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Background: With chronic transfusion in sickle cell disease (SCD), equipoise exists regarding whether increasing the post-procedure hematocrit (Hct) suppresses endogenous erythropoiesis. Reticulocytosis predicts SCD morbidity and mortality, so this study's objective was to clarify the role of the post-procedure Hct in suppressing reticulocytosis and to identify other potential red cell exchange (RCE) parameters predictive of reticulocytosis., Study Design and Methods: This retrospective analysis of 17 patients who underwent chronic RCE at a single institution between 2014 and 2022 examined both standard red cell exchanges (SRCE) and exchanges preceded by isovolemic hemodilution (IVH-RCE). Post-procedure parameters with biologic plausibility to influence the subsequent procedure's absolute reticulocyte count (sPre-ARC) were examined using regression modeling., Results: Neither post-hematocrit, nor post-hemoglobin (Hb), nor ΔHb/day was associated with sPre-ARC or the change in HbS% per day (ΔHbS%/day). Concurrent Hb was predictive for SRCE but not IVH-RCE, where ARC trended lower than with SRCE. Male gender and post-procedure neutrophil and white cell counts were predictors of sPre-ARC, consistent with their associations with SCD morbidity and mortality. IVH-RCE had a stronger correlation than standard RCE between pre-Hct and neutrophil or white cell depletion., Discussion: Although targeting a post-procedure Hct maintains a higher subsequent pre-procedure Hb and a lower sPre-HbS%, it does not lead to sustained suppression of reticulocytosis as measured by the sPre-ARC or the ΔHbS%/day. IVH-RCE or the addition of hydroxyurea could be considered in those patients with high reticulocyte, white blood cell, or neutrophil counts., (© 2024 AABB.)