Introduction: Hemoglobin (Hb) S beta thalassemia plus (β+) is a variant of sickle cell disease (SCD) characterized by inheritance of HbS and Hbβ+ gene, resulting in sickling and mild hemolytic anemia. While considered “mild”, it is associated with variable complication risks including chronic kidney disease (CKD), avascular necrosis (AVN), pulmonary hypertension (PH), acute chest syndrome (ACS), multiorgan failure (MOF), stroke, frequent hospitalizations/emergency room (ER) visits, and a high prevalence of psychiatric disorders. Our study aimed to assess clinical features, healthcare utilization, and opioid utilization patterns in patients with HbSβ+ and highlight factors that may be related to this.

Methods: IRB-approved retrospective study at the Georgia Comprehensive Sickle Cell Center, Grady Memorial Hospital, Atlanta, GA, analyzing adults (≥18 years) with HbSβ+ who received care from 2015-2025. Data on Hb, fetal hemoglobin percentage (%HbF), absolute reticulocyte count (ARC) and lactate dehydrogenase (LDH) were obtained. Comorbidities, acute healthcare visits, hospitalizations and opioid utilization patterns (morphine milligram equivalents per day, MME/day) were assessed. High healthcare utilization was defined as ≥ 2 hospitalizations or ≥ 4 acute healthcare visits over 12 months. High opioid use was defined as mean MME/day of ≥ 50 MME/day over 12 months. Statistical analyses (t-tests, Chi-square, Mann-Whitney U test, logistic regression analysis) were performed to identify significant differences (p ≤ 0.05). Abbreviations: Confidence interval (CI), odds rations (OR), adjusted odds ratio (aOR), interquartile range (IQR).

Results: Our cohort included 193 patients (mean age, 41.3±14.3 years, 56% female) with a mean Hb of 11.2±1.4 g/dL, %HbF 7.3±5.9, ARC 123±53×10³/μL and LDH 227±66 U/L. Comorbidities included hypertension (29.6%), psychiatric disorders (28.5%), diabetes (8.3%). SCD-related complications included AVN (43%), CKD (26.9%), VTE (23.8%), stroke (13.5%), chronic pain (13.5%), PH 7.3% (N=14/193) and SCD retinopathy 28.4% (N=22/74).

In our cohort, 49.7% had ≥ 1 hospitalization (median 0 [IQR 0-3]), while 63.5% had ≥ 1 ER visit over 24 months (median 1 [IQR 0-4]). Chronic opioid use was seen in 30.1% of patients (median dose of 62 MME/day [IQR 30-162] in the opioid utilizers).

Hydroxyurea (HU) was utilized in 18.7% of patients (mean dose 13.6±5.7 mg/kg). Patients on HU had higher %HbF compared to those not on HU (mean of 11.2±8.5% vs 6.2±4.6%, p<0.01) but this did not translate to less healthcare utilization or opioid use in the HU group.

Patients who developed ACS/MOF (N=21) had elevated LDH/platelet ratio at initial presentation compared to those who presented with uncomplicated VOC (N=46) (median 3.1 vs 1.1). LDH/platelet ratio >2 was associated with 12.2-fold increase odds of ACS/MOF (95% CI: 3.8-45.5, p<0.0001).

Patients with psychiatric comorbidity had higher median hospitalization (2 vs 0 visits/24 months, p=0.008), ER visits (2.5 vs 1 visits/24 months, p=0.055) and opioid utilization (4 vs 0 median MME/day, p=0.003) in comparison to those without psychiatric diagnosis. Independent predictors of high healthcare utilization included chronic opioid use (aOR 3.63, p<0.05), psychiatric comorbidity (aOR 3.08, p<0.05), chronic pain (aOR 2.75, p<0.05). Predictors of high opioid utilization included chronic pain (aOR 16.85, p<0.05), psychiatric comorbidity (aOR 2.54, p<0.05), and AVN (aOR 2.50, p<0.05).

Mortality occurred in 8.3% (N=16) of our cohort (median age 51.5 [IQR 37-57] years) with 68.8% related to SCD and 31.2% having unknown etiology.

Conclusion: Patients with HbSβ+ have significant disease burden with high healthcare utilization and opioid use despite the “mild” designation. Psychiatric comorbidities, chronic pain and AVN appeared to be the major independent predictors of high acute healthcare utilization and opioid use. This underscores the importance of dedicated, comprehensive care and investigational therapeutic approaches rather than being dismissed as having “milder” disease. In addition, an elevated LDH/platelet ratio >2 at the time of presentation corelates with a higher odd of developing ACS/MOF, highlighting a potential risk assessment tool in these patients but this would require prospective validation. Although HU had expected biochemical effects, its impact on decreasing healthcare utilization/opioid use was not apparent in our cohort, however this is likely related to selection bias.

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2025
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