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.

项目总结/摘要 该提案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 在睾丸激素介导的细胞变化的知识，影响红细胞（RBC）和血小板功能， 储存和输血后。我们假设，睾丸激素诱导的生理性睾丸激素信号传导的中断， 遗传、特发性或治疗性干预（睾酮替代疗法，TRT）有助于供体间 血液成分质量的异质性，以及输血有效性的改变。科学前提 基于我们的发现，超生理浓度（>890 ng/dL;常见于TRT）的游离（生物可利用） 血浆中的睾酮与增加的氧化性溶血和降低的膜变形性相关。 与输血有效性相关，TRT供体的γ射线照射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，以及患者的血红蛋白增量 在单次RBC单位输注后，TRT供体的RBC单位与TRT供体的RBC单位相比有所减少。 非TRT男性供体（非TRT的75%）。我们在血小板中的研究表明，外源性睾酮具有 对血小板的引发作用通过增加聚集和线粒体生物能量学来证明， 与储存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 来自NHLBI的REDS-III RBC组学的男性供体血浆中游离和总睾酮浓度 这项研究提供了完整的基因分型信息和红细胞输注事件后受体结局的相关数据。 通过测量血浆睾酮浓度，我们将能够确定亚- 男性供体中的生理性（性腺功能减退）和超生理性睾酮;全基因组行为 相关性（GWA）研究，以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测量），使用 REDS-III静脉间数据库。目的2：评价性腺功能减退和TRT对血小板的影响， 表型和止血功能在治疗中，在存储中，和在小鼠输血模型。目标是 评估扩大TRT患者血液成分利用的可行性。我们 预计该项目的结果将使我们能够：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，以及储存和储存后的RBC/血小板存活率 输血;通过建立献血者睾酮， 脆弱患者人群（新生儿/雄激素）中输血有效性和安全性的阈值 改善TRT供体筛选，以最大限度地减少受体暴露于超生理游离睾酮; 重新审查限制或禁止TRT捐献者捐献血小板的现行政策;并探索差异利用 基于TRT血小板在急性出血（如创伤和手术）的临床情况下的特征。