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B8 - Genetic Disorders of the Blood and Immune System (Including hemoglobinopathies, hematopoietic lineages, and inherited immune deficiencies such as ADA, X-SCID, and WAS, etc.)

1158: A Comparison of Red Blood Cell (RBC) Functional Biomarkers in Successful Hematopoietic Stem Cell Transplantation (HSCT) versus Graft Failure

Type: Poster Session

Poster Board Number: 1158
Presentation Details
Session Title: Thursday Posters: Genetic Disorders of the Blood and Immune System

Introduction: Sickle cell disease (SCD) is characterized by a mutation in the hemoglobin subunit β (HBB). Allogeneic HSCT is the most widely available cure, and the use of haploidentical donors has expanded the donor pool. Successful HSCT (S-HSCT) is associated with absence of SCD manifestations, including pain, normalized hemoglobin (Hb), and reversal of hemolysis. Critical aspects of red blood cell health (RBCH), such as adhesion and Hb polymerization, can predict future SCD severity and may provide earlier and more precise insight into HSCT efficacy. We assessed changes in flow adhesion of whole blood to vascular cell adhesion molecule (FA-WB-VCAM) and P-selectin (FA-WB-Psel), and RBC sickling with the dynamic sickling assay (DSA) before and after HSCT. Graft failure (GF), pain, opioid use, and clinical labs were captured.
Methods: Samples were collected from 4 SCD subjects and 4 donors enrolled in NHLBI HSCT protocol 17-H-0069 or 000539-H. FA-WB-VCAM and FA-WB-Psel utilized a microfluidic well-plate system and were reported as cells/mm2. DSA samples were exposed to a proprietary enzymatically-induced hypoxic environment, time-lapse photomicroscopy and AI-based SICKLE image analysis software quantifying RBC sickling. Parameters measured include: time to 5% and 50% morphological point of sickling (mPoS@5%, mPoS@50%), maximum rate of sickling (% /min), maximum sickling (%), and AUC10 (%*min). All values presented are mean ± standard error; p<0.05 considered statistically significant.
Results: 3 subjects had S-HSCT, 1 experienced GF. In S-HSCT, Hb increased from 9.2±0.3 to 11±2 g/dL, bilirubin was reduced significantly from 1.7±0.3 at BL to 0.4±0.06 mg/dL at 6M (p<0.01). FA-WB-VCAM and FA-WB-Psel BLs in S-HSCT were 369±63 and 36±18 cells/mm2, respectively. FA-WB-VCAM decreased significantly (26±9 cells/mm2, p<0.01) by 3M and sustained at 6M (59±8 cells/mm2, p<0.01). Although FA-WB-Psel decreased p-HSCT, it was not statistically significant. In GF, FA-WB-VCAM increased p-HSCT and FA-WB-Psel adhesion doubled from BL to 6M. Max rate of sickling in S-HSCT significantly decreased from 38±7 to 1.1±0.7 %/min (p<0.01) at 3M, and further to 0.4±0.4 %/min (p<0.01) at 6M. In GF, an initial reduction in sickling rate from BL to 3M was followed by an increase at 6M p-HSCT. Max sickling in S-HSCT significantly decreased from 0.68±0.16 at BL to 0.1±0.01 (p=0.02) and 0.06±0.01 (p=0.02) at 3M and 6M, respectively. In contrast, max sickling increased in GF from a BL of 0.50 to 0.75 at 6M (Fig.1).
Conclusions: RBC health normalizes following S-HSCT as evidenced by statistically significant reductions in adhesive properties, reduced sickling rate and amplitude within 3 months. The subject experiencing GF demonstrated a worsening of adhesive and sickling parameters of RBC health consistent with sickle RBCs. A longer post HSCT follow-up period is needed to establish clinical improvement following S-HSCT, but reduced pain and lower opioid usage in patients is encouraging. These findings suggest that FA-WB-VCAM, FA-WB-Psel and DSA could serve as objective indicators of RBC health normalization p-HSCT. Future studies will determine if these biomarkers could be surrogates for long-term clinical efficacy.

Plain Language Summary
This study on sickle cell disease (SCD) looked at how effective a treatment called hematopoietic stem cell transplant (HSCT) is. It focused on changes in red blood cells (RBCs) before and after the treatment using special tests. These tests measured how the RBCs stick to certain molecules and how they change shape under low oxygen conditions. The study found that after successful HSCT, RBCs became healthier, sticking less and changing shape less often, similar to normal RBCs. This improvement was linked to less pain and reduced need for pain medication. However, one patient who didn't respond well to the treatment showed worsening RBC health. This research suggests these tests could help doctors understand how well HSCT is working in SCD patients.

Aliya U. Zaidi1, Rasa Borhan1, Robert Goodrich1, Marta Ferranti1, Xiufeng Gao1, Cynthia Joseph2, Emily Limerick2, Courtney D. Fitzhugh2, Patrick C. Hines1,3,4

1Functional Fluidics Inc., Detroit, MI,2NHLBI/NIH, Bethesda, MD,3Division of Pediatric Critical Care Medicine, Wayne State University, Detroit, MI,4Division of Pediatric Critical Care Medicine, Wayne Pediatrics, Detroit, MI"

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