title: Statins improve the resolution of established murine venous thrombosis: reductions in thrombus burden and vein wall scarring.
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.
authors: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Chase W
authors: CW
authors: Kessinger
authors: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Multimodal Imaging and Theranostic Lab, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea.
authors: Jin Won
authors: JW
authors: Kim
authors: Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Peter K
authors: PK
authors: Henke
authors: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Brian
authors: B
authors: Thompson
authors: Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Jason R
authors: JR
authors: McCarthy
authors: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Tetsuya
authors: T
authors: Hara
authors: Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Martin
authors: M
authors: Sillesen
authors: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Ronan J P
authors: RJ
authors: Margey
authors: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Peter
authors: P
authors: Libby
authors: Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Ralph
authors: R
authors: Weissleder
authors: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Charles P
authors: CP
authors: Lin
authors: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Farouc A
authors: FA
authors: Jaffer
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D002921:Cicatrix / Q000150:complications / Q000188:drug therapy*; D005342:Fibrinolysis / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D014680:Veins / Q000187:drug effects*; D020246:Venous Thrombosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors