Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice

Abstract

To explore the role of the key coagulation factor, fibrinogen, in development, hemostasis, wound repair, and disease pathogenesis, we disrupted the fibrinogen Aα chain gene in mice. Homozygous, Aα chain-deficient (Aα(- /-)) mice are born normal in appearance, and there is no evidence of fetal loss of these animals based on the Mendelian pattern of transmission of the mutant Aα chain allele. All of the component chains of fibrinogen (Aα, Bβ, and γ) are immunologically undetectable in the circulation of both neonatal and adult Aα(-/-) mice, and blood samples fail to either clot or support platelet aggregation in vitro. Overt bleeding events develop shortly after birth in ~30% of Aα(-/-) mice, most frequently in the peritoneal cavity, skin, and soft tissues around joints. Remarkably, most newborns displaying signs of bleeding ultimately control the loss of blood, clear the affected tissues, and survive the neonatal period. Juveniles and young adult Aα(-/-) mice are predisposed to spontaneous fatal abdominal hemorrhage, but long- term survival is variable and highly dependent on genetic background. The periodic rupture of ovarian follicles in breeding-age Aα(-/-) females does not appear to significantly diminish life expectancy relative to males; however, pregnancy uniformly results in fatal uterine bleeding around the tenth day of gestation. Microscopic analysis of spontaneous lesions found in Aα(-/-) mice suggests that fibrin(ogen) plays a fundamental role in the organization of cells at sites of injury.