Abstract 52: Statin Therapy Accelerates Venous Thrombus Resolution: Assessment In Stasis And Chemical Injury Induced Thrombosis

Abstract

Introduction In deep vein thrombosis (DVT), both the induced inflammation response and fibrinolytic capacity are critical in resolving experimental DVT. Unresolved, obstructing thrombi can lead to the burdensome and costly sequelae of the post-thrombotic syndrome. Recently, statins have shown to reduce the incidence of DVT (JUPITER trial). In this study, we investigated the in vivo effects of statin therapy on resolution of already formed DVT using serial intravital microscopy (IVM) imaging and thrombus mass measurements. Methods DVT was induced in C57Bl/6J male mice (N=190) by topical ferric chloride of the femoral vein (chemical injury) or ligation of the IVC (stasis). One day after DVT induction, mice started treatment of atorvastatin (1.14mg/kg), mevastatin (10 mg/kg) or PBS by once daily oral gavage. Serial IVM was preformed at days 2, 4 and 6 utilizing FITC-dextran (ex/em 490/520nm), CLIO-AF555 (ex/em 555/565nm), and MMPSense680 (ex/em 680/700nm) imaging agents for thrombus architecture, macrophage content and MMP activity measurements. Thrombus masses were collected at days 4, 7, 10 in stasis DVT mice and combination statin/enoxaparin (10mg/kg/d, s.c.) were also compared to statin therapy. Platelet activation and coagulation were analyzed using aggregometry and thromboelastography on whole-blood. Results We found that statin therapy reduced DVT burden and inflammation in both chemical- and stasis-induced established DVT up to 10 days compared to control (p<0.05). Serial IVM imaging of statin animals showed an increase in DVT resolution from day 2 to 4 (Δlength -21± 6.0 vs. control -7.1± 5.6%, p<0.01), and decreased inflammation compared to controls (p<0.001). Inflammation was also found to predict the extent of DVT resolution(r=0.84). Statin therapy also reduced thrombus plasminogen activator inhibitor-1, tissue factor, and Mac-3 levels, as well as reducing platelet activation and clot strength(p<0.05). Conclusion Statin therapy accelerates DVT resolution despite reducing thrombus related inflammation. The net reduction of thrombus burden tracked with statin-mediated favorable effects on fibrinolysis, coagulation, and platelet function. These results support statins as a translatable therapy to improve the resolution of DVT.