Genetic supplementation of APC by PC transgene expression. (A-B) The D168F/N173K protein C transgene (mAPC^HI) increased plasma levels of PC (A) and activated PC (B) as measured in mice with normal Thbd gene expression. To assess the expression of the mAPC^HI transgene in the absence of endogenous aPC, PC-deficient mice with and without the transgene were added as additional experimental groups. Transgene-derived D168F/N173K PC expression was determined in APC^HI mice lacking endogenous PC (PC^−/−). Heterozygous PC-deficient mice (PC^+/−) were included as controls. (C) The transgene partially restored the body weight of Thbd-null mice (for each time point: Thbd-null, n ≥ 24; mAPC^HI Thbd-null, n ≥ 16; Thbd-expressing littermates, n ≥ 92). (D) D168F/N173K PC supplementation reduced mortality of tamoxifen-induced ERCre-Thbd^loxP mice as well as of constitutively Thbd-deficient Meox2Cre-Thbd-null mice. (E) Pregnant Thbd-null mAPC^HI mice showed pregnancy-induced bleeding, as shown by hemosiderin depositions in the lungs (left; original magnification ×4, hematoxylin and eosin stain) and hemorrhage in the uterus (right).