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DOI: 10.1055/s-0037-1615841
The Plasminogen (Fibrinolytic) System
Publikationsverlauf
Publikationsdatum:
09. Dezember 2017 (online)
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Introduction
The plasminogen (fibrinolytic) system (Fig. 1) comprises an inactive proenzyme, plasminogen, that can be converted to the active enzyme, plasmin. Plasmin degrades fibrin and activates matrix metalloproteinases (MMPs) that, in turn, degrade the extracellular matrix (ECM).1-3 Two physiological plasminogen activators (PAs) have been identified: tissue-type PA (t-PA) and urokinase-type PA (u-PA), which binds to a cellular u-PA receptor (u-PAR). Inhibition of the plasminogen/MMP system occurs at the level of the PA, by specific PA inhibitors (PAIs), at the level of plasmin, primarily by α2-antiplasmin, or at the level of MMPs, by tissue inhibitors of MMPs (TIMPs).
The dual roles of the plasminogen system are presently well established. The t-PA-mediated pathway is primarily involved in fibrin homeostasis, and the u-PA-mediated pathway is primarily involved in phenomena, such as cell migration and tissue remodeling. Consequently, the terminology “fibrinolytic system” has become inadequate and, therefore, will be replaced by “plasminogen system” in the present review.
In 1980, the state of knowledge concerning the plasminogen system was summarized.4 At that time, most of the components of the system (except the PAIs) were identified and biochemically characterized (except t-PA), but thrombolytic therapy was still in its infancy. The pathophysiologic role of the plasminogen system was deduced indirectly from correlations between levels of its components and clinical disease states, whereas its role in vascular biology, matrix remodeling, tumor growth and dissemination, wound healing, and infection was largely unknown. The last 20 years have witnessed a rapidly progressing elucidation of the biochemistry, (patho)physiology, and therapeutic applications of the plasminogen system. This development has been catalyzed by the emergence of powerful molecular biological technologies, including recombinant DNA techniques for the expression of heterologous proteins and targeted gene manipulation in vivo for the elucidation of the (patho)physiological role of their translation products.
The aim of the present review is to summarize the main developments in the plasminogen field since the 1980s. This account will be incomplete, since references to much significant work were omitted due to space limitations. To alleviate this shortcoming, reference is made primarily to review articles, in which more details and citations to original work can be found.
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References
- 1 Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991; 78: 3114-3124.
- 2 Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995; 7: 728-735.
- 3 Lijnen HR, Collen D. Matrix metalloproteinase system deficiencies and matrix degradation. Thromb Haemost.. (this volume).
- 4 Collen D. On the regulation and control of fibrinolysis. Thromb Haemost. 1980; 43: 77-89.
- 5 Collen D, Haber E. The fibrinolytic system and thrombolytic therapy. In: Chien KR. ed. Molecular Basis of Cardiovascular Disease. W.B. Saunders; Philadelphia: 1998: 537-565.
- 6 Carmeliet P, Collen D. Gene manipulation and transfer of the plasminogen and coagulation system in mice. Semin Thromb Haemost. 1996; 22: 525-542.
- 7 Collen D. Regulation of fibrinolysis: plasminogen activator as a thrombolytic agent. In: Nossel HL, Vogel HJ. eds. Pathobiology of the Endothelial Cell. Academic Press; New York: 1982: 183-189.
- 8 Lijnen HR, Collen D. Mechanisms of physiological fibrinolysis. Baillières Clin Haematol. 1995; 8: 277-290.
- 9 Kruithof EKO. Plasminogen activator inhibitors – A review. Enzyme. 1988; 40: 113-121.
- 10 Loskutoff DJ. Regulation of PAI-1 gene expression. Fibrinolysis. 1991; 5: 197-206.
- 11 Hajjar KA. Cellular receptors in the regulation of plasmin generation. Thromb Haemost. 1995; 74: 294-301.
- 12 Lijnen HR, Collen D. Congenital and acquired deficiencies of components of the fibrinolytic system and their relation to bleeding or thrombosis. Fibrinolysis. 1989; 3: 67-77.
- 13 Collen D. Fibrin-selective thrombolytic therapy for acute myocardial infarction. Circulation. 1996; 93: 857-865.
- 14 Collen D, Verstraete M. Systemic thrombolytic therapy of acute myocardial infarction?. Circulation. 1983; 68: 462-465.
- 15 Becker RC. (Ed). The Modern Era of Coronary Thrombolysis. Kluwer Academic Publisher; Boston: 1994
- 16 Collen D. Trials comparing the available thrombolytic agents. Coron Artery Dis. 1992; 3: 117-122.
- 17 Grünewald M, Seifried E. Meta-analysis of all available published clinical trials (1958-1990) on thrombolytic therapy for AMI: relative efficacy of different therapeutic strategies. Fibrinolysis. 1994; 8: 67-86.
- 18 The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993; 329: 673-682.
- 19 The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993; 329: 1615-1622.
- 20 Braunwald E. The open-artery theory is alive and well-again. N Engl J Med. 1993; 329: 1650-1652.
- 21 Collins R, Peto R, Baigent C, Sleight P. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med. 1997; 336: 847-860.
- 22 Califf RM, White HD, Van de Werf F, Sadowski Z, Armstrong PW, Vahanian A, Simoons ML, Simes RJ, Lee KL, Topol EJ. One-year results from the Global Utilization of Streptokinase and T-PA for Occluded Coronary Arteries (GUSTO-I) Trial. Circulation. 1996; 94: 1233-1238.
- 23 Califf RM, Woodlief LH, Harrell Jr. FE, Lee KL, White HD, Guerci A, Barbash GI, Simes RJ, Weaver WD, Simoons ML, Topol EJ. Selection of thrombolytic therapy for individual patients: development of a clinical model. Am Heart J. 1997; 133: 630-639.
- 24 Schlandt R.C.. (Chairman). Reperfusion in acute myocardial infarction. Circulation. 1994; 90: 2091-2102.
- 25 Collen D. Towards improved thrombolytic therapy. Lancet. 1993; 342: 34-36.
- 26 Gulba DC, Bode C, Runge MS, Huber K. Thrombolytic agents–an updated overview. Fibrinol Proteol. 1998; 12 (Suppl. 02) 39-58.
- 27 Collen D, Lijnen HR, Gold HK. Towards better thrombolytic therapy. Prog Cardiovasc Dis. 1991; 34: 101-112.
- 28 Moliterno DJ, Topol EJ. Conjunctive use of platelet glycoprotein IIb/IIIa antagonists and thrombolytic therapy for acute myocardial infarction. Thromb Haemost. 1997; 78: 214-219.
- 29 Verstraete M, Zoldhelyi P, Willerson JT. Specific thrombin inhibitors. In: Verstraete M, Fuster V, Topol EJ. eds. Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology. 2nd ed.. Lippincott-Raven Publishers; Philadelphia: 1998: 141-172.
- 30 Jespers L, Vanwetswinkel S, Lijnen HR, Van Herzeele N, Collen D, De Maeyer M. Interface scanning and 3D model of the staphylokinase: plasmin activator complex. Fibrinol Proteol. 1998; 12 (Suppl. 01) 4
- 31 Jespers L, Vanwetswinkel S, Lijnen HR, Van Herzeele N, Van Hoef B, Demarsin E, Collen D, De Maeyer L. Structural and functional basis of plasminogen activation by staphylokinase. Thromb Haemost. 1999; 81: 479-485.
- 32 Collen D. Staphylokinase: a potent, uniquely fibrin-selective thrombolytic agent. Nat Med. 1998; 4: 279-284.
- 33 Collen D, Van de Werf F. Coronary thrombolysis with recombinant staphylokinase in patients with evolving myocardial infarction. Circulation. 1993; 87: 1850-1853.
- 34 Collen D. Identification, production and use of new staphylokinase derivatives with reduced immunogenicity, reduced clearance or both. PCT application. (PCT/EP99/00748).
- 35 Heymans S, Vanderschueren S, Stockx L, Verhaeghe R, Vermylen J, Nevelsteen A, Collen D, Suy R. Short term and one year results of intra-arterial infusion of recombinant staphylokinase variants in patients with peripheral arterial infarction. Circulation (AHA Meeting). 1999
- 36 Collen D, Zhao ZA, Holvoet P, Marijnen P. Primary structure and gene structure of staphylokinase. Fibrinolysis. 1992; 6: 226-231.
- 37 Collen D. Engineered staphylokinase variants with reduced immunogenicity. Fibrinol Proteol. 1998; 12 (Suppl. 02) 59-65
- 38 Carmeliet P, Collen D. Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res. 1998; 91: 255-285.
- 39 Carmeliet P, Moons L, Lijnen R, Baes M, Lemaître V, Tipping P, Drew A, Eeckhout Y, Shapiro S, Lupu F, Collen D. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet. 1997; 17: 439-444.
- 40 Carmeliet P, Collen D. Genetic analysis of blood vessel formation. Role of endothelial versus smooth muscle cells. Trends Cardiovasc Med. 1997; 7: 271-281.
- 41 Bajou K, Noël A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med. 1998; 4: 923-928.
- 42 Bugge TH, Kombrinck KW, Flick MJ, Daugherty CC, Danton MJ, Degen JL. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell. 1996; 87: 709-719.
- 43 Coleman JL, Gebbia JA, Piesman J, Degen JL, Bugge TH, Benach JL. Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for the enhancement of spirochetemia in mice. Cell. 1997; 89: 1111-1119.