Thrombin Inhibition Prevents Against Severe Atherosclerosis Progression in Prothrombotic Mice

Abstract

AbstractAbstract 103 Background:Besides its well-known role in initiation and propagation of thrombus formation, thrombin may have multiple pro-atherogenic actions. Hypothesis:Pharmacologic thrombin inhibition attenuates the onset and progression of atherosclerosis and favors plaque stability in hypercoagulable mice prone to aggressive atherosclerosis development. Methods and Results:Hypercoagulability in TMPro/Pro:ApoE−/− mice resulted in severe atherosclerotic burden formation compared to ApoE−/− mice (389.1*103 μm2 vs. 187.0*103 μm2, p<0.0005). Pro-coagulant mice showed larger necrotic cores, decreased plaque collagen content, vast stenosis (up to 90%) and enhanced outward remodeling. Hypercoagulability markedly increased systemic and vascular inflammation, represented by significantly higher CXCL1, MCP-1 and G-CSF plasma levels, pronounced neutrophilia, enhanced Ly6G+ cells arrest to carotid plaques, increased neutrophil recruitment (IHC/Intravital Microscopy), massive intraplaque hemorrhage and spontaneous plaque ruptures. Genetically diminished prothrombin levels (FII-/WT:ApoE−/− mice) caused a significant decrease in atherosclerosis (72.5*103 μm2 vs. 128.4*103 μm2, p<0.01) with a pronounced stable phenotype with less/smaller necrotic cores, thicker fibrous caps and abundant collagen and vascular smooth muscle cell content. Ly6G+ cell intraplaque recruitment was reduced and white blood cell counts and IL-6 levels (3.8±1.66 vs. 8.8±5.34 pg/mL, p<0.05) were diminished compared to control mice. Remarkably, administration of the oral direct thrombin inhibitor Dabigatran etexilate or the anticoagulant activated protein C (APC) in TMPro/Pro:ApoE−/− mice reduced lesions formation by > 80%, suppressed leukocyte recruitment, enhanced plaque stability, whereas numerous pro-inflammatory cytokines were diminished to levels comparable to non-atherosclerotic mice. Conclusion:These data establish a pivotal role for thrombin generation in controlling the level of inflammation related to atherosclerosis development in ApoE−/− mice. The potential clinical impact of long term administration of novel classes of anticoagulants on atherosclerosis merits further study. Disclosures:Weiler:BloodCenter of Wisconsin: Patents & Royalties. van Ryn:Boehringer Ingelheim Pharma GmbH & Co KG: Employment.