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

献血者性别和血浆睾酮个体间差异对红细胞和血小板输血有效性和止血潜力的影响

• 批准号: 10930183
• 负责人: Tamir Kanias
• 金额: $ 73.95万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10930183
• 关键词: Acute; Address; Allogenic; Award; Bilirubin; Bioenergetics; Biological; Biological Availability; Biological Markers; Blood; Blood Banks; Blood Donations; Blood Platelets; Blood donor; Cell Survival; Cell physiology; Characteristics; Clinical; Collection; Data; Databases; Donor Selection; Effectiveness; Erythrocyte Transfusion; Erythrocytes; Erythrocytoses; Evaluation; Event; Exposure to; Frequencies; Genes; Genetic; Genetic Determinism; Genetic Induction; Genetic Polymorphism; Genotype; Goals; Health; Hemoglobin; Hemolysis; Hemorrhage; Hemostatic Agents; Hemostatic function; Heterogeneity; High Prevalence; Hypogonadism; Immunodeficient Mouse; Individual; Infusion procedures; Knowledge; Leukocytes; Link; Longitudinal Studies; Measures; Mediating; Membrane; Mitochondria; Mus; National Heart, Lung, and Blood Institute; Obesity; Operative Surgical Procedures; Orchiectomy; Osmotic Fragility test; Outcome; Patient-Focused Outcomes; Patients; Phosphatidylserines; Physiological; Pilot Projects; Plasma; Platelet Activation; Platelet Count measurement; Policies; Prevalence; Recovery; Red Blood Cell Count; Residual state; Risk Factors; SHBG gene; Safety; Signal Induction; Single Nucleotide Polymorphism; Supplementation; Testing; Testosterone; Therapeutic Intervention; Thrombin; Thrombosis; Thrombus; Time; Transfusion; Trauma; Veins; Virilism; androgen sensitive; effectiveness measure; genome wide association study; genome-wide; improved; inter-individual variation; male; mouse model; neonate; novel strategies; patient population; platelet function; platelet phenotype; real-time images; screening; sex; testosterone replacement therapy; transfusion medicine

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.

项目概要/摘要 该提案的长期目标是通过弥补差距来提高输血有效性和安全性 了解睾酮介导的影响红细胞 (RBC) 和血小板功能的细胞变化 我们努力应对由储存和输血引起的生理睾酮信号的破坏。 遗传、特发性或治疗性干预（睾酮替代疗法，TRT）有助于捐赠者之间 血液成分质量的异质性以及改变输血效果的科学前提。 基于我们的发现，游离（生物可利用）的超生理协调（>890 ng/dL；常见于 TRT） 血浆中的睾酮与氧化溶血增加和膜变形能力降低相关。 与输血有效性相关，来自 TRT 供体的经伽马射线照射的红细胞单位短期内存活率较低 与非 TRT 对照相比，输注到免疫缺陷小鼠体内后，患者的血红蛋白增加 与来自 TRT 捐献者的红细胞单位相比，单次红细胞输注后，来自 TRT 捐献者的红细胞单位减少 非 TRT 男性捐献者（75% 的非 TRT 患者）的血小板研究表明，外源性睾酮具有一定的抑制作用。 通过增加聚集和线粒体生物能量来证明对血小板的启动效应，并且 TRT 与储存中血小板活化标记物的表达增加有关。在目标 1 中，我们将量化 来自 NHLBI REDS-III RBC-Omics 的男性捐献者血浆中游离睾酮和总睾酮的浓度 研究具有完整的基因分型信息和红细胞输血事件后受者结果的关联数据。 通过血浆测量睾酮浓度，我们将能够确定亚健康的患病率 男性捐赠者的生理（性腺功能减退）和超生理睾酮水平进行全基因组研究； 协会 (GWA) 研究鉴定与供体血浆相关的单核苷酸多态性 (SNP) 睾酮浓度；并定义睾酮浓度和确定的 SNP 对 输血有效性（通过患者血红蛋白和胆红素增量的变化来衡量）使用 REDS-III 静脉间数据库在目标 2 中，我们评估性腺功能减退和 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。 评估扩大 TRT 个体血液成分利用的可行性。 预计该项目的成果将使我们能够： 确定血浆睾酮的遗传决定因素 影响患者睾酮治疗的有效性以及储存期间和之后的红细胞/血小板存活率 输血；通过建立献血者睾酮，造福精准输血医学的新兴领域 弱势患者群体（新生儿/雄激素）输血有效性和安全性的阈值 敏感）；改进 TRT 供体筛选，以尽量减少受者接触超生理游离睾酮的情况； 重新审查现行限制或禁止 TRT 捐献者捐献血小板的政策，并探索差异化利用； 基于临床创伤和手术等急性出血场景中的 TRT 血小板特征。