To explore the role of the key coagulation factor, fibrinogen, in development, hemostasis, wound repair, and disease pathogenesis, we disrupted the fibrinogen As chain gene in mice. Homozygous, As chain-deficient (As-/-) 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 Ac~ chain allele. All of the component chains of fibrinogen (A¢~, B~, and y) are immunologically undetectable in the circulation of both neonatal and adult As -/-mice, and blood samples fail to either clot or support platelet aggregation in vitro. Overt bleeding events develop shortly after birth in --~30% of Ac~-/-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 As-/-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 As -/-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 As -/-mice suggests that fibrin(ogen) plays a fundamental role in the organization of cells at sites of injury.[Key Words" Fibrinogen-deficient mice; coagulation; hemostasis; afibrinogenemia; platelet aggregation; wound healing; development] Received May 15, 1995; revised version accepted June 28, 1995.Fibrin(ogen) is the ultimate target of two sophisticated and opposing regulatory systems, the coagulation and fibrinolytic cascades, that together preserve vascular integrity and maintain hemostatic balance (Davie et al. 1991;Esmon 1993;Collen and Lijnen 1994). The coagulation system includes more than a dozen soluble and cell-associated factors that initiate, promote, and ultimately limit the formation of insoluble fibrin polymer (Davie et al. 1991}. A key step in coagulation is the generation of the serine protease, thrombin, which triggers platelet activation (Majerus 1994), converts fibrinogen into a spontaneously polymerizing fibrin monomer (Doolittle 1994), activates the transglutaminase (factor XIII) that covalently cross-links fibrin matrices (Chung and Ichinose 1995), and activates regulatory pathways that both promote and suppress coagulation (Davie et al.