Figure 4
Figure 4. Heparin prevents histone-induced thrombocytopenia, tissue damage, and mortality. Platelets contribute to histone-induced mortality. (A) Platelet depletion protects from histone-induced death. Infusion of platelet-depleting antibodies (anti-GP1b) but not control IgG protected mice from a lethal dose of histones (60 mg/kg). (B) β3-Integrin deficiency partially protects from histone-induced death. Survival time of wild-type and β3-integrin–deficient mice infused with histones (60 mg/kg). (C) β3-Integrin deficiency does not protect from histone-induced thrombocytopenia (25 mg/kg). Platelet counts of β3−/− mice 10 minutes after infusion with vehicle or histones. (D) Platelet depletion does not protect from histone-induced tissue damage. H&E stainings of lungs from platelet-depleted mice (anti-Gp1b) 90 minutes after the infusion of vehicle or histones. Hemorrhage indicates histone-induced damage of the vascular endothelium. Scale bars = 250 μm. (E) At high concentrations, heparin prevents the interaction of histones with platelets. Flow cytometric analysis of histone binding to platelets in the presence of indicated concentrations of heparin (***compared with 0). (F) Heparin prevents HiPA. Aggregometry of platelets mixed with plasma in the presence (red) or absence (black) of heparin and in response to recombinant histone H4 or ADP. (G) Heparin neutralizes histone-induced cytotoxicity. Overlays of SytoxGreen fluorescence and phase-contrast images. A murine endothelial cell line was incubated in the presence or absence of heparin (100 μg/mL) with recombinant histone H4 (20 μg/mL). Cell death was detected by staining with the cell-impermeable DNA dye SytoxGreen. The presence of heparin prevented cytotoxicity. (H) Heparin prevents histone-induced thrombocytopenia. Platelet counts of untreated mice, mice infused with histones (50 mg/kg), and mice treated with heparin (50 mg/kg) before histone infusion. (I) Heparin prevents histone-induced lethality. Survival of mice treated with 50 mg/kg heparin or vehicle before infusion of 75 mg/kg histones. (J) Heparin prevents histone-induced hemorrhage in lungs. H&E stainings of lungs from mice treated with heparin after the infusion of vehicle or histones. Data are representative of ≥ 3 independent experiments. *P < .05, **P < .01, and ***P < .001.

Heparin prevents histone-induced thrombocytopenia, tissue damage, and mortality. Platelets contribute to histone-induced mortality. (A) Platelet depletion protects from histone-induced death. Infusion of platelet-depleting antibodies (anti-GP1b) but not control IgG protected mice from a lethal dose of histones (60 mg/kg). (B) β3-Integrin deficiency partially protects from histone-induced death. Survival time of wild-type and β3-integrin–deficient mice infused with histones (60 mg/kg). (C) β3-Integrin deficiency does not protect from histone-induced thrombocytopenia (25 mg/kg). Platelet counts of β3−/− mice 10 minutes after infusion with vehicle or histones. (D) Platelet depletion does not protect from histone-induced tissue damage. H&E stainings of lungs from platelet-depleted mice (anti-Gp1b) 90 minutes after the infusion of vehicle or histones. Hemorrhage indicates histone-induced damage of the vascular endothelium. Scale bars = 250 μm. (E) At high concentrations, heparin prevents the interaction of histones with platelets. Flow cytometric analysis of histone binding to platelets in the presence of indicated concentrations of heparin (***compared with 0). (F) Heparin prevents HiPA. Aggregometry of platelets mixed with plasma in the presence (red) or absence (black) of heparin and in response to recombinant histone H4 or ADP. (G) Heparin neutralizes histone-induced cytotoxicity. Overlays of SytoxGreen fluorescence and phase-contrast images. A murine endothelial cell line was incubated in the presence or absence of heparin (100 μg/mL) with recombinant histone H4 (20 μg/mL). Cell death was detected by staining with the cell-impermeable DNA dye SytoxGreen. The presence of heparin prevented cytotoxicity. (H) Heparin prevents histone-induced thrombocytopenia. Platelet counts of untreated mice, mice infused with histones (50 mg/kg), and mice treated with heparin (50 mg/kg) before histone infusion. (I) Heparin prevents histone-induced lethality. Survival of mice treated with 50 mg/kg heparin or vehicle before infusion of 75 mg/kg histones. (J) Heparin prevents histone-induced hemorrhage in lungs. H&E stainings of lungs from mice treated with heparin after the infusion of vehicle or histones. Data are representative of ≥ 3 independent experiments. *P < .05, **P < .01, and ***P < .001.

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