Studies on Serial Phlebotomy in Voluntary Blood Donors

描述（由申请人提供）：Sullivan于1981年首次提出，减少体内铁储存可以预防心血管疾病。已知献血可减少铁储存，并在观察性研究中暂时与心血管风险降低相关，但解释这一发现的机制尚未得到很好的表征。我们的初步数据表明，与零星献血相比，高频献血与铁储备严重减少，氧化应激降低和血管内皮功能改善有关。由于已知血管内皮功能的改善与心血管发病率和死亡率的降低相关，这些初步数据支持献血和心血管风险降低之间的潜在机制联系。我们现在提出一项前瞻性干预试验，以调查自愿献血者献血和血管内皮功能之间的潜在机制。我们假设，连续放血与改善血管功能有关的生理和生化作用的铁去除和血液清除。为了检验这一假设，将150名目前因非医疗原因推迟主动献血的铁充足的自愿献血者随机分配到3个治疗组：6个月内进行4次500 ml静脉切开术，不补充丢失的铁，6个月内进行4次500 ml静脉切开术，静脉补充丢失的铁，或假静脉切开术。该3组研究设计提供了区分失血与铁丢失对连续静脉切开术生物学反应的相对贡献的方法。在分配的研究干预之前和之后，将获得基础状态下和对一过性高同型半胱氨酸血症的响应的肱动脉中的流量介导的扩张（血管内皮功能的非侵入性测量）、铁储备和氧化应激的血清和尿液测量、红细胞和血浆容量、局部动脉壁剪切应力和促红细胞生成素水平。将使用多变量混合效应模型确定研究治疗与血管功能之间的相关性，以及铁和血液清除的生理和生化相关性是否为该相关性的介质。这项研究将为铁储存和血管功能之间的关系提供新的见解，并将提供有关献血对健康影响的新数据，这些数据可能会影响国家的血液供应。超过50%的美国人一生中至少需要献血一次。我们提出一项前瞻性随机双盲研究，以确定献血对血管功能的影响。该提案的总体目标是更好地描述献血对心血管健康的潜在影响。这项研究的结果将提供新的数据，可能对国家的血液供应产生有利影响，并可能影响血色素沉着症（美国最常见的遗传疾病之一）筛查和营养补充剂和食品中铁含量监管的公共政策决策。

DESCRIPTION (provided by applicant): Sullivan first proposed in 1981 that reduction in body iron stores may protect against cardiovascular disease. Blood donation is known to reduce iron stores and has been tentatively associated with reduced cardiovascular risk in observational studies, but the mechanisms to account for this finding are not well characterized. Our preliminary data demonstrate that high-frequency blood donation is associated with severe reductions in iron stores, decreased oxidative stress, and improved vascular endothelial function when compared with sporadic donation. Since improved vascular endothelial function is known to be associated with decreased cardiovascular morbidity and mortality, these preliminary data support a potential mechanistic link between blood donation and reduced cardiovascular risk. We now propose a prospective interventional trial to investigate potential mechanisms linking blood donation and vascular endothelial function in voluntary blood donors. We hypothesize that serial phlebotomy is associated with improved vascular function related to physiological and biochemical effects of iron removal and blood removal. To test this hypothesis, 150 iron-replete voluntary blood donors currently deferred from active donation for non-medical reasons will be randomly assigned to 3 treatment groups: four 500 ml phlebotomy procedures over 6 months without replacement of lost iron, four 500 ml phlebotomy procedures over 6 months with intravenous replacement of lost iron, or sham phlebotomy. This 3-arm study design provides the means to distinguish the relative contributions of blood loss vs. iron loss on biological responses to serial phlebotomy. Flow-mediated dilation in the brachial artery (a non-invasive measure of vascular endothelial function) in the basal state and in response to transient hyperhomocysteinemia, serum and urinary measures of iron stores and oxidative stress, red cell and plasma volume, regional arterial wall shear stress, and erythropoietin levels will be obtained before and after the assigned study intervention. Mulitvariate mixed effects models will be used to determine the association between study treatment and vascular function and whether physiological and biochemical correlates of iron and blood removal are mediators of this association. This study will provide new insight into the relationship between iron stores and vascular function and will provide new data on the health effects of blood donation that could impact the nation's blood supply. More than 50% of all Americans will require a blood donation at least one time in their lives. We propose a prospective randomized double-blind study to determine the effects of blood donation on vascular function. The overall goal of the proposal is to better characterize the potential impact of blood donation on cardiovascular health. The findings of this study will provide novel data that could favorably impact the nation's blood supply, and could influence public policy decisions on screening for hemochromatosis (one of the most common genetic diseases in the US) and regulation of iron content in nutritional supplements and foods.