Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia augments deep vein thrombosis Jose A. Diaz, MD, Nicole E. Ballard-Lipka, BS,

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Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia augments deep vein thrombosis Jose A. Diaz, MD, Nicole E. Ballard-Lipka, BS, Diana M. Farris, LVT, Angela E. Hawley, MS, Shirley K. Wrobleski, BS, Daniel D. Myers, DVM, Peter K. Henke, MD, Daniel A. Lawrence, PhD, Thomas W. Wakefield, MD Journal of Vascular Surgery Volume 55, Issue 3, Pages 815-822 (March 2012) DOI: 10.1016/j.jvs.2011.08.038 Copyright © 2012 Society for Vascular Surgery Terms and Conditions

Fig 1 Thrombus size was increased in mice with hyperlipidemia. The thrombus weight was significantly increased by 14%, in apolipoprotein E gene-deleted (ApoE-/-) mice at day 2 (P < .05), and by 24% at day 14 (P < .01), vs wild type (WT). No differences were observed at day 6 between ApoE-/- and WT mice. In plasminogen activator inhibitor-1 gene deleted (PAI-1-/-) mice, the thrombus weight was significantly decreased at all time points compared with ApoE-/-, 45% at day 2 (P < .01); 33% at day 6 (P < .01) and 41% at day 14 (P < .01). TC, True controls. Journal of Vascular Surgery 2012 55, 815-822DOI: (10.1016/j.jvs.2011.08.038) Copyright © 2012 Society for Vascular Surgery Terms and Conditions

Fig 2 The fibrinolytic system was impaired mainly at acute time point in mice with hyperlipidemia. A, A trend of decreased plasmin levels in apolipoprotein E gene-deleted (ApoE-/-) mice compared with wild type (WT) was noted; 19% at day 2, 13% at day 6, and 22% at day 14. B, Levels of plasminogen activator inhibitor-1 (PAI-1) were significantly increased by 41% in ApoE-/-mice, vs WT at day 2 (P < .05). No significant differences were observed at days 6 and 14, post deep vein thrombosis (DVT). TC, True controls. Journal of Vascular Surgery 2012 55, 815-822DOI: (10.1016/j.jvs.2011.08.038) Copyright © 2012 Society for Vascular Surgery Terms and Conditions

Fig 3 The urokinase-type plasminogen activator (u-PA) system was impaired in mice with hyperlipidemia. A, This graph showed that it was possible to quantify levels of u-PA in both vein wall and thrombus in C57BL/6 mice. B, Using the same assay for apolipoprotein E gene-deleted (ApoE-/-) mice, undetectable levels of u-PA were found at all time points in both the vein wall and thrombus. TC, True controls. Journal of Vascular Surgery 2012 55, 815-822DOI: (10.1016/j.jvs.2011.08.038) Copyright © 2012 Society for Vascular Surgery Terms and Conditions

Fig 4 The decreased urokinase-type plasminogen activator (u-PA) system activity was reflected by matrix metalloproteinases (MMPs) in apolipoprotein E gene-deleted (ApoE-/-) mice. Zymography results: A, Graph showing that the protein concentration of MMP-2 was significantly decreased at days 6 and 14 in the vein wall. B, Graph showing the protein concentration of MMP-9 in the vein wall. It was significantly decreased at day 2 and day 6. TC, True controls. Journal of Vascular Surgery 2012 55, 815-822DOI: (10.1016/j.jvs.2011.08.038) Copyright © 2012 Society for Vascular Surgery Terms and Conditions

Fig 5 The decreased urokinase-type plasminogen activator (u-PA) system activity was reflected by monocyte chemotactic protein-1 (MCP-1) and monocyte recruitment in mice with hyperlipidemia. A, This graph shows the vein wall protein concentration of MCP-1 to be significantly decreased by 38% at day 2 (P < .01) and by 67% at day 6 (P < .01) after deep vein thrombosis (DVT) in apolipoprotein E gene-deleted (ApoE-/-) mice vs wild type (WT). B, Monocyte cell counts, average counts of 5 high-power fields (HPF) in at least five specimens per each time point, were significantly reduced at day 6 (P < .01) and day 14 (P < .05) in mice with hyperlipidemia vs controls. TC, True controls. Journal of Vascular Surgery 2012 55, 815-822DOI: (10.1016/j.jvs.2011.08.038) Copyright © 2012 Society for Vascular Surgery Terms and Conditions

Fig 6 Schematic representation of our findings. Fibrinolysis and thrombus resolution were found to be impaired in mice with hyperlipidemia undergoing deep vein thrombosis (DVT). Increased plasminogen activator inhibitor-1 (PAI-1) contributes to an early increase in thrombus size, due to impaired fibrinolysis. Additionally, undetectable levels of urokinase-type plasminogen activator (u-PA) led to decreased vein wall matrix metalloproteinase (MMP)-2 and MMP-9, and lower levels of monocyte chemotactic protein-1 (MCP-1) affecting monocyte recruitment, thus impairing thrombus resolution. ApoE-/-, Apolipoprotein E gene-deleted. Journal of Vascular Surgery 2012 55, 815-822DOI: (10.1016/j.jvs.2011.08.038) Copyright © 2012 Society for Vascular Surgery Terms and Conditions