An ABO Blood Type Defined ARDS Endotype in Sepsis

摘要 急性呼吸窘迫综合征(ARDS)是一种肺部炎症、肺泡炎的异质性综合征。 毛细血管屏障功能障碍和脓毒症常见的微血栓形成。死亡率在30%以上，没有 ARDS有多种药物治疗方法。我们之前发现ABO血型之间存在可重复的联系 在脓毒症中，A型血与O型血相比，ARDS的绝对风险约高14%。阿波 血型由ABO基因决定，该基因编码一系列糖基转移酶 负责催化红细胞上糖链和糖蛋白上特定的碳水化合物修饰， 内皮细胞和血小板。决定血型的基因变异与罹患 多发性凝血性疾病，包括心肌梗塞和静脉血栓栓塞症，以及 多种内皮细胞衍生糖蛋白的血浆水平。我们公布的初步数据显示， A型血型的遗传决定的A1亚型之间的关联性，区别为高出30-50倍 相对于A2亚型的“A”转移酶活性，ARDS风险最高。此外，我们还确定了一个 脓毒症早期血型与血浆两种蛋白水平的相关性 血管内皮细胞活化和凝血、血管性血友病因子(VWF)和可溶性血栓调节蛋白(STM) 与弥散性血管内凝血(DIC)的风险一样。这些相同的蛋白质被认为与 阿兹。在vWF上，A抗原减少了ADAMTS13的降解，导致了促凝作用，提示 A型败血症患者可能需要更高的ADAMTS13水平。因此，我们假设存在一个 ABO血型对ARDS内型的影响，可用于临床识别和靶向。世界银行的目标是 在这项申请中提出的研究是为了获得识别人口最关键的必要信息 可能从针对ABO影响的血管生物学的治疗中受益，并了解ABO的效果 受伤肺上的葡聚糖。我们将通过以下目标实现这一目标；目标1将决定 基因决定的ABO血型A1与脓毒症和脓毒症相关性ARDS死亡率的关系 在两个重症脓毒症患者的大队列中。AIM 2将派生并验证一个预测工具，该工具包括 ABO基因型，血浆vWF和STM水平，以及DIC评分的组成部分，以识别一个人群 脓毒症患者出现ABO定义的凝血病理ARDS内型的风险很高。目标3将决定纵向 体外肺灌注模型中ABO血型对肺损伤恢复的生理学影响 测试这些效应是否被重组ADAMTS13所改变。多学科团队 调查人员包括一名转化学家和遗传学专家(迈耶)，两名分子流行病学家 拥有ARDS和预测建模方面的专业知识(Ware，Christie)，EVLP专家(坎图)，生物统计学家 在重症监护研究(冯)和翻译流行病学家PI(Reilly)方面有合作的历史 世卫组织最先确定了ABO血型与ARDS风险之间的关联。

ABSTRACT Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome of lung inflammation, alveolar capillary barrier dysfunction, and micro-thrombosis that is common in sepsis. Mortality is above 30% and no pharmacotherapies exist for ARDS. We previously identified a reproducible association between ABO blood type A and an approximately 14% higher absolute risk of ARDS compared to blood type O in sepsis. ABO blood type is genetically determined by the ABO gene, which encodes a family of glycosyltransferases responsible for catalyzing specific carbohydrate modifications on glycans and glycoproteins on erythrocytes, endothelial cells, and platelets. The genetic variation that determines blood type is associated with risk to multiple coagulopathic diseases, including myocardial infarction and venous thromboembolism, as well as plasma levels of multiple endothelial-derived glycoproteins. Our published preliminary data, demonstrate an association between the genetically determined A1 subtype of blood type A, distinguished by 30-50 fold higher “A” transferase activity relative to the A2 subtype, and highest ARDS risk. Additionally, we identified an association of blood type with plasma levels of two proteins measured early in sepsis and important in endothelial activation and coagulation, von Willebrand factor (vWF) and soluble thrombomodulin (sTM), as well as with risk of disseminated intravascular coagulation (DIC). These same proteins have been implicated in ARDS. On vWF, A antigens reduce degradation by ADAMTS13, resulting in a pro-coagulant effect, suggesting septic blood type A patients may require higher ADAMTS13 levels. Therefore, we hypothesize that there is an endotype of ARDS influenced by ABO blood type that can be identified and targeted clinically. The goals of the research proposed in this application is to obtain critical information necessary to identify a population most likely to benefit from therapies targeting ABO-influenced vascular biology and to understand the effect of ABO glycans on injured lungs. We will accomplish this through the following Aims; Aim 1 will determine the association of genetically determined ABO blood type A1 and mortality in sepsis and sepsis-associated ARDS, in two large cohorts of critically ill sepsis patients. Aim 2 will derive and validate a predictive tool that includes ABO genotype, plasma levels of vWF and sTM, and components of the DIC score to identify a population at high risk for an ABO-defined coagulopathic endotype of ARDS in sepsis. Aim 3 will determine the longitudinal physiologic effects of ABO blood type on lung injury recovery in an ex vivo lung perfusion (EVLP) model and test if these effects are modified by the administration of recombinant ADAMTS13. The multidisciplinary team of investigators includes a translational scientist and genetics expert (Meyer), two molecular epidemiologist with expertise in ARDS and predictive modeling (Christie, Ware), an EVLP expert (Cantu), a bio-statistician with a history of collaboration in critical care research (Feng), and the PI (Reilly), a translational epidemiologist who first identified an association between ABO blood type and ARDS risk.