A profound genetic diminution of prothrombin in adult mice is not compatible with long-term survival. Representative survival profiles in Mx⁺fII^lox/− mice after a single intraperitoneal injection of either 0.05 μg/g (cohort of 10; ■) or 5 μg/g (cohort of 11; ●) of poly I:C to induce hepatic recombination of the prothrombin floxed allele. A parallel survival analysis using Mx⁻fII^lox/− animals lacking the Cre recombinase transgene, but treated with 5 μg/g of poly I:C, is shown for comparison (cohort of 5; ○). A dose-dependent loss in viability was observed in poly I:C–treated Mx⁺fII^lox/− mice, whereas no deaths were observed in Mx⁻fII^lox/− animals treated with poly I:C. Gross analyses of tissues at autopsy revealed severe hemorrhage within multiple tissues of Cre-induced mice, including heart, pleural cavity, and brain. Identical results were obtained in multiple independent experiments of the same design. Kaplan-Meier analysis established a statistically significant difference in survival in Cre transgene-positive and Cre transgene-negative fII^lox/− mice after administration of 5 μg/g poly I:C (P < .002).