Abstract
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.
References
Astrup T. Fibrinolysis: an overview. In: Davidson JF, Rowan RM, Samama MM, Desnoyers PC, eds. Progress in chemical fibrinolysis and thrombolysis. New York, Raven; 1978:1–57.
Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991; 78:3114.
Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88:1067.
Lala PK, Graham CH. Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors. Cancer Metastasis Rev 1990; 9:369.
Blasi F, Verde P. Urokinase-dependent cell surface proteolysis and cancer. Semin Cancer Biol 1990; 1:117.
Lijnen HR, Collen D. Congenital and acquired deficiencies of components of the fibrinolytic system and their relation to bleeding or thrombosis. Fibrinolysis 1989; 3:67.
Wiman B, Hamsten A. The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease. Semin Thromb Hemost 1990; 16:207.
Declerck PJ, Juhan-Vague I, Felez J, Wiman B. Pathophysiology of fibrinolysis. J Intern Med 1994; 236:425.
Carmeliet P, Collen D. Evaluation of the plasminogen/plasmin system in transgenic mice. Fibrinolysis 1994; 8 [Suppl 1]:269.
Carmeliet P, Collen D. Role of the plasminogen/plasmin system in thrombosis, hemostasis, restenosis and atherosclerosis. Evaluation in transgenic animals. Trends Cardiovasc Med 1995; 5:117.
Lijnen HR, Bachmann F, Collen D, Ellis V, Pannekoek H, Rijken DC, Thorsen S. Mechanisms of plasminogen activation. J Intern Med 1994; 236:415.
Dolan G, Greaver M, Cooper P, Preston FE. Thrombovascular disease and familial plasminogen deficiency: a report of three kindreds. Br J Haematol 1988; 70:417.
Azuma H, Uno Y, Shigekiyo T, Sarzo S. Congenital plasminogen deficiency caused by Ser672 to Pro mutation. Blood 1993; 82:475.
Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, Collen D. Effects of disruption of the plasminogen gene on thrombosis, growth and health in mice. Circulation 1995; 92:2585.
Bugge TH, Flick MJ, Daugherty CC, Degen JL. Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes Dev 1995; 9:794.
Huarte J, Belin D, Bosco D, Sappino AP, Vassalli JD. Plasminogen activator and mouse spermatozoa: urokinase synthesis in the male genital tract and binding of the enzyme to the germ cell surface. J Cell Biol 1987; 104:1281.
Plow EF. The major fibrinolytic proteases of human leukocytes. Biochim Biophys Acta 1980; 630:47.
Simon DI, Ezratty AM, Francis SA, Rehnke H, Loscalzo J. Fibrinogen is internalized and degraded by activated human monocytoid cells via Mac-1 (CD11b/CD18): a nonplasmin fibrinolytic pathway. Blood 1993; 82:2414.
Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, De Vos R, Oord JJ van den, Collen D, Mulligan RC. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994; 368:419.
Nilsson IM, Ljungner H, Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. BMJ 1985; 290:1453.
Juhan-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip-Joet C, Holvoet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemost 1987; 57:67.
Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor 1 and atherothrombosis. Thromb Haemost 1993; 70:138.
Prins MH, Hirsh J. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991; 151:1721.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Shen C, Newcomer LM, Goldhaver SZ, Hannekens CH. Baseline fibrinolytic state and the risk of future venous thrombosis. A prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor. Circulation 1992; 85:1822.
Carmeliet P, Kieckens L, Schoonjans L, Ream B, Van Nuffelen A, Prendergast G, Cole M, Bronson R, Collen D, Mulligan RC. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest 1993; 92:2746.
Carmeliet P, Stassen JM, Schoonjans L, Ream B, Oord JJ van den, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 1993; 92:2756.
Lijnen HR, Moons L, Beelen V, Carmeliet P, Collen D. Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. Thromb Haemost 1995; 74:1126.
Bugge TH, Suh TT, Flick MJ, Daugherty CC, Romer J, Solberg H, Ellis V, Dano K, Degen JL. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility. J Biol Chem 1995; 270:16886.
Dewerchin M, Van Nuffelen A, Wallays G, Bouché A, Moons L, Carmeliet P, Mulligan RC, Collen D. Generation and characterization of urokinase receptor-deficient mice. J Clin Invest 1996; 97:870.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lijnen, H.R. Pathophysiology of the plasminogen/plasmin system. Int J Clin Lab Res 26, 1–6 (1996). https://doi.org/10.1007/BF02644767
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02644767