It is well established that advanced age is an independent risk factor for developing venous thromboembolism (VTE). However, mechanisms that contribute to enhanced clot formation in the elderly are incompletely understood. There is a growing body of evidence that platelets are involved in the pathogenesis of VTE and several studies have demonstrated that alterations in platelet function occur with aging. Most of these geriatric-based studies have focused on 'classic'platelet responses such as adhesion, aggregation and secretion. It is now known, however, that platelets possess other activities that may influence VTE. In this regard, our group has identified novel gene expression pathways in platelets that modulate thrombotic and inflammatory responses. We have characterized these gene expression pathways in young volunteers and hypothesize that they become dysregulated in the elderly, contributing to impaired clot formation and resolution in this population. In line with the objectives of this RFA, our proposal uses a multidisciplinary research team with expertise in basic and clinical investigation to address the following three specific aims.
In specific aim 1 we will compare mRNA expression patterns and associated protein synthetic responses between platelets isolated from young and elderly donors. Studies in aim 1will focus on pre-mRNA splicing and mTOR-dependent translation, two post-transcriptional gene expression pathways that operate in platelets and generate proteins that may contribute to VTE.
In aim 2 we will determine if platelets from elderly donors induce the synthesis of mediators in target leukocytes that have been implicated in VTE. Comparisons will be made to young donors where these types of responses have been characterized in detail by our group. We will also determine if the gene expression pathways characterized in aims 1and 2 are influenced by drugs that are commonly prescribed to reduce the risk of thrombosis and vascular disease in the elderly. In the last aim we will initiate a prospective clinical study to determine if the gene expression pathways characterized in aims 1 and 2 identify elderly patients that develop VTE after elective orthopedic surgery. Together these studies will provide new information on how platelets influence the pathogenesis of VTE.
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