Red Cell Survival Following Transfusion in Infants

项目1的主要目标是改善贫血患者的红细胞（RBC）输注实践， 危重婴儿，给予多次RBC输注的高危患者组。新生儿和 lamb研究的提出是及时的，因为他们解决了实质性的未解决的问题，在新生儿 RBC输血实践，例如，使用储存21-42天的成人同种异体红细胞（对比仅使用新鲜 RBC <7 d）和使用自体胎盘RBC，这可能是一种更安全的选择，通过床旁护理变得可行 测试设备。我们的建议扩展了我们以前的PPG的工作，首次考虑在 储存对婴儿红细胞输血后恢复和存活的影响，考虑到独特的 以及干扰从而混淆RBC存活测量的关键因素。项目1整体 假设可以准确地测定同种异体和自体红细胞输血后存活率， 使用基于生物素标记RBC的新生羔羊模型在贫血人类婴儿中定量 与数学建模相结合，以补偿混淆变量， 在新生儿早期遇到的（例如，由于放血造成的RBC损失，由于 输血和红细胞生成导致的红细胞稀释，这两种情况都是对贫血和血液循环增加的反应。 快速增长）。临床上有用的RBC恢复和存活参数，我们称之为 “RBC动力学”（即，短期输血后24小时恢复（“PTR 24”）和长期平均 潜在寿命（“MPL”））将使用我们的研究开发的RBC生物素化方法来确定。 之前的PPG。项目1提出了四个具体目标：1）在成年绵羊中开发和验证 能够以多达5种离散密度生物素化RBC，以确定多种RBC的“RBC动力学” 2）应用来自目标#1的RBC生物素化方法来测量 应激性红细胞生成对正常成年绵羊稳态红细胞生成中红细胞存活的影响; 3） 在新生羔羊中使用目标1中的RBC生物素化方法，以开发符合伦理的 可接受的，数学上精确的模型，以补偿上述因素的唯一 影响危重婴儿输血后RBC动力学的测量;以及4）使用RBC 在目标#1和#3中验证的生物素化和数学建模方法， 测量输血新鲜自体血的贫血新生儿输血后红细胞动力学， 新鲜的同种异体和储存的同种异体RBC。使用生物素，一种无毒、无放射性的B族维生素， 通过流式细胞术同时区分不同的红细胞群对于 完成项目1的目标，并在两个方面都具有明显优于其他RBC标记方法的优势 安全性和准确性。在利用四个具体目标，以实现我们的目标，建立更有效的 通过确定用于贫血婴儿的最佳红细胞输注产品， 项目1支持我们PPG的研究机制和优化管理的主题 新生儿贫血

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.