Pharmacological Reduction of Coagulation Factor XI Reduces Macrophage Accumulation and Accelerates Deep Vein Thrombosis Resolution in a Mouse Model of Venous Thrombosis

Overview

Journal J Thromb Haemost

Publisher Elsevier

Specialty Hematology

Date 2022 May 31

PMID 35638310

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Transcriptomic profiling of lncRNAs and mRNAs in a venous thrombosis mouse model.

Hao R, Li H, Li X, Liu J, Ji X, Zhang H iScience. 2025; 28(2):111561.

PMID: 39949957 PMC: 11821396. DOI: 10.1016/j.isci.2024.111561.

Monocyte/macrophage-mediated venous thrombus resolution.

Lu M, Zhang J, Nie Z, Yan T, Cao Y, Zhang L Front Immunol. 2024; 15:1429523.

PMID: 39100675 PMC: 11297357. DOI: 10.3389/fimmu.2024.1429523.

Ferumoxytol-enhanced MRI assessment of venous Thrombus resolution and macrophage content in a murine deep vein thrombosis model.

Morrison L, Smoody B, Woltjer R, Hinds M, Loftis J, Wyatt C Thromb Res. 2024; 240:109063.

PMID: 38878741 PMC: 11239555. DOI: 10.1016/j.thromres.2024.109063.

The foundation for investigating factor XI as a target for inhibition in human cardiovascular disease.

Ali A, Becker R J Thromb Thrombolysis. 2024; 57(8):1283-1296.

PMID: 38662114 PMC: 11645312. DOI: 10.1007/s11239-024-02985-0.

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

Wang H, Tang C, Xiang Y, Zou C, Hu J, Yang G J Nanobiotechnology. 2024; 22(1):146.

PMID: 38566213 PMC: 10988797. DOI: 10.1186/s12951-024-02446-z.

References

Buller H, Gailani D, Weitz J . Factor XI antisense oligonucleotide for venous thrombosis. N Engl J Med. 2015; 372(17):1672. DOI: 10.1056/NEJMc1503223. View

Tucker E, Verbout N, Leung P, Hurst S, McCarty O, Gailani D . Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis. Blood. 2012; 119(20):4762-8. PMC: 3367876. DOI: 10.1182/blood-2011-10-386185. View

Gailani D, Bane C, Gruber A . Factor XI and contact activation as targets for antithrombotic therapy. J Thromb Haemost. 2015; 13(8):1383-95. PMC: 4516614. DOI: 10.1111/jth.13005. View

DeLoughery E, Olson S, Puy C, McCarty O, Shatzel J . The Safety and Efficacy of Novel Agents Targeting Factors XI and XII in Early Phase Human Trials. Semin Thromb Hemost. 2019; 45(5):502-508. PMC: 6657806. DOI: 10.1055/s-0039-1692439. View

Modarai B, Humphries J, Burnand K, Gossage J, Waltham M, Wadoodi A . Adenovirus-mediated VEGF gene therapy enhances venous thrombus recanalization and resolution. Arterioscler Thromb Vasc Biol. 2008; 28(10):1753-9. DOI: 10.1161/ATVBAHA.108.170571. View

Iv M, Samghabadi P, Holdsworth S, Gentles A, Rezaii P, Harsh G . Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study. Radiology. 2018; 290(1):198-206. PMC: 6312434. DOI: 10.1148/radiol.2018181204. View

Kruger P, Eikelboom J, Douketis J, Hankey G . Deep vein thrombosis: update on diagnosis and management. Med J Aust. 2019; 210(11):516-524. DOI: 10.5694/mja2.50201. View

Wu Y . Contact pathway of coagulation and inflammation. Thromb J. 2015; 13:17. PMC: 4421925. DOI: 10.1186/s12959-015-0048-y. View

Huang S, Kim C, Miller M, Gupta R, Lessne M, Horvath J . Abdominopelvic and lower extremity deep venous thrombosis: evaluation with contrast-enhanced MR venography with a blood-pool agent. AJR Am J Roentgenol. 2013; 201(1):208-14. DOI: 10.2214/AJR.12.9611. View

10.

Silasi R, Keshari R, Lupu C, Van Rensburg W, Chaaban H, Regmi G . Inhibition of contact-mediated activation of factor XI protects baboons against -induced organ damage and death. Blood Adv. 2019; 3(4):658-669. PMC: 6391670. DOI: 10.1182/bloodadvances.2018029983. View

11.

Tucker E, Gailani D, Hurst S, Cheng Q, Hanson S, Gruber A . Survival advantage of coagulation factor XI-deficient mice during peritoneal sepsis. J Infect Dis. 2008; 198(2):271-4. PMC: 2654284. DOI: 10.1086/589514. View

12.

Ngo A, Jordan K, Mueller P, Hagen M, Reitsma S, Puy C . Pharmacological targeting of coagulation factor XI mitigates the development of experimental atherosclerosis in low-density lipoprotein receptor-deficient mice. J Thromb Haemost. 2021; 19(4):1001-1017. PMC: 8549080. DOI: 10.1111/jth.15236. View

13.

Cheng Q, Tucker E, Pine M, Sisler I, Matafonov A, Sun M . A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood. 2010; 116(19):3981-9. PMC: 2981546. DOI: 10.1182/blood-2010-02-270918. View

14.

Singh I, Burnand K, Collins M, Luttun A, Collen D, Boelhouwer B . Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation. 2003; 107(6):869-75. DOI: 10.1161/01.cir.0000050149.22928.39. View

15.

Puy C, Rigg R, McCarty O . The hemostatic role of factor XI. Thromb Res. 2016; 141 Suppl 2:S8-S11. PMC: 6135087. DOI: 10.1016/S0049-3848(16)30354-1. View

16.

von Bruhl M, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M . Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012; 209(4):819-35. PMC: 3328366. DOI: 10.1084/jem.20112322. View

17.

Kimball A, Tara Obi A, Luke C, Dowling A, Cai Q, Adili R . Ly6CLo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis. Thromb Haemost. 2019; 120(2):289-299. PMC: 7365023. DOI: 10.1055/s-0039-3400959. View

18.

Humphries J, Gossage J, Modarai B, Burnand K, Sisson T, Murdoch C . Monocyte urokinase-type plasminogen activator up-regulation reduces thrombus size in a model of venous thrombosis. J Vasc Surg. 2009; 50(5):1127-34. PMC: 2778796. DOI: 10.1016/j.jvs.2009.06.047. View

19.

Aghighi M, Theruvath A, Pareek A, Pisani L, Alford R, Muehe A . Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation. Clin Cancer Res. 2018; 24(17):4110-4118. PMC: 6125171. DOI: 10.1158/1078-0432.CCR-18-0673. View

20.

Wakefield T, Myers D, Henke P . Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol. 2008; 28(3):387-91. DOI: 10.1161/ATVBAHA.108.162289. View