Pathophysiology of the plasminogen/plasmin system.

Circumstantial evidence has been provided for a role of the human fibrinolytic or plasminogen/plasmin system in a variety of biological phenomena. Recently, generation of mice with single or combined deficiencies of main components of the fibrinolytic system, including plasminogen, tissue-type and urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and the cellular receptor for urokinase-type plasminogen activator has allowed the role of the fibrinolytic system in vivo to be established more conclusively. Plasminogen-deficient mice survive embryonic development, but develop spontaneous fibrin deposition due to an impaired thrombolytic potential, and suffer retarded growth and reduced fertility and survival. Plasminogen deficiency in man is extremely rare, but viable, although it is associated with thrombolic complications. Disruption of the plasminogen activator inhibitor-1 gene in mice induces a mild hyperfibrinolytic state and a greater resistance to venous thrombosis, but does not impair hemostasis. In contrast, in man, the inhibitor deficiency results in delayed rebleeding. Tissue-type plasminogen activator-deficient mice have a reduced thrombolytic potential, whereas mice deficient in the urokinase-type plasminogen activator occasionally develop spontaneous fibrin deposits in tissues and display deficient plasmin-mediated macrophage function. Mice deficient in both types of activator develop normally but are significantly less fertile, have retarded growth and shorter survival, and display a severe thrombotic phenotype in normal and inflamed tissues. At present, genetic deficiencies of either type activator have not been reported in man. The urokinase-type plasminogen activator/receptor system has been implicated in localized extracellular proteolytic activity. Receptor-deficient mice are, however, healthy, and fertile, and have a normal endogenous thrombolytic capacity; their macrophages have, however, an impaired (urokinase-type plasminogen activator mediated) plasminogen activating potential. Mice with single or combined inactivation of components of the plasminogen/plasmin system thus may be valuable models for studying physiological and pathophysiological processes in vivo.