Thrombotic Susceptibility in Veterans: Influence of prediabetes

Iowa City Va Medical Center, Iowa City IA

Investigators

Abstract

Background, Innovation, and Impact to Veterans Healthcare: Thrombotic complications like myocardial infarction (MI), stroke and venous thrombosis are the leading causes of morbidity/mortality in elderly, and are common triggers for hospitalization in Veteran Health Administration system. Further, the risk factors encountered during young or middle age may predispose to early thrombotic outcomes. For example, the incidence of pre-diabetes in US is increasing, including in Veterans, and a growing literature in last 5-8 years has linked prediabetes to arterial and venous thrombotic outcomes in aged as well as young cohort. In Veterans, thrombotic complications are apparent prior to a clinical diagnosis of diabetes is established, suggesting a link to prediabetic state. Therefore, a major goal of this proposal is to understand the early mechanisms of increased susceptibility to arterial and venous thrombosis in understudied prediabetic young and middle-aged Veterans. Findings from our on-going studies in Veterans establishes that while a moderate platelet activation occurs in healthy middle-aged, a greater effect is seen due to prediabetes regardless of age. Moreover, the increased platelet activity is inhibitable by decreasing mitochondrial reactive oxygen species (mito-ROS) with SOD-mimetic. However, the molecular mechanisms for increased mito-ROS generation remain to be determined. Our novel pilot data suggests that a defect in electron transport chain (ETC) and altered metabolic pathways such as fatty acid oxidation upstream to ETC may lead to premature electron leakage and could be the key mechanisms of ROS-burden within mitochondria. We will test the innovative hypothesis, that dysregulation in ETC is central to platelet activation and NETosis mediated arterial or venous thrombosis in prediabetes and is partly modulated by age. The proposed study is conceptually novel because it will first time define a unique role of ETC in thrombosis and has several innovative technical aspects, including study of metabolic pathways in causing ETC dysregulation and study role of a common human polymorphism V16A in SOD2 using a novel humanized SOD2 mouse model. Using blood samples from Veterans, mouse models of aging and early diabetes, as well as hSOD2V16A and platelet-specific SOD2-KO models we will test the hypothesis under two independent aims. Aim 1: Determine the mechanistic role of ETC and ETC-linked pathways in regulating mito-ROS, platelet activation and arterial thrombosis in young and middle-age prediabetic Veterans, and test contribution of endogenous SOD2. Aim 2: Determine whether ETC and ETC- linked pathways within neutrophils regulate release of NETs, cfDNA/mtDNA/EVs and mediate venous thrombosis in aged or prediabetic Veterans and test a role of endogenous SOD2. Significance and Path to translation/implementation: This study is anticipated to make a significant positive clinical impact by providing key insight into the mechanisms of age- and prediabetes-associated arterial and venous thrombosis in the Veterans. Secondly, it will first time uncover the contributing role of a common SOD2 polymorphism in the thrombotic phenotype, that may implement inclusion of V16A polymorphism in testing panel for thrombophilia. Finally, the success of this proposal may support testing of MitoQ/GC4419 in the clinical trial for antithrombotic effects in age/prediabetes.