ABSTRACT
Aatira Vijay, PhD
Postdoctoral Fellow
Massachusetts General Hospital & Harvard Medical School
Boston, Massachusetts, United States
Despite anticoagulation+/-catheter-directed thrombolysis/thrombectomy (CDT), up to 50% of DVT patients will develop post-thrombotic syndrome (PTS). Delivery of pro-healing pharmacotherapeutics into vein wall appears intriguing for improving CDT outcomes. Here we evaluated the effects of locally administered anti-inflammatory dexamethasone (DEX) steroid therapy on murine acute DVT resolution, including restoration of blood flow (RBF)/recanalization, thrombus burden, and vein wall fibrosis.
Methods:
Utilizing a novel model, C57/BL6 male mice (n=116) underwent IVC complete ligation to develop stasis VT followed by de-ligation on day 2 (D2) to spur RBF and simulate CDT. Post-de-ligation, mice underwent surgical IVC exposure and were randomized to local perivenous delivery of PBS or DEX (dose: 0.1, 0.2, or 0.5 mg/mouse, 60µl volume). At D8, IVC DVT underwent measurement of thrombus burden, or histological/picrosirius red assessment of vein wall injury/fibrosis. Subgroups of mice also underwent D4&D8 serial ultrasound imaging (Visualsonics-Vevo3100) of IVC blood flow to assess RBF, defined as an IVC mean flow velocity > 0 mL/sec.
Results:
Following D2 mechanical de-ligation, mice were evaluated following peri-adventitial IVC DVT delivery of DEX or PBS (n=6-11 mice/group). Low-dose DEX (0.1mg/mouse) significantly improved DVT resolution at D8 (Figure 1A-1D), by decreasing thrombus burden (p=0.026) and weight (p=0.016), and vein wall fibrosis (p=0.001). In parallel, low-dose DEX increased D4 ultrasound RBF rates (Fig. 1E-G; n=17-18/group). At D8, thrombi exhibited reduced macrophage content in the DEX-treated group (Fig. 2; n=15-18 sections/group, p=0.007). Interestingly, DEX dose of 0.5mg/mouse had a neutral effect on thrombus burden (p=0.557).
Conclusions:
Low-dose DEX reduces thrombus burden and vein wall injury, macrophage content, and increases RBF rates in murine acute DVT. These data provide a scientific foundation for the ongoing DEXTERITY studies testing adjuvant DEX treatment of DVT patients undergoing CDT.
Support sources: R41HL160434 & Mercator, Inc.