Biotin-RBC Transfusion in SCD

Sickle cell disease (SCD) carries significant morbidity as a result of red blood cell (RBC) sickling and hemolysis. Stroke is one of the most devastating sequelae of SCD. Chronic transfusion therapy (CTT) reduces stroke risk by supplying normal, non-sickle RBC to circulation, thereby reducing the percentage of endogenous sickle RBC in circulation, and maintaining a higher hemoglobin (Hb), thereby suppressing erythropoiesis of new sickle RBC. While the efficacy of CTT in stroke prophylaxis is well-established, nearly 45% of children continue to have silent or overt strokes despite CTT. The failure of CTT to prevent stroke events may be related to inadequate reduction of circulating sickle RBC and erythropoiesis. The amount of circulating sickle-RBC is related to the survival kinetics of both transfused RBC and endogenous sickle RBC.

In a large, longitudinal analysis of CTT in SCD, the researchers found wide variation in the survival of donor RBC following transfusion, with faster clearance associated with patient immune features (historical RBC alloimmunization and spleen presence) and with donor RBC glucose-6-phosphate-dehydrogenase (G6PD) deficiency. To better understand the roles of patient and donor factors in the survival and clearance of transfused RBC, the researchers propose a mechanistic, clinical trial during chronic transfusion episodes in patients with SCD, in which a small aliquot of each transfused unit is labeled with biotin conjugated to RBC surface proteins, to safely identify and measure the in vivo survival of donor RBC.

Aim 1 will examine the relationships of the recipient's immune system (past alloimmunization, splenic volume, and markers of reticuloendothelial system function) on the post-transfusion survival of biotin-labeled donor RBC.

Aim 2 will examine the relationships of donor RBC G6PD levels and donor RBC metabolomics with the in vivo survival and changes in donor RBC senescence markers.

Aim 3 will compare the in vivo survival and clearance rate of phenotype-matched RBCs prepared with an investigational pathogen-reduction system (INTERCEPT Blood System) vs. the in vivo survival and clearance rate of conventional, phenotype-matched RBCs (not treated with INTERCEPT). Biotin labeling of donor RBC will be used to measure RBC survival. This is an optional study activity for study participants.

Completion of these aims will increase the understanding of mechanisms for the variability in RBC survival during CTT, identifying donor and recipient risk factors for decreased RBC survival. Ultimately this knowledge will inform the management of CTT to improve the prevention of strokes in SCD.

Inclusion criteria

• Hemoglobinopathy:

• Any sickle cell disease genotype, or
• Transfusion-dependent thalassemia (TDT)
• Receiving CTT for ≥3 months prior to enrollment
• For participants with past BioRBC transfusion exposure, BioRBC antibody screens must have been conducted through at least 6 months post exposure, with negative results

Exclusion criteria

• Anticipated cessation of CTT in the next ≤2 months
• Ongoing consumption of biotin or raw egg dietary supplements
• Antibody specific of INTERCEPT RBCs at baseline (for subjects consenting to the optional arm)
• BioRBC-specific antibodies ever detected in the past, or detected on post-enrollment screening prior to first infusion of Bio-RBC