Raising pre-transfusion HbS levels from 30% to 50% does not increase ischemic stroke recurrence in sickle cell disease: Results from a long-term single-center study Free

Introduction: Exchange transfusion remains the only strategy for the secondary prevention of ischemic stroke in sickle cell disease (SCD). Most guidelines recommend maintaining pre-transfusion levels of hemoglobin S (HbS) below 30%. However, lifelong frequent transfusions can increase iron overload, red blood cell (RBC) alloimmunization, and may negatively affect patient adherence to treatment. Additionally, no prospective clinical studies have evaluated the safety or efficacy of maintaining higher pre-transfusion HbS levels in the context of secondary stroke prevention. Since 2002, based on a small cohort study, our center has adopted an individualized approach for patients with no neurological events for at least 3 years following the initial stroke. In such cases, we increased the maximum HbS target from 30% to 50%. This study reports the long-term incidence of recurrent ischemic stroke in patients under transfusion program with pretransfusion HbS levels < 50%.

Methods: Data from patients followed at the SCD outpatient service of the Hospital das Clínicas da FMUSP were collected and managed using REDCap electronic data capture tools hosted at HCFMUSP. Analyses were performed using IBM SPSS Statistics v31.0.0.0 and Rstudio v2025.05.0+496.

Results: Among 65 patients who experienced at least one neurological event, 5 were excluded due to lack of data. Additionally, 11 patients were not enrolled in a chronic exchange transfusion program due to the nature of their events: hemorrhagic stroke (n=3), transient ischemic attack (n=3), thrombotic event secondary to patent foramen ovale (n=2), or because factors such as older age, stroke location and SCD genotype (SC) suggested that the etiology was not directly related to SCD (n=3). The remaining 48 patients had an ischemic stroke and underwent chronic exchange transfusion. The median age at the time of the first stroke was 11.2 (range, 4-65) years, and 54% were female. Regarding self-reported ethnicity, 33% identified as mixed race, 27% as black, and 40% as white. The median follow-up (FUP) time was 16.4 (range, 2.7-35) years, with a 806 person-years FUP. Imaging revealed moya-moya in 29% of patients and cerebral aneurysm in 4%. Half of the patients received partial manual exchange transfusion, 29% underwent automated exchange, and 21% received simple transfusion. Iron chelation therapy was used by 48% of the patients, and 17% had RBC alloimmunization. At last FUP, 63% of patients were alive, 31% had died, and 6% were lost to FUP. Six patients did not have their target pre-transfusion HbS increased to 50% and were excluded from further analyses. Among the 42 patients who were maintained with a pre-transfusion HbS target of <50%, with a 732 person-years FUP, only one experienced a recurrence of ischemic stroke. Notably, this patient had a history of multiple prior strokes, secondary epilepsy, and was hospitalized due to decompensated heart failure at the time of this new stroke; social circumstances had contributed to the HbS level being maintained at 50%. No other patient experienced ischemic stroke recurrence while under transfusion program. Two patients had a hemorrhagic stroke that resulted in death. Two additional patients had an ischemic stroke after discontinuing chronic exchange transfusions: one due to severe alloimmunization, and the other due to poor adherence.

Discussion: To date, this represents the largest and longest-followed cohort of SCD patients in whom pre-transfusion HbS levels were increased to 50%, as part of a chronic transfusion program for secondary stroke prevention. The observed stroke recurrence rate was lower than previously reported in similar settings, and comparable to that seen in cohorts maintaining HbS levels below 30%. This finding suggests that increasing the pre-transfusion HbS levels to 50% is safe and does not compromise stroke prevention efficacy. This strategy may improve patient adherence and reduce transfusion-related complications, thereby helping to prevent alloimmunization and exacerbation of iron overload. Furthermore, reduced use of RBC units and apheresis kits may result in significant cost savings, an especially relevant benefit in resource-limited settings. These results provide a strong rationale for revisiting current guidelines and considering more flexible targets for HbS levels in the secondary prevention of ischemic stroke in SCD.