Local Periadventitial Delivery Of Dexamethasone Improves Murine Deep Vein Thrombosis Resolution

Background: Post deep vein thrombosis (DVT), up to 30-50% of patients will develop post-thrombotic syndrome (PTS), despite anticoagulation. Currently no preventive therapies, including catheter-based thrombectomy/thrombolysis (CDT), have shown to reduce PTS. Local steroid therapy adjunct to CDT is being tested clinically for DVT patients in the DEXTERITY trials, but minimal mechanistic data exists on DVT resolution. Here, we investigate effects of local dexamethasone (DEX) therapy on murine DVT resolution. Method: C57/BL6 male mice (n=146) underwent inferior vena cava (IVC) complete ligation to develop stasis DVT on day 0 (D0) followed by mechanical de-ligation on D2 to spur restoration of blood flow (RBF). On D2, mice were injected with PBS/DEX (0.1, 0.2, or 0.5 mg/mouse, 60μl volume, across four zones) in the periadventitial tissue of thrombosed IVC, with or without de-ligation (Fig. A-B). Mice underwent D4&D8 serial ultrasound imaging of IVC blood flow to assess RBF-defined as IVC mean flow velocity > 0 mL/sec. D8 thrombus burden was measured followed by histological/picrosirius red assessment of vein wall fibrosis. Results: N=6-11 mice per group underwent IVC DVT creation. Low-dose (0.1 mg) but not higher doses of DEX reduced thrombus burden (p=0.02) and weight (p=0.01) on D8 (Fig. C-D). Low-dose DEX increased D4 RBF rates and mean flow velocity (MFV) (Fig. E-F). Complete IVC stasis without de-ligation but with DEX non-significantly reduced thrombus burden and weight (Fig. G-H). Low-dose DEX further decreased vein wall fibrosis (Fig. I; p=0.001). D8 thrombi exhibited reduced macrophage content with DEX (Fig. J; n=15-18 sections/group, p=0.007). Conclusion: Following stasis DVT induction, locally delivered low-dose DEX improves DVT resolution by reducing thrombus burden, vein wall injury, macrophage content, and increases RBF rate. These data provide a scientific foundation for ongoing DEXTERITY trail testing adjunct DEX for DVT patients undergoing CDT.