Subscribe to RSS
DOI: 10.1055/s-0038-1649570
The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis
Publication History
Received 14 September 1992
Accepted after revision 05 February 1993
Publication Date:
04 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199302/lookinside/thumbnails/10-1055-s-0038-1649570-1.jpg)
Summary
The relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.
-
References
- 1 Collen D. On the regulation and control of fibrinolysis. Thromb Haemostas 1980; 43: 77-89
- 2 Lijnen HR, Collen D. Interactions of plasminogen activators and inhibitors with plasminogen and fibrin. Semin Thromb Hemostas 1982; 8: 2-10
- 3 Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue-plasminogen activators. Role of fibrin. J Biol Chem 1982; 257: 2912-2919
- 4 Collen D. Identification of some properties of a new fast-reacting plasmin inhibitor in human plasma. Eur J Biochem 1976; 69: 209-216
- 5 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387
- 6 Moroi M, Aoki N. Isolation and characterization of alpha2-plasmin inhibitor from human plasma. J Biol Chem 1976; 251: 5956-5965
- 7 Wiman B, Collen D. Purification and characterization of human antiplasmin, the fast-acting plasmin inhibitor in plasma. Eur J Biochem 1977; 78: 19-26
- 8 Plow EF, Collen D. The presence and release of α2-antiplasmin from human platelets. Blood 1981; 58: 1069-1074
- 9 Kruithof EKO, Tran-Thang C, Ransijin A, Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood 1984; 64: 907-913
- 10 Booth NA, Simpson AJ, Croll A, Bennett B, MacGregor IR. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 1988; 70: 327-333
- 11 Declerck PJ, Alessi MC, Verstreken EKO, Kruithof I, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzymelinked immunosorbent assay. Blood 1988; 71: 220-225
- 12 Sprengers ED, Akkerman JWN, Jansen BG. Blood platelet plasminogen activator inhibitor: two different pools of endothelial cell type plasminogen activator inhibitor in human blood. Thromb Haemostas 1986; 55: 325-329
- 13 Simpson AJ, Booth NA, Moore NR, Bennett B. The platelet and plasma pools of plasminogen activator inhibitor PAI-1 vary independently in disease. Br J Haematol 1990; 75: 543-548
- 14 Kruithof EKO, Gudinchet A, Bachmann F. Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states. Thromb Haemostas 1988; 59: 7-12
- 15 Chmielewska J, Ranby M, Wiman B. Kinetics of the inhibition of plasminogen activators by the plasminogen activator inhibitor. Biochem J 1988; 251: 327-332
- 16 Sakata Y, Aoki N. Cross-linking of α2-antiplasmin inhibitor to fibrin by fibrin-stabilizing factor. J Clin Invest 1980; 65: 290-297
- 17 Aoki N, Harpel PC. Inhibitors of the fibrinolytic enzyme system. Semin Thromb Hemostas 1984; 10: 24-41
- 18 Wagner OF, de Vries C, Hohmann C, Veerman H, Pannekoek H. Interaction between plasminogen activator inhibitor typel (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA) Binding of t-PA-PAI-1 complexes to fibrin mediated by both finger and kringle-2 domain of t-PA. J Clin Invest 1989; 84: 647-655
- 19 Keijer J, Linders M, van Zonneveld A-J, Ehrlich HJ, de Boer J-P, Pannekoek H. The interaction of plasminogen activator inhibitor 1 (PAI-1) with plasminogen activators (t-PA, u-PA) and fibrin: localization of interaction sites and physiological relevance. Blood 1991; 78: 401-409
- 20 Booth NA, Anderson JA, Bennett B. Platelet release protein which inhibits plasminogen activators. J Clin Pathol 1985; 38: 825-830
- 21 de Fouw NJ, de Jong YF, Haverkate F, Bertina RM. The influence of thrombin and platelets on fibrin clot lysis rates in vitro: a study using a clot lysis system consisting of purified human proteins. Fibrinolysis 1988; 2: 235-244
- 22 Jones AJS, Meunier AM. A precise and rapid microtitre plate clot lysis assay: methodology, kinetic modelling and measurement of catalytic constants for plasminogen activation during fibrinolysis. Thromb Haemostas 1990; 64: 455-463
- 23 MacGregor IR, Booth NA. An enzyme-linked immunosorbent assay (ELISA) used to study the cellular secretion of endothelial plasminogen activator inhibitor (PAI). Thromb Haemostas 1988; 59: 68-72
- 24 Deutsch DG, Mertz ET. Plasminogen purification from human plasma by affinity chromatography. Science 1970; 170: 1095-1096
- 25 Booth NA, MacGregor IR, Hunter NR, Bennett B. Plasminogen activator inhibitor from human endothelial cells. Purification and partial characterization. Eur J Biochem 1987; 165: 595-600
- 26 Paramo JA, Gascoine PS, Pring JB, Gaffney PJ. The relative inhibition by α2-antiplasmin and plasminogen activator inhibitor-1 of clot lysis in vitro. Fibrinolysis 1990; 4: 169-175
- 27 Lambers JWJ, Cammenga M, Konig BW, Mertens K, Pannekoek H, Van Mourik JA. Activation of human endothelial type plasminogen activator inhibitor by negatively charged phospholipids. J Biol Chem 1987; 262: 17492-17496
- 28 Booth NA, Anderson JA, Bennett B. The plasma inhibitors of plasminogen activator, studied by a zymographic technique. Thromb Res 1985; 38: 261-267
- 29 Reith AR, Bennett B, Booth NA. Plasminogen activator inhibitor (PAI-2) in pregnancy plasma and ovarian cysts, studied by zymography after non-denaturing gel electrophoresis. Fibrinolysis 1989; 3: 159-163
- 30 Booth NA, Croll AM, Bennett B. The activity of plasminogen activator inhibitor-1 (PAI-1) of human platelet. Fibrinolysis 1990; 4: 138-140
- 31 Booth NA, Robbie LA, Croll AM, Bennett B. Lysis of platelet-rich thrombi: the role of PAI-1. NY Acad Sci USA 1992; 667: 70-86
- 32 Potter van LoonBJ, Rijken DC, Brommer EJP, van der MaasAPC. The amount of plasminogen, tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in human thrombi and the relation to ex-vivo lysibility. Thromb Haemostas 1992; 67: 101-105
- 33 Levi M, Biemond BJ, van Zonnevald A-J, ten Cate JW, Pannekoek H. Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 1992; 85: 305-312
- 34 Reed GL, Matsueda GR, Haber E. Platelet factor XIII increases the fibrinolytic resistance of platelet-rich clots by accelerating the crosslinking of α2-antiplasmin to fibrin. Thromb Haemostas 1992; 68: 315-320