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

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

doi:10.1371/journal.pone.0116621

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.

Highlights

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]
This study evaluated these hypotheses by investigating the in vivo time-dependent and dose-dependent effects of daily atorvastatin or rosuvastatin oral therapy initiated either 1 day or 3 days after venous thrombosis (VT) formation, in established, already formed stasis or nonstasis chemical-induced murine VT
Low-dose atorvastatin (ATV Low, 0.38 mg/kg) and low-dose rosuvastatin (ROS Low, 0.28 mg/kg) did not significantly reduce VT mass compared to PBS at day 4 (Fig. 1A)

Summary

Introduction

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]. Improving the outcomes of patients with DVT and those at risk for PTS will require new approaches beyond anticoagulation [8]. The primary therapeutic approach to prevent PTS involves strategies to improve DVT resolution or eliminating thrombus burden, for large-vein (e.g., iliofemoral) DVT [9,10]. Given their pleiotropic anti-thrombotic and anti-inflammatory effects beyond their lipid-lowering actions [11,12], 3-hydoxy-3methyl-glutaryl coenzyme A inhibitors, statins, are an intriguing option to improve DVT resolution and thereby limit PTS. Minimal data exists on whether statins can serve as an effective therapy after subjects present with a DVT–a common clinical scenario

Methods

Results

Conclusion