An ABO Blood Type Defined ARDS Endotype in Sepsis

摘要

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.