RESOLUTION OF SPONTANEOUS BLEEDING EVENTS BUT FAILURE OF PREGNANCY INFIBRINOGEN-DEFICIENT MICE

To explore the role of the key coagulation factor, fibrinogen, in deve lopment, hemostasis, wound repair, and disease pathogenesis, we disrup ted the fibrinogen A alpha chain gene in mice. Homozygous, A alpha cha in-deficient (A alpha(-/-)) mice are born normal in appearance, and th ere is no evidence of fetal loss of these animals based on the Mendeli an pattern of transmission of the mutant A alpha chain allele. All of the component chains of fibrinogen (A alpha, B beta, and gamma) are im munologically undetectable in the circulation of both neonatal and adu lt 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. Remarkab ly, most newborns displaying signs of bleeding ultimately control the loss of blood, clear the affected tissues, and survive the neonatal pe riod. Juveniles and young adult A alpha(-/-) mice are predisposed to s pontaneous fatal abdominal hemorrhage, but long-term survival is varia ble and highly dependent on genetic background. The periodic rupture o f ovarian follicles in breeding-age A alpha(-/-) females does not appe ar to significantly diminish life expectancy relative to males; howeve r, pregnancy uniformly results in fatal uterine bleeding around the te nth day of gestation. Microscopic analysis of spontaneous lesions foun d in A alpha(-/-) mice suggests that fibrin(ogen) plays a fundamental role in the organization of cells at sites of injury.