American Society of Hematology

Figure 7

$Figure 7. In vivo antithrombotic and anti-inflammatory efficacies of polyP inhibitors. (A-B) Murine model of venous thrombosis. Inhibitors were administered intravenously to mice before initiation of electrolytic injury of the femoral vein (time = 0 in the graphs). Data are mean relative intensities for accumulation of fluorescently labeled fibrin-specific antibodies (A) or labeled platelets (B) in the developing thrombus for mice receiving: red circles, 4 μg/g generation 1.0 dendrimer (n = 10); blue squares, 2 μg/g polymyxin B (n = 8); orange inverted triangles, 100 units/kg unfractionated heparin (n = 5); or open triangles, vehicle only (n = 14). Bars represent 1 SE. (C) Murine model of arterial thrombosis, with Kaplan-Meier curves showing percentage of mice with patent arteries. Inhibitors were injected retro-orbitally 10 minutes before ferric chloride injury to the carotid artery. Blood flow was monitored by Doppler, with occlusion defined as no flow for 1 minute. Log-rank analyses indicated that median patency time was significantly longer for mice injected with 8 μg/g generation 1.0 dendrimer (P < .01, n = 8), 4 μg/g polymyxin B (P < .01, n = 10), or 5 μg/g low MW polyethyleneimine (P < .01, n = 8) versus mice injected with vehicle (n = 11). (D) Murine model of polyP-induced vascular leakage. Mice were given separate retro-orbital injections with Evans blue dye and either a polyP inhibitor (48 μg/g generation 1.0 dendrimer or 20 μg/g polymyxin B) or vehicle. After 40 minutes, saline, bradykinin, and polyP were injected intradermally at 3 respective sites on the back. After an additional 30 minutes, mice were killed and dye was extracted from skin biopsies for quantification. Plots show median (central horizontal lines), mean (triangles), 25th-75th percentile (top and bottom of boxes), and 10th-90th percentile (whiskers) concentrations of extracted dye. Dendrimer administration resulted in significantly less dye leakage at the site of polyP injection compared with control animals (P < .001). Each group (no inhibitor, dendrimer, and polymyxin B) contained 15 mice.$

In vivo antithrombotic and anti-inflammatory efficacies of polyP inhibitors. (A-B) Murine model of venous thrombosis. Inhibitors were administered intravenously to mice before initiation of electrolytic injury of the femoral vein (time = 0 in the graphs). Data are mean relative intensities for accumulation of fluorescently labeled fibrin-specific antibodies (A) or labeled platelets (B) in the developing thrombus for mice receiving: red circles, 4 μg/g generation 1.0 dendrimer (n = 10); blue squares, 2 μg/g polymyxin B (n = 8); orange inverted triangles, 100 units/kg unfractionated heparin (n = 5); or open triangles, vehicle only (n = 14). Bars represent 1 SE. (C) Murine model of arterial thrombosis, with Kaplan-Meier curves showing percentage of mice with patent arteries. Inhibitors were injected retro-orbitally 10 minutes before ferric chloride injury to the carotid artery. Blood flow was monitored by Doppler, with occlusion defined as no flow for 1 minute. Log-rank analyses indicated that median patency time was significantly longer for mice injected with 8 μg/g generation 1.0 dendrimer (P < .01, n = 8), 4 μg/g polymyxin B (P < .01, n = 10), or 5 μg/g low MW polyethyleneimine (P < .01, n = 8) versus mice injected with vehicle (n = 11). (D) Murine model of polyP-induced vascular leakage. Mice were given separate retro-orbital injections with Evans blue dye and either a polyP inhibitor (48 μg/g generation 1.0 dendrimer or 20 μg/g polymyxin B) or vehicle. After 40 minutes, saline, bradykinin, and polyP were injected intradermally at 3 respective sites on the back. After an additional 30 minutes, mice were killed and dye was extracted from skin biopsies for quantification. Plots show median (central horizontal lines), mean (triangles), 25th-75th percentile (top and bottom of boxes), and 10th-90th percentile (whiskers) concentrations of extracted dye. Dendrimer administration resulted in significantly less dye leakage at the site of polyP injection compared with control animals (P < .001). Each group (no inhibitor, dendrimer, and polymyxin B) contained 15 mice.

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