Abstract Body: Background: Deep vein thrombosis (DVT) leads to post-thrombotic syndrome (PTS) in around 30-50% of patients despite anticoagulation. Catheter-based thrombectomy/ thrombolysis (CDT) lacks consistent efficacy in preventing PTS. Locally delivered steroids such as dexamethasone (DEX), are currently under clinical evaluation as an adjunct to CDT in the DEXTERITY-AFP trial (NCT04862468) with the aim of reducing PTS, but minimal mechanistic data for DEX exists regarding DVT resolution. Here, we hypothesized that perivascular local DEX will improve DVT resolution and reduce vein wall fibrosis in experimental murine DVT.
Method: Male C57BL/6J mice (n=146) underwent complete inferior vena cava (IVC) ligation to induce stasis DVT on day 0, followed by surgical de-ligation on day 2 to simulate CDT/MT and spur restoration of blood flow (RBF), as determined by a non-invasive ultrasound (IVC flow velocity > 0 mL/sec). On day 2, periadventitial PBS or DEX (0.05–0.5 mg/mouse) was administered via a 30G needle, followed by serial ultrasonography to evaluate RBF. On day 8, thrombus burden and vein wall remodeling were assessed using immunohistochemistry, RNA sequencing, and qRT-PCR.
Results: DEX 0.1mg/mouse significantly reduced day 8 thrombus burden (p=0.0006), thrombus weight (p=0.008), and intra-thrombus CD68+ macrophages (p=0.007) in IVC DVT (Fig. A). Higher (0.2–0.5 mg/mouse) and lower (0.05 mg/mouse) DEX doses also did not worsen thrombus burden. DEX 0.1mg/mouse decreased day 8 vein wall collagen thickness (p=0.0001), DDR2+ fibroblasts (p=0.001) and CD68+ macrophages (p=0.04) in vein wall and perivascular region (Fig. B, C) and improved mean blood flow velocity in thrombosed IVCs on days 4-8. Predictively, the day 4 RBF+ status correlated with reduced day 8 vein wall collagen thickness with DEX reducing VWCT irrespective of RBF status (RBF+PBS; 62.04µm, RBF-PBS; 51.31µm, RBF-DEX; 29.05µm, RBF+DEX; 20.63µm, Fig. D). Further, global transcriptome of DEX/PBS treated vein walls revealed downregulation of collagen synthesis pathways (Fig. E), supporting the antifibrotic effects of DEX.
Conclusion: In conclusion, locally delivered DEX improves murine stasis DVT resolution by improving early venous blood flow, and then reducing thrombus burden, vein wall injury, and macrophage content. These findings underscore the potential of targeted perivascular steroid therapy as an adjuvant to CDT in patients undergoing thrombectomy and provide mechanistic support for the DEXTERITY trials.