risk of AVN and 5% lower health care utilization albeit without statistical significance. Conclusions: Our study demostrates that patients with HbSC disease have significant healthcare utilization and chronic opioid use. They also demonstrated distinct age-related complication patterns including early onset-retinopathy within the first 3 decades of life and late onset SNHL occurring beyond the 4th decade of life. There was a strong association between ACS and VTE risk which is likely reflective of a more severe HbSC phenotype increasing VTE risk. HU utilization was overall low with mild biological effects but its clinical benefit on healthcare and opioid utilization was not apparent in our population. Lower ferritin trended towards less SCD complications albeit without statistical significance. This brings up a potential question of exploring phlebotomy and hepcidin memetics to drive iron restrictive erythropoiesis and help improve hemorheology and clinical outcomes in patients with HbSC disease.
Ajayi et al. (Mon,) studied this question.