Effect of blood donor sex and inter-individual variability in plasma testosterone on the transfusion effectiveness and hemostatic potential of red blood cells and platelets

项目摘要/摘要 这项建议的长期目标是通过解决差距来提高输血的有效性和安全性。 在了解睾酮介导的细胞变化影响红细胞(RBC)和血小板功能的基础上 储存和输血后。我们假设，生理睾酮信号的中断是由 遗传、特发性或治疗性干预(睾酮替代疗法，TRT)有助于供者间 血液成分质量的异质性，以及输血效果的改变。科学的前提是 基于我们的发现，超生理学浓度(890 ng/dL；在TRT中常见)游离(生物可利用) 血浆中的睾酮与氧化溶血增加和膜变形性降低有关。 与输血有效性有关，来自TRT捐赠者的伽马照射的红细胞单位短期内存活率较低 输注免疫缺陷小鼠后与非TRT对照组相比，患者的血红蛋白增加 在单个RBC单位输注后，来自TRT捐赠者的RBC单位输血量比来自TRT捐赠者的RBC单位输血量减少 非TRT男性捐献者(占非TRT的75%)。我们对血小板的研究表明，外源性睾丸素具有 血小板的启动效应表现为聚集增加和线粒体生物能量学，而TRT 与储存过程中血小板活化标志物的表达增加有关。在目标1中，我们将量化 NHLBI‘s Reds-III RBC-OMICS男性献血者血浆中游离和总睾酮的浓度 用完整的基因分型信息和红细胞输注事件后受者结局的相关数据进行研究。 通过测量血浆睾丸素浓度，我们将能够确定亚 男性捐赠者中的生理性(性腺机能减退)和生理超生理学睾酮；进行全基因组 用于确定与供者血浆相关的单核苷酸多态(SNP)的关联(GWA)研究 睾酮浓度；确定睾酮浓度和已识别的SNPs对 输血有效性(通过患者的血红蛋白和胆红素增量的变化来衡量)使用 REDS-III静脉对静脉数据库。在目标2中，我们评估了性腺功能减退和TRT对血小板的影响。 治疗、储存和小鼠输血模型中的表型和止血功能。我们的目标是 评估扩大个体血液成分在TRT中应用的可行性。我们 预计这个项目的结果将使我们能够：识别血浆睾酮的基因决定因素， 影响患者睾酮治疗的有效性以及保存和保存后的红细胞/血小板存活率 输血；通过建立献血者睾酮造福于精密输血医学的新兴领域 脆弱患者人群(新生儿/雄激素)输血有效性和安全性的阈值 敏感)；改进TRT捐赠者筛查，以最大限度地减少受者对超生理学游离睾酮的暴露； 重新审视限制或禁止TRT捐献者捐献血小板的现行政策；探索差异化利用 基于TRT在创伤和手术等急性出血的临床场景中的血小板特性。

PROJECT SUMMARY / ABSTRACT The long-term goal of this proposal is to advance transfusion effectiveness and safety by addressing the gaps in knowledge of testosterone-mediated cellular changes that impact red blood cell (RBC) and platelet function in storage and after transfusion. We hypothesize that disruption of physiological testosterone signaling induced by genetic, idiopathic or therapeutic intervention (testosterone replacement therapy, TRT) contributes to inter-donor heterogeneity in the quality of blood components, and to altered transfusion effectiveness. The scientific premise is based on our findings that supraphysiological concertation (>890 ng/dL; common in TRT) of free (bioavailable) testosterone in plasma is correlated with increased oxidative hemolysis and decreased membrane deformability. Relevant to transfusion effectiveness, gamma-irradiated RBC units from TRT donors had lower survival shortly after infusion into immunodeficient mice compared with non-TRT controls, and patients’ hemoglobin increments following a single RBC unit transfusion were reduced for RBC units from TRT donors compared to those from non-TRT male donors (75% of non-TRT). Our studies in platelets suggested that exogenous testosterone has a priming effect on platelets evidenced by increased aggregation and mitochondrial bioenergetics, and that TRT was associated with increased expression of platelet activation markers in storage. In Aim 1, we will quantify the concentrations of free and total testosterone in plasma from male donors from NHLBI’s REDS-III RBC-Omics study with complete genotyped information and linked data of recipient outcomes after RBC transfusion events. By measuring plasma testosterone concentration, we will be able to determine the prevalence of sub- physiological (hypogonadism) and supraphysiological testosterone among male donors; conduct genome-wide association (GWA) studies to identify single nucleotide polymorphism (SNP) associated with donor plasma testosterone concentration; and define the impact of testosterone concentration and identified SNPs on transfusion effectiveness (measured by changes in patient’s hemoglobin and bilirubin increments) using the REDS-III vein-to-vein database. In Aim 2, we evaluate the impact of hypogonadism and TRT on platelet phenotype and hemostatic function in therapy, in storage, and in a mouse model of transfusion. The goal is to evaluate the feasibility of expanding the utilization of blood components derived from individuals on TRT. We anticipate that this project’s outcomes will allow us to: identify genetic determinants of plasma testosterone that impact the effectiveness of testosterone therapy in patients, and RBC/platelet survival in storage and after transfusion; benefit the emerging field of precision transfusion medicine by establishing blood donor testosterone threshold values for transfusion effectiveness and safety in vulnerable patient populations (neonates/androgen sensitive); improve TRT donor screening to minimize recipient exposure to supraphysiological free testosterone; reexamine current policies that limit or ban platelet donation by TRT donors; and explore differential utilization based on TRT platelet characteristics in clinical scenarios of acute bleeding like trauma and surgery.