Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction

Abstract

Plasminogen (Plg)-deficient mice were generated to define the physiological roles of this key fibrinolytic protein and its proteolytic derivatives, plasmin and angiostatin, in development, hemostasis, and reproduction. Plg(-/-) mice complete embryonic development, survive to adulthood, and are fertile. There is no evidence of fetal loss of Plg(-/-) mice based on the Mendelian pattern of transmission of the mutant Plg allele. Furthermore, embryonic development continues to term in the absence of endogenous, sibling-derived, or maternal Plg. However, Plg(-/-) mice are predisposed to severe thrombosis, and young animals developed multiple spontaneous thrombotic lesions in liver, stomach, colon, rectum, lung, pancreas, and other tissues. Fibrin deposition in the liver was a uniform finding in 5- to 21-week-old mice, and ulcerated lesions in the gastrointestinal tract and rectal tissue were common. A remarkable finding, considering the well-established linkage between plasmin and the proteolytic activation of plasminogen activators, was that the level of active urokinase- type plasminogen activator in urine was unaffected in Plg(-/-) mice. Therefore, Plg plays a pivotal role in fibrinolysis and hemostasis but is not essential for urokinase proenzyme activation, development, or growth to sexual maturity.