Studies on Serial Phlebotomy in Voluntary Blood Donors

描述（由申请人提供）：Sullivan于1981年首次提出，减少体内铁储备可以预防心血管疾病。在观察性研究中，献血已知可以减少铁的储存，并初步与降低心血管风险相关，但解释这一发现的机制尚未得到很好的描述。我们的初步数据表明，与零星献血相比，高频献血与铁储量的严重减少、氧化应激的降低和血管内皮功能的改善有关。由于已知改善血管内皮功能与降低心血管发病率和死亡率相关，这些初步数据支持献血与降低心血管风险之间的潜在机制联系。我们现在提出一项前瞻性干预性试验，以调查自愿献血者献血与血管内皮功能之间的潜在机制。我们假设连续放血与血管功能的改善有关，这与除铁和除血的生理生化效应有关。为了验证这一假设，150名目前因非医疗原因而推迟主动献血的含铁自愿献血者将被随机分配到3个治疗组：4个500毫升静脉采血6个月，不补充失去的铁，4个500毫升静脉采血6个月，静脉补充失去的铁，或假静脉采血。这项三组研究设计提供了区分失血和铁流失对连续放血生物反应的相对贡献的方法。在指定的研究干预前后，将获得基础状态和瞬态高同型半胱氨酸血症、血清和尿液铁储存和氧化应激、红细胞和血浆体积、区域动脉壁剪切应力和促红细胞生成素水平时肱动脉血流介导的扩张（血管内皮功能的无创测量）。多变量混合效应模型将用于确定研究治疗与血管功能之间的关系，以及铁和血液去除的生理生化相关是否为这种关系的介质。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，并将为献血对健康的影响提供新的数据，这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来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。这项研究的发现将提供新的数据，有利于影响国家的血液供应，并可能影响血色素沉着症（美国最常见的遗传性疾病之一）筛查和营养补充剂和食品中铁含量调节的公共政策决定。

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.