Only minor consolidations in about 10% of the lung tissue were found upon necropsy. To assess a potential link between hemostatic alterations with total virus titers we generated the areas under the curve (AUC) from the virus titer as shown in Table 2. Table 2 Viral parameters

for correlation tests with coagulation results from 0.5-4 dpi Virus Day Virus titer* Lung virus AUC# Respiratory tract AUC# H3N2 0.5 3.5 (2.9-4.2) neg 0 1 7.0 (5.5-8.5) neg 2.6 2 6.3 (5.4-7.3) neg FK228 9.3 3 5.1 (3.9-6.2) neg 15 4 4.8 (3.4-6.1) neg 19.9 pH1N1 0.5 26.0 (24.3-27.7) 0 0 1 31.7 (31.1-32.3) 3.6 14.4 2 27.0 (26.4-27.6) 10.0 43.8 3 27.0 (25.7-28.4) 15.4 70.8 4 25.7 (23.4-28.0) 20.1 97.1 H5N1 0.5 22.3 (19.5-25.2)

0 0 1 27.61 (24.4-30.8) 3.1 12.5 2 24.8 (22.3-27.3) 9.0 38.7 3 26.1 (22.0-30.8) 14.5 64.3 4 26.0 (23.9-28.0) 19.9 90.5 *Total virus titer in log TCID50 (cumulative titers of all organs with significant virus titers: “lung, nasal concha, trachea, bronchus and bronchial lymph nodes”) SN-38 chemical structure (+/- SD). # AUC was calculated from virus titers curves. 7 dpi and 14 dpi were excluded from the analysis because we data points from 5 & 6 dpi are not available buy Sapitinib potentially resulting in over or underestimation of the true AUC. Both prothrombin time and activated partial thromboplastin time show transient prolongations during influenza virus infection in ferrets To evaluate tissue factor pathway activation of the coagulation cascade we tested the prothrombin time (PT) for all samples.

Before Cepharanthine inoculation all ferrets had PTs within normal range. Figure 1 (row A) summarizes the PT results over time for all four groups. For both the H3N2 virus and pH1N1 virus groups, PT values increased with approximately 4 seconds at 4 dpi compared to pre-inoculation samples (H3N2 p = 0.001, pH1N1 p = 0.02) and the mock infected animals at the same day (H3N2 p = 0.03, pH1N1 p = 0.03). In the H5N1 infected ferrets, PT prolongation started at 2 dpi with a prolongation up to 16 seconds in individual animals. A clear trend is seen with PT increasing up to 30 seconds at 3 dpi. On multiple occasions ferrets died before samples could be drawn, consequently the data depend on a small number of observations with a potentially strong survival bias. On 4 dpi only one sample met the quality criteria for PT testing in the H5N1 group with a PT of 13.4 seconds, a 1.4 second increase compared to mean + SD from day 0 and mock samples (+/- SD). No significant changes in PT were observed over time in the mock infected group. Row B in Figure 1 shows the Activated partial thromboplastin time (APTT) a measurement of the intrinsic pathway of coagulation.