siRNA-mediated hepatic knockdown of F12 worsens thrombotic coagulopathy induced by knockdown of Serpinc1 and Proc. (A) Plasma FXII activity in mice 3 days after injection with an siRNA targeting F12 (solid circles) or siNEG (open circles) (Mann-Whitney rank sum test P = .029). Normal pooled plasma was used as an internal reference. (B) Clinical phenotype in mice treated with siRNAs targeting Serpinc1 and Proc. Animals showing characteristic clinical signs (hatched bars) and unaffected animals (open bars) 2 days after siRNA treatment (end of experiment) (Fisher’s exact test P = .011). (C-D) Representative hematoxylin and eosin–stained coronal head sections from (C) the –siF12 group and (D) the +siF12 group. Scale bars represent 1000 μm. Arrowhead indicates extravasated red blood cells. (E) Scoring for the presence of thrombi: 0, no thrombi found; I and II, thrombi categories based on structure and layering. Open bars, –siF12 (n = 20); solid bars, +siF12 (n = 18). (F) Levels of fibrin deposition in the liver of the FXII deficient group (+siF12) and the control group (–siF12) (Mann-Whitney rank sum test P = .944). Solid and dashed lines indicate fibrin levels found only in siNEG-injected C57BL/6J female mice (median, 7.1 ng/mg; range, 6.1-8.0 mg/mg). br, brain; to, tongue; n.d., not detected.