DESCRIPTION (provided by applicant): Despite standard care, 25%-50% of patients with acute deep vein thrombosis (DVT) progress to chronic post- thrombotic syndrome (PTS) resulting in significant disability, loss of productivity, and healthcare costs. This is a problem encountered frequently among our numerous Veterans undergoing surgery, anesthesia, traumatic and acute injury, and surgical critical care. Venous valvular reflux from an organized thrombus is the primary cause of PTS. Veins with rapid and complete thrombus resolution have a lower incidence of reflux. We have observed that thrombus resolution is enhanced by increased blood flow and that moderate upper or lower extremity exercise result in increased venous blood flow. Hence, we postulate that a progressive exercise training program in patients with DVT will increase lower extremity venous flow, accelerate thrombus resolution, and decrease the risk of PTS. The primary hypothesis is that increased blood flow across the thrombus (induced by supervised exercise) will accelerate thrombus resolution and decrease PTS. The overall goal is to determine whether exercise can lower the risk of PTS in patients with acute DVT, and to investigate possible mechanisms by which this occurs. We propose a 2-year randomized clinical trial of standard therapy compared to standard therapy plus exercise in patients with acute lower extremity DVT. Aim 1 will test whether a 3-month exercise training program prevents PTS and improves quality of life over 2 years of follow-up. Patients with acute lower extremity DVT (iliac-femoral-popliteal) will be randomized to standard therapy (control group receiving: anticoagulation, compression, ambulation ad-lib) alone, or to exercise plus standard therapy. The study will recruit 164 patients to achieve 80% power to detect a 50% decrease in prevalence of PTS at 2 years, and a decrease in severity of PTS through 2 years of follow-up in the exercise group vs. standard care. Aim 2 will investigate mechanisms by which the exercise program may act to prevent PTS, namely systemic markers of fibrinolysis and thrombus resolution. Aim 3 will investigate alternate mechanisms of decreased PTS that are more direct results of the exercise therapy, namely: improving venous hemodynamics and functional capacity. Collectively, these results will allow us to understand the basis of a novel conceptual model that progressive aerobic and resistive exercise aids in the treatment of DVT and prevention of PTS through mechanisms of enhanced thrombus resolution, fibrinolytic and vascular repair, calf muscle pump action, and functional ability. This will be a novel therapeutic intervention for maintenance and restoration of tissue function after DVT.