RESOLUTION OF SPONTANEOUS BLEEDING EVENTS BUT FAILURE OF PREGNANCY IN FIBRINOGEN-DEFICIENT MICE

To explore the role of the key coagulation factor, fibrinogen, in development, hemostasis, wound repair, and disease pathogenesis, we disrupted the fibrinogen A alpha chain gene in mice. Homozygous, A alpha chain-deficient (A alpha(-/-)) 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 A alpha chain allele. All of the component chains of fibrinogen (A alpha, B beta, and gamma) are immunologically undetectable in the circulation of both neonatal and adult A alpha(-/-) mice, and blood samples fail to either clot or support platelet aggregation in vitro. Overt bleeding events develop shortly after birth in similar to 30% of A alpha(-/-) 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 A alpha(-/-) 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 A alpha(-/-) 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 A alpha(-/-) mice suggests that fibrin(ogen) plays a fundamental role in the organization of cells at sites of injury.