Pharmacological reduction of coagulation factor XI reduces macrophage accumulation and accelerates deep vein thrombosis resolution in a mouse model of venous thrombosis

Abstract

Background: Deep vein thrombosis (DVT) and post-thrombotic syndrome (PTS) remain highly prevalent despite modern medical therapy. Contact activation is a promising target for safe antithrombotic anticoagulation. The anti-factor XI (FXI) monoclonal antibody 14E11 reduces circulating levels of FXI without compromising hemostasis. The human recombinant analog, AB023, is in clinical development. The role of FXI in mediation of inflammation during DVT resolution is unknown. Objectives: Investigate the effects of pharmacological targeting of FXI with 14E11 in an experimental model of venous thrombosis. Methods: Adult wild-type CD1 mice were treated with subcutaneous anti-FXI antibody (14E11, 5 mg/kg) versus saline prior to undergoing surgical constriction of the inferior vena cava (IVC). Mice were evaluated at various time points to assess thrombus weight and volume, as well as histology analysis, ferumoxytol enhanced magnetic resonance imaging (Fe-MRI), and whole blood flow cytometry. Results: 14E11-treated mice had reduced thrombus weights and volumes after IVC constriction on day 7 compared to saline-treated mice. 14E11 treatment reduced circulating monocytes by flow cytometry and macrophage content within thrombi as evaluated by histologic staining and Fe-MRI. Collagen deposition was increased at day 3 while CD31 and smooth muscle cell actin expression was increased at day 7 in the thrombi of 14E11-treated mice compared to saline-treated mice. Conclusion: Pharmacologic targeting of FXI enhances the early stages of experimental venous thrombus resolution in wild-type CD1 mice, and may be of interest for future clinical evaluation of the antibody in DVT and PTS.

Tea polyphenol-derived nanomedicine for targeted photothermal thrombolysis and inflammation suppression

“…To do so, we first examined the cell viability of TPNs/ICG-cRGD. As macrophages, endothelial cells, and smooth muscle cells are known to play a significant role in thrombosis [ 31 – 33 ], we evaluated the cell viability of TPNs, TPNs-PEG, TPNs/ICG-PEG, and TPNs/ICG-cRGD in these cell lines. Remarkably, these nanoparticles exhibited minimal cytotoxicity across a wide concentration range (up to 100 µg·mL − 1 ) (Fig.…”

Association between venous thromboembolism‐associated genetic variants, coagulation factor levels, and thrombin generation potential

“…Lowering FXI activity was associated with improved fibrin clot permeability, which indicated increased susceptibility to clot lysis in coronary artery disease [41]. Decreased FXI levels reduced macrophage accumulation and improved the early‐stage thrombus resolution in mice [43]. Overall, the association between ABCA6 rs77542162 and FXI levels may be mediated through lipid metabolism, which may influence VTE risks.…”

“…Lowering FXI activity was associated with improved fibrin clot permeability, which indicated increased susceptibility to clot lysis in coronary artery disease [41]. Decreased FXI levels reduced macrophage accumulation and improved the early-stage thrombus resolution in mice [43].…”

Platelet–Neutrophil Crosstalk in Thrombosis

“…Dose-dependent effects on thrombus formation were observed with an anti-FXIa antibody in a vein thread-induced rabbit model, with no concurrent increases in bleeding [ 163 ]. Using a monoclonal antibody against FXI also proved to be effective in thrombus resolution within the early stages of DVT in mouse models [ 164 ]. Additionally, an inhibitory antibody against FXI, Abelacimab, as well as a selective inhibitor for FXI, Milvexian, were shown to be effective in preventing postoperative VTE in patients who had undergone knee arthroplasties [ 165 , 166 ].…”