Real-World Study of the Impact of Hemoglobin on End-Organ Damage in Sickle Cell Disease
E Leila Jerome Clay, Adam Wufsus, Anh Thy Nguyen, Shelby Corman, Nicole Bariahtaris, Jing Voon Chen, Katharine BattAbstract
Background
Sickle cell disease (SCD) is caused by a genetic mutation in the hemoglobin (Hb) gene, resulting in crescent-shaped red blood cells that can block blood flow and cause severe pain crises known as vaso-occlusive crises (VOCs), that can lead to end-organ damage (EOD). The interplay between laboratory markers such as Hb and VOCs have been well studied. However, there has been limited research on the relationship between Hb and EOD. The aim of this study was to describe the impact of Hb on the risk of EOD in patients with SCD.
Methods
This was a retrospective, longitudinal cohort study of patients ≥12 years of age with SCD. Data from October 1, 2015, to May 30, 2024, were extracted from the TriNetX Dataworks™ electronic health records database. International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes were used to identify patients with SCD and ≥1 recorded Hb measurement between April 1, 2016, and May 30, 2023 (index date) and ≥1 health care encounter within 6 months before and 12 months after the index date. The analysis first investigated the combined impact of Hb and 3 hemolysis markers (ie, reticulocytes, unconjugated bilirubin, and lactate dehydrogenase) on EOD (ie, chronic kidney disease [CKD], pulmonary hypertension [PH], leg ulcer, stroke, and avascular necrosis [AVN]). Due to the expected correlation between hemolysis markers, each marker was separately assessed as a time-varying covariate: model 1 included reticulocytes; model 2 included unconjugated bilirubin; and model 3 included lactate dehydrogenase. Each model consisted of a Cox regression with time-varying covariates (Hb, sickle hemoglobin, fetal hemoglobin, transfusions, SCD treatments) and fixed covariates (age, sex, race, ethnicity, region, SCD genotype, Charlson Comorbidity Index [CCI] score, comorbidities, and baseline rate of stroke and leg ulcer [for the relevant outcomes]). A secondary analysis assessed the association between Hb (without other laboratory markers) and EOD as sensitivity analyses. Model A accounted for demographic and disease-related factors, and model B further adjusted for the CCI, comorbidities with prevalence >5%, and time-varying transfusion status and SCD treatments.
Results
A total of 15,350 patients were included in the study; the patient population was predominantly female (59.0%), Black or African American (79.8%), with Hb-SS genotype (58.0%). Effect estimates for models 1-3 were similar within each EOD in general (Table 1). Across all models, increases in Hb resulted in the greatest statistically significant reduction in PH (20%-26%), followed by leg ulcer (18%-23%) and CKD (16%-17%) (all P < 0.05). Stroke (models 1 and 3: 10%-11%, P < 0.05; model 2: 5%, P=ns) and AVN (model 1: 5%, P < 0.05; models 2 and 3: 3%-7%, P=ns) demonstrated reduced but significant effect estimates. The secondary analysis indicated that across models A and B, a 1 g/dL increase in Hb was associated with the following reduction in risk: 23%-24% for PH, 24% for leg ulcer, 11%-17% for stroke, 9% for CKD, and 8% for AVN (all P < 0.05).
Conclusions
These data reveal an association between increased Hb levels and reduced risk of EODs, suggesting that disease-modifying treatments that increase Hb levels may result in reduced incidence of SCD-related complications, thereby lowering disease burden and improving long-term outcomes and quality of life for patients. Overall, a multi-modal approach to SCD management is important to address the needs of this at-risk group of patients.