Plasminogen Activator Inhibitor Type-1 Determines Plasmin Formation in Patients with Ischaemic Heart Disease

Summary

The aim of the present study was to find out whether plasminogen activator inhibitor type-1 (PAI-1) controls the formation of plasmin in patients with ischaemic heart disease.

We examined PAI activity, PAI-1 antigen, tissue type plasminogen activator (t-PA) activity, t-PA antigen, plasmin-α₂-antiplasmin complex (PAP-complex) and fibrin degradation products D-dimer in 62 patients before (unstimulated) and after infusion of l-desamino-8- D-arginine vasopressin (DDAVP; stimulated). DDAVP was used in a standardized dose to trigger the release of t-PA from the vascular endothelium.

We observed that under basal conditions (unstimulated) median plasma t-PA activity for the whole group of patients was 86.5 mlU/ml (0-900), and after stimulation 2550 mlU/ml (0-6800), P <0.0001; median plasma concentration of t-PA antigen was 14.7 ng/ml (7.0-115.5) under basal conditions, and after stimulation 34.1 ng/ml (15.8-58.6), P <0.0001; median plasma PAI activity was 16.9 IU/ml (1.5-144.8) under basal conditions, and after stimulation 3.1 IU/ml (0-118.5), P <0.0001; median plasma concentration of PAI-1 antigen was 21.5 ng/ml (8.1-132.2) under basal conditions, and after stimulation 14.9 ng/ml (4.8-149.0), P <0.0001; the median plasma concentration of PAP-complex was 469.5 ng/ml (185.0-1802.0) under basal conditions, and after stimulation 695.5 (243.0-2292.0), P <0.0001; median plasma concentration of D-dimer was 298.0 ng/ml (103.0-948.0) under basal conditions, and after stimulation 296.5 ng/ml (97.0-917.0), P <0.0008.

Under basal conditions plasma PAI activities and plasma concentrations of PAI-1 antigen were both significantly negatively correlated with plasma concentrations of PAP-complex (r_s = -0.32; P <0.02 and r_s = -0.42; P <0.002, respectively). After stimulation of the fibrinolytic system by infusion of DDAVP, plasma PAI activities and plasma concentrations of PAI-1 antigen were also significantly negatively correlated with plasma concentrations of PAP-complex (r_s = -0.41; P <0.002 and r_s = - 0.33; P <0.009, respectively).

Our results indicate that PAI-1 regulates formation of plasmin in patients with ischaemic heart disease. These observations support that PAI-1 may play a critical role in the evolution of thrombosis.

• References

• 1 Gram J, Jespersen J. A selective depression of tissue plasminogen activator (t-PA) activity in euglobulins characterises a risk group among survivors of acute myocardial infarction. Thromb Haemost 1987; 57: 137-139
• 2 Hamsten A, Walldius G, Szamosi A, Blomback M, de Faire U, Dahlen G. et a l Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9
• 3 Lee MH, Vosburgh E, Anderson K, McDonagh J. Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding. Blood 1993; 81: 2357-2362
• 4 Schleef RR, Higgins DL, Pillemer E, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest 1989; 83: 1747-1752
• 5 Jespersen J, Munkvad S, Gram J. The fibrinolysis and coagulation systems in ischaemic heart disease. Risk markers and their relation to metabolic dysfunction of the arterial intima Dan Med Bull 1993; 40: 495-502
• 6 Chandler WL. A kinetic model of the circulatory regulation of tissue plasminogen activator. Thromb Haemost 1991; 66: 321-328
• 7 Cugno M, Uziel L, Fabrizi I, Bottasso B, Maggiolini F, Agostoni A. Fibrinolytic response in normal subjects to venous occlusion and DDAVP infusion. Thromb Res 1989; 56: 625-634
• 8 Kluft C, Verheijen J H. Leiden fibrinolysis working party. Blood collection and handling procedures for assessment of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAl-1). Fibrinolysis 1990; 4 supp (Suppl. 02) 155-161
• 9 Munkvad S, Gram J, Jespersen J. Possible role of vascular intima for generation of coagulant activity in patients undergoing coronary thrombolysis with recombinant tissue-type plasminogen activator. A randomised, placebo-controlled study Scand J Clin Lab Invest 1991; 51: 581-590
• 10 Kluft C. C1-inactivator-resistant fibrinolytic activity in plasma euglobulin fraction: its relation to vascular activator in blood and its role in euglobulin fibrinolysis. Thromb Res 1978; 13: 135-151
• 11 Jespersen J, Astrup T. A study of the fibrin plate assay of fibrinolytic agents: optimal conditions, reproducibility and precision. Haemostasis 1983; 13: 301-315
• 12 Pelzer H, Schwartz A, Merte D, Hock J. A novel enzyme-linked immunosorbent assay (ELISA) for the determination of α-antiplasmin-plasmin complex in human plasma. Thromb Haemost 1991; 65: 1265
• 13 Wiman B, Haegerstrand-Bjorkman M. Plasmin/α₂-antiplasmin complex in plasma-a global fibrinolytic assay. Thromb Haemost 1993; 69: 1091
• 14 Kluft C, Meijer P, van Bergen PF M M, Przespolewski EF. Active tissue- type plasminogen activator (t-PA) in the circulation is a major determinant of the levels of plasmin-α₂-antiplasmin complexes at baseline and during bicycle exercise testing. Thromb Haemost 1993; 69: 1093
• 15 Burggraaf J, Schoemaker HC, Kroon JM, Huisman L, Kluft C, Cohen AF. Influence of l-desamino-8-D-vasopressin on endogenous fibrinolysis, haemodynamics and liver blood flow in healthy subjects. Clinical Science 1994; 86: 497-503
• 16 Takahashi H, Tatewaki W, Wada K, Niwano H, Hanano M, Shibata A. Plasmin generation and fibrin(ogen)olysis following desmopressin infusion. Am J Hematol 1991; 36: 255-258
• 17 Levi M, de BoerJ, Roem D, ten CateJ, Hack CE. Plasminogen activation in vivo upon intravenous infusion of DDAVP. Thromb Haemost 1992; 67: 111-116
• 18 Hamsten A, Wiman B, de FaireU, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
• 19 Prins MH, Hirsh J. A critical review of the relationship between impaired fibrinolysis and myocardial infarction. Am Heart J 1991; 122: 545-551
• 20 Torr-Brown SR, Sobel BE. Attenuation of thrombolysis by release of plasminogen activator inhibitor type-1 from platelets. Thromb Res 1993; 72: 413-421
• 21 Handt S, Jerome WG, Braaten JV, Lewis JC, Kirkpatrick CJ, Hantgan RR. PAI-1 released from cultured human endothelial cells delays fibrinolysis and is incorporated into the developing fibrin clot. Fibrinolysis 1994; 8: 104-112
• 22 Loon BJ, Rijken DC, Brommer EJ, Maas AP C. The amount of plasminogen, tissue-type plasminogen activator inhibitor type-1 in human thrombi and the relation to ex-vivo lysibility. Thromb Haemost 1992; 67: 101-105
• 23 Rijken DC, Juhan-Vague I, Collen D. Complexes between tissue-type plasminogen activator and proteinase inhibitors in human plasma, identified with an immunoradiometric assay. J Lab Clin Med 1983; 101: 285-294
• 24 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387