Abstract Body: Background:
Icosapent Ethyl (IPE) is a highly purified ethyl ester of eicosapentaenoic acid (EPA), shown to reduce the risk of major adverse cardiovascular events (MACE) and mortality in patients with atherosclerosis and hypertriglyceridemia. Preclinical investigations of atherosclerosis and arterial thrombosis demonstrate anti-inflammatory and anti-thrombotic properties of IPE in vivo. However, its mechanistic and functional impact on deep venous thrombosis (DVT) and post-thrombotic syndrome (PTS) remains undefined. Here, we investigated the effect of IPE on murine DVT resolution and post-thrombotic vein wall fibrosis, a key driver of PTS.
Methods:
C57/BL6 male mice (n=57) underwent inferior vena cava (IVC) ligation to induce complete stasis DVT on Day 0. On Day 2, mice were randomized to receive vehicle control (phosphate buffered saline (PBS) with 0.5% Tween80) or IPE (615 mg/kg/day with Tween80 0.5%), via gavage. Treatment continued for six days until D8 sacrifice. Then, thrombus with and without the vein wall were harvested for weight, length, width and normalized thrombus weight (weight/length) measurements and vein wall analysis. D8 vein wall collagen thickness (VWCT) was assessed using picrosirius red (PSR) analysis.
Results:
IPE reduced VWCT at day 8 (IPE: 28.90 ± 0.69 µm vs. Control: 34.84 ± 4.27 µm, n=16 sections/group; p= 0.029, Fig. 1A), as assessed by PSR analysis. Two-way repeated measures ANOVA revealed a consistent overall treatment effect across thrombus levels (p=0.039, Fig. 1C). In addition, IPE treatment resulted in trend reduction in median thrombus weight (IPE: 13.50 mg, IQR 4.50 vs. Control: 15.00 mg, IQR 4.00; n=12-19/group; p=0.130, Fig. 1D) and normalized thrombus weight (IPE: 19.22 mg/cm, IQR 4.22 vs. Control: 21.46 mg/cm, IQR 3.89; n=12-19/group; p=0.064, Fig. 1E). IPE treatment did not significantly affect median thrombus width or length (IPE: 0.65 cm, IQR 0.18 vs. Control: 0.73 cm, IQR 0.12; n=12-19/group; p=0.435, Fig. 1F). Unless noted, comparisons used the Mann–Whitney U test.
Conclusion:
IPE attenuates vein wall fibrosis and modestly reduces thrombus burden in complete stasis murine DVT. These findings suggest that IPE favourably influences thrombus resolution and vein wall remodelling and support further mechanistic investigation of IPE’s potential as an adjunct therapy for reducing PTS. Ongoing analyses will further characterize the effect of IPE on inflammatory and collagen synthetic mediators in DVT resolution.