Statins improve the resolution of established murine venous thrombosis: Reductions in thrombus burden and vein wall scarring

Chase W. Kessinger, Jin Won Kim, Peter K. Henke, Brian Thompson, Jason R. McCarthy, Tetsuya Hara, Martin Sillesen, Ronan J.P. Margey, Peter Libby, Ralph Weissleder, Charles P. Lin, Farouc A. Jaffer

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25 Citations (Scopus)

Abstract

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins - lipid-lowering agents with anti-thrombotic and anti-inflammatory properties - in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy.

Original languageEnglish
Article numbere0116621
JournalPLoS One
Volume10
Issue number2
DOIs
Publication statusPublished - 2015 Feb 13

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Kessinger, C. W., Kim, J. W., Henke, P. K., Thompson, B., McCarthy, J. R., Hara, T., Sillesen, M., Margey, R. J. P., Libby, P., Weissleder, R., Lin, C. P., & Jaffer, F. A. (2015). Statins improve the resolution of established murine venous thrombosis: Reductions in thrombus burden and vein wall scarring. PLoS One, 10(2), [e0116621]. https://doi.org/10.1371/journal.pone.0116621