Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring

PLOS ONE, Dec 2019

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.

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Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring

February Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring Chase W. Kessinger 0 2 3 Jin Won Kim 0 2 3 Peter K. Henke 0 2 3 Brian Thompson 0 2 3 Jason R. McCarthy 0 2 3 Tetsuya Hara 0 2 3 Martin Sillesen 0 2 3 Ronan J. P. Margey 0 2 3 Peter Libby 0 2 3 Ralph Weissleder 0 2 3 Charles P. Lin 0 2 3 Farouc A. Jaffer 0 2 3 0 1 Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts, United States of America, 2 Multimodal Imaging and Theranostic Lab, Cardiovascular Center, Korea University Guro Hospital , Seoul , Republic of Korea, 3 Section of Vascular Surgery, Department of Surgery, University of Michigan , Ann Arbor , Michigan, United States of America, 4 Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts, United States of America, 5 Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts, United States of America, 6 Center for Systems Biology, Massachusetts General Hospital , Boston , Massachusetts, United States of America, 7 Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Harvard Medical School , Boston , Massachusetts, United States of America, 8 Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts , United States of America 1 13GRNT17060040, F.A.J.), by a Howard Hughes Medical Institute Early Career Award (F.A.J.), and by the Cardiovascular Research Foundation (J.W.K.) 2 Funding: F. Jaffer, Research Support, Merck and Kowa, Ltd. This research was supported in part by grants from the U.S. National Institutes of Health (NIH R01 HL108229 , F.A.J.); T32 HL076136 (C.W.K).; and UO1-HL080731, (R.W., J.R.M., and P.L. ); by an American Heart Association Scientist Development Grant ( 3 Academic Editor: Christian Schulz, University of Munich , GERMANY 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 statintreated 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 - The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: We have the following interests: Our study was partly funded by Merck and Kowa, Ltd. This does not alter our adherence to all PLOS ONE policies on sharing data and materials. pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy. Due to its sequelae of pulmonary embolism and the post-thrombotic syndrome (PTS), deep vein thrombosis (DVT) causes a substantial burden of cardiovascular morbidity and mortality worldwide, affecting more than 250,000 patients in the United States annually [1]. PTS, a syndrome driven by venous hypertension arising from obstructing thrombi and local vein wall scarring and dysfunction [24], occurs more frequently when anticoagulation is subtherapeutic [5,6]. Moreover, up to 50% of DVT patients receiving anticoagulation still develop PTS. Patients with severe PTS can experience debilitating symptoms, such as venous claudication, stasis dermatitis, and skin ulceration, and select cases may even require limb amputation [2,3,7]. Advance (...truncated)


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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. Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring, PLOS ONE, 2015, 2, DOI: 10.1371/journal.pone.0116621