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 andlamb studies proposed are timely because they address substantive unresolved issues in neonatalRBC transfusion practices, e.g., use of 21-42 d stored adult allogeneic RBCs (vs. exclusive use of freshRBCs <7 d) and use of autologous placental RBCs, potentially a safer option made feasible by point-ofcaretesting devices. Our proposal extends our previous PPG's work by considering for the first time ininfants the effect of storage on RBC post-transfusion recovery and survival, taking into account uniqueand critical factors that perturb, thereby confounding, RBC survival measurements. Project 1's overallhypothesis is that post-transfusion survival of allogeneic and autologous erythrocytes can be accuratelyquantified in anemic human infants using a newborn lamb model based on biotin-labeled RBCscombined with mathematical modeling to compensate for confounding variables commonlyencountered in the early newborn period (e.g., RBC loss due to phlebotomy, RBC gain due totransfusion, and RBC dilution due to erythropoiesis both in response to anemia and to increased bloodvolume 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 meanpotential life span ('MPL')) will be determined using RBC biotinylation methodologies developed in ourprevious PPG. Project 1 proposes, in four specific aims, to: 1) develop and validate in adult sheep theability to biotinylate RBCs at up to 5 discrete densities to determine 'RBC kinetics' of multiple RBCpopulations simultaneously; 2) apply the RBC biotinylation methodology from Aim #1 to measure theeffect 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 ethicallyacceptable, mathematically accurate model to compensate for the above-noted factors uniquelyinfluencing measurements of posttransfusion RBC Kinetics in critically ill infants; and 4) use the RBCbiotinylation and mathematical modeling methodologies validated in Aims #1 and #3 to accuratelymeasure 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 foraccomplishing Project 1's aims and holds clear advantages over other RBC labeling methods in bothsafety and accuracy. In utilizing the four Specific Aims to achieve our goal of establishing more effectivetransfusion 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 managementof neonatal anemia.
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