Abstract 10433: Inhibition of Plasminogen Activator Inhibitor Type 1 in Experimental Venous Thrombosis

Introduction: Conventional treatment of deep vein thrombosis is suboptimal, requiring continuous improvement in knowledge about the disease and a search for new therapeutic approaches. Hypothesis: Blood flow affects the composition of an acute venous thrombus (VT). Aim 1: Compare VT composition under flow and stasis conditions. Aim 2: Evaluate the antithrombotic properties of the novel PAI-1 inhibitor MDI-2268 in-vivo. Methods: C57BL/6 mice, 10-12w, 20-25g were used in electrolytic (EIM) and ligation (LM) models of venous thrombosis. Aim 1: The thrombus weight (TW) and the microstructure of an acute VT (Day 2) in the EIM (n=5) and the LM (n=5) were compared. Expression of PAI-1, tPA, and uPA in the vein wall and plasma levels of D-dimer were investigated. Aim 2: Five EIM groups (n=5) were studied: MDI-2268 1.5 mg/kg (Group 1), MDI-2268 3 mg/kg (Group 2), enoxaparin 7.3 mg/kg (Group 3), MDI-2268 3 mg/kg plus enoxaparin 1.8 mg/kg (Group 4), and DMSO controls (Group 5). TW and bleeding time (BT) on Day 2 were measured. Results: Aim 1: VT within the EIM was smaller compared to the LM (6.2.5±3.6 vs. 26.2±3.6, P<0.05). VT formed within the EIM had a significantly higher amount of plasminogen. The level of D-dimer was 23.4±12.5 and 4.5±1.3 ng/mL/mg in the EIM and LM, respectively (p<0.05). Aim 2: TW was 6.9±3.3 (p>.05), 5.5±1.6 (p=.035), 3.8±1.3 (p=.005), and 4.8±2.4 mg (p=.035) for groups 1,2,3, and 4; compared to 12.7±5.7 mg in the controls. BT was not affected by the MDI-2268. Conclusions: Blood flow pattern significantly affects VT composition. Non-occlusive thrombus has a higher potential to be targeted by the fibrinolytic system due to a higher plasminogen content. MDI-2268 demonstrates strong antithrombotic properties in-vivo and may be associated with a lower risk of bleeding compared to enoxaparin. This data may contribute to a better understanding of the disease process, different outcomes after venous thrombosis, and new therapeutic targets.