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Fibrin(ogen) is central to hemostasis and thrombosis and also contributes to multiple physiologic and pathologic processes beyond coagulation. However, the precise contribution of soluble fibrinogen vs insoluble fibrin matrices to vascular integrity, tissue repair, inflammation, and disease has been undefined and unapproachable. To establish the means to distinguish fibrinogen- and fibrin-dependent processes in vivo, Fib^AEK mice were generated that carry normal levels of circulating fibrinogen but lack the capacity for fibrin polymer formation due to a germ-line mutation in the Aα chain thrombin cleavage site. Homozygous Fib^AEK mice developed to term and exhibited postnatal survival superior to that of fibrinogen-deficient mice. Unlike fibrinogen-deficient mice, platelet-rich plasma from Fib^AEK mice supported normal platelet aggregation in vitro, highlighting that fibrinogen^AEK retains the functional capacity …