The primary goal of Project 1 is to improve red blood cell (RBC) transfusion practices for anemic, critically ill infants, a high-risk patient group given multiple RBC transfusions. The newborn infant and lamb studies proposed are timely because they address substantive unresolved issues in neonatal RBC transfusion practices, e.g., use of 21-42 d stored adult allogeneic RBCs (vs. exclusive use of fresh RBCs <7 d) and use of autologous placental RBCs, potentially a safer option made feasible by point-ofcare testing devices. Our proposal extends our previous PPG's work by considering for the first time in infants the effect of storage on RBC post-transfusion recovery and survival, taking into account unique and critical factors that perturb, thereby confounding, RBC survival measurements. Project 1's overall hypothesis is that post-transfusion survival of allogeneic and autologous erythrocytes can be accurately quantified in anemic human infants using a newborn lamb model based on biotin-labeled RBCs combined with mathematical modeling to compensate for confounding variables commonly encountered in the early newborn period (e.g., RBC loss due to phlebotomy, RBC gain due to transfusion, and RBC dilution due to erythropoiesis both in response to anemia and to increased blood volume with rapid growth). Clinically useful RBC recovery and survival parameters, which we refer to as """"""""RBC kinetics"""""""" (i.e., short-term post-transfusion recovery at 24 hr (""""""""PTR24"""""""") and long-term mean potential life span (""""""""MPL"""""""")) will be determined using RBC biotinylation methodologies developed in our previous PPG. Project 1 proposes, in four specific aims, to: 1) develop and validate in adult sheep the ability to biotinylate RBCs at up to 5 discrete densities to determine """"""""RBC kinetics"""""""" of multiple RBC populations simultaneously;2) apply the RBC biotinylation methodology from Aim #1 to measure the effect of stress erythropoiesis on RBC survival in normal adult sheep in steady-state erythropoiesis;3) utilize in newborn lambs the RBC biotinylation methodology from Aim #1 to develop an ethically acceptable, mathematically accurate model to compensate for the above-noted factors uniquely influencing measurements of posttransfusion RBC Kinetics in critically ill infants;and 4) use the RBC biotinylation and mathematical modeling methodologies validated in Aims #1 and #3 to accurately measure post-transfusion RBC kinetics in anemic newborn infants transfused with fresh autologous, fresh allogeneic and stored allogeneic RBCs. The use of biotin, a non-toxic, non- radioactive B vitamin, to distinguish among different RBC populations simultaneously by flow cytometry is critical for accomplishing Project 1's aims and holds clear advantages over other RBC labeling methods in both safety and accuracy. In utilizing the four Specific Aims to achieve our goal of establishing more effective transfusion practices by identifying the optimal RBC transfusion product for use in anemic infants, Project 1 supports our PPG's themes of investigating the mechanisms and optimizing the management of neonatal anemia.
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