Type 1 IFN signaling mediates the activation of coagulation cascades by amplifying the release of HMGB1 into the bloodstream. (A-B) Plasma HMGB1 concentration was detected in mice of indicated genotypes primed with 0.4 mg/kg of LPS for 7 hours and then challenged with 10 mg/kg of LPS for 8 hours. (C) Quantitative analysis of fibrin in the liver microcirculation in SD-IVM images. (D) Representative SD-IVM images of thrombin (green), platelets (blue), and fibrin (dark red, AF594) in the liver microvasculature. (E) Quantitative analysis of thrombin generation and platelet activation in the liver microvasculature. (F-G) Mice of indicated genotypes were primed with 0.4 mg/kg of LPS for 7 hours and then challenged with 10 mg/kg of LPS for 8 hours. Plasma TAT and PAI-1 concentrations were detected (F). Representative images of immunohistochemical staining of fibrin in livers and lungs are shown (G) (×400). (H-I) WT mice were injected with or without monoclonal HMGB1 neutralizing antibody (2G7, 160 μg/mouse) or the isotype control IgG (160 μg/mouse) 30 minutes before administration of 10 mg/kg of LPS (TAT and PAI-1) or 4 mg/kg of LPS (SD-IVM). Quantitative analysis of thrombin generation and platelet activation within the liver microvasculature (H) and plasma levels of TAT complexes and PAI-1 (I) are shown. Data are shown as mean ± standard error of the mean. *P < .05; **P < .01; ***P < .001. N = 3 to 7 mice per group. Scale bar, 50 μm. NS, no significant.