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

Kelley R. Jordan, Cory R. Wyatt, Meghan E. Fallon, Randy Woltjer, Edward A. Neuwelt, Quifang Cheng, David Gailani, Christina Lorentz, Erik I. Tucker, Owen J.T. McCarty, Monica T. Hinds, Khanh P. Nguyen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2035-2045
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume20
Issue number9
DOIs
StatePublished - Sep 2022

Keywords

  • contact activation
  • factor XI
  • thrombosis
  • vein

ASJC Scopus subject areas

  • Hematology

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