The Post Thrombotic Syndrome (PTS) is an important, surprisingly common chronic complication of deep venous thrombosis (DVT) that develops in up to 50% of DVT patients, despite appropriate anticoagulation. The symptoms of PTS are often debilitating, and include constant or intermittent limb swelling, aching, cramps, or numbness/tingling. In fact, PTS is a key determinant of long-term quality of life among patients with venous thromboembolism (VTE) and is linked to important declines in physical and mental health. Impairments in quality of life induced by PTS are as severe as from diabetes or congestive heart failure. As 300,000-600,000 patients develop a new DVT each year in the US alone, it is critical to prevent DVT-induced PTS. There are two key important issues in the field of PTS. First, few therapies are available, and disappointingly, the recent SOX trial showed that compression stockings are ineffective. Invasive thrombectomy can reduce PTS, but even the thrombectomy group remains with a 41% incidence of PTS. Second, limited study has been focused on vein wall injury in patients with DVT. Vein wall injury and scarring, induced by inflammation, leads to valvular incompetence and venous hypertension, the driving pathophysiologic feature of PTS. The objectives of this bench-to-bedside application are A) To demonstrate that DVT-based inflammation, as measured by in vivo FDG-PET inflammation imaging, independently predicts PTS in patients; and B) To develop new anti-inflammatory strategies to reduce murine DVT-induced vein wall scarring, a key driver of PTS. Our long-term goal is to better understand the role of in vivo inflammation in the pathophysiology of PTS, and to leverage this knowledge to reduce PTS in patients. The Specific Aims of this proposal are: Specific Aim 1. To perform a first-in-human clinical trial assessing DVT-based inflammation using FDG- PET/CT to predict the risk of subsequent PTS in patients independently and in multivariate analyses. Specific Aim 2. To develop three new anti-inflammatory pharmacotherapeutic strategies to reduce vein wall scarring in experimental DVT. Additionally, in synergy with Aim 1, we will assess whether the FDG-PET measure of VT inflammation predicts the final VWS thickness during anti-inflammatory therapy. Overall Impact: This clinical, imaging, and biological research proposal will transform the field of DVT by: A) Establishing the first clinical relationship between DVT inflammation and subsequent PTS; B) Establishing that FDA-approved therapies can reduce experimental DVT inflammation and VWS; and C) Developing FDG-PET to predict PTS, and to identify at-risk subjects that may benefit from new PTS therapies. The overall results will provide a rigorous, precision medicine-based foundation to test anti-inflammatory therapies against PTS.