Biomarkers and Predictors of Treatment Response in Chronic Anemia in Sickle Cell Disease

/Abstract: Sickle cell disease (SCD), a major global health burden affecting millions worldwide, is characterized by chronic anemia that drives progressive multi-organ damage through a vicious cycle of tissue hypoxia, sickling, and hemolysis. However, safe and effective therapies for anemia in SCD are limited, and recent withdrawals of SCD therapies have emphasized the importance of understanding patient-specific benefits and risks of therapies. While hemoglobin (Hb)-raising therapies such as hydroxyurea (HU), blood transfusions, and novel agents aim to alleviate anemia, their effects on hemorheology (e.g., blood viscosity, red blood cell [RBC] deformability) and tissue perfusion remain poorly understood. This knowledge gap is critical, as excessive Hb increases in SCD may increase blood viscosity and paradoxically worsen vaso-occlusion and impair tissue perfusion, particularly in HbSC disease, where higher baseline Hb levels result in higher blood viscosity. Current clinical practice lacks biomarkers to guide individualized therapy, relying instead on Hb levels—a flawed surrogate biomarker that fails to capture the interplay between anemia correction, blood flow dynamics, and tissue oxygenation. This study seeks to address existing knowledge gaps by evaluating the impact of anemia therapies on tissue perfusion and hemorheological biomarkers and identifying baseline predictors of therapeutic response in patients with SCD. The aims of this study are: 1) To determine the effects of anemia treatments (HU, transfusions) on cerebral tissue oxygenation (StO₂) and hemorheology in adults with SCD, leveraging an international cohort in Nigeria to enhance sample size and reduce treatment heterogeneity, and 2) To define how clinico-demographic factors (SCD genotype, geographic setting) influence hemorheological profiles and StO₂. Using near-infrared spectroscopy (NIRS) to measure StO₂ as a primary physiological endpoint, this study will longitudinally assess treatment effects while incorporating a comprehensive panel of hemorheological biomarkers, including whole blood viscosity, RBC deformability, and cellular adhesion, to monitor individual physiological responses. Additionally, understanding whether SCD genotype or geographic cohort influences baseline hemorheology and StO₂ will establish a foundation for appropriate comparisons and treatment strategies across diverse SCD populations and inform future international clinical trial designs. Successful completion of these aims will identify translatable biomarkers to guide personalized anemia treatment, elucidate mechanisms underlying phenotypic variability in SCD, and inform the design of a future adaptive clinical trial comparing anemia therapies. Through this career development award and guidance from my multidisciplinary mentorship team, I will acquire advanced skills in hemorheological assays, optical biomarkers (NIRS), advanced clinical trial design, Bayesian statistical analysis, and global translational research leadership and execution. This training will position me to conduct innovative and efficient trials that address the global burden of SCD, fostering my transition to independence as a physician-scientist focused on optimizing anemia management in SCD. Project Number: 1K23HL175249-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: JULIA XU | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $190,188 | Activity Code: K23 | Study Section: Special Emphasis Panel[ZRG1 IVBH-A (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HL17524901A1