IAIP and HMW-HA prevent histone-induced thrombocytopenia, prolonged bleeding time, microthrombosis, and fibrinogen accumulation. (A-B) Percentage of (A) platelet consumption and (B) tail bleeding time in mice injected intravenously with 50 mg/kg histones without (n = 6) or with preincubation with IAIP (50 mg/kg; n = 6) or HMW-HA (90 mg/kg; n = 6). Data are presented as mean ± SEM of 3 independent experiments using one-way ANOVA with Bonferroni’s multicomparison test. ****P < .0001 and **P < .01 compared with the histones challenge group. (C-D) Pathologic changes in mouse lungs 3 hours after intravenous injection of 50 mg/kg histones with or without preincubation with IAIP or HMW-HA. (C) Toluidine blue staining on semi-thin epon sections (upper row) and electron microscopy (EM; lower row), and (D) immunofluorescence staining for platelet marker P-selectin (upper row; red) and fibrinogen and/or fibrin (lower row; green) demonstrate the presence of platelet and fibrin-rich intravascular microthrombi (mt) in histone-only treated mice compared with controls and mice injected with histones pretreated with IAIP or HMW-HA. Magnification bars for (C): toluidine blue, 100 µm; EM, 1 µm; for (D): all bars are 100 µm. av, alveoli; RBC, red blood cells.