Types 1 and 2 Plasminogen Activator lnhibitor and Tirmor Necrosis Factor Alpha in Fatients with Sepsis^[*]

Summary

We have determined the plasma concentrations of types 1 and 2 of plasminogen activator inhibitor (PAI-1 and PAI-2), tumor necrosis factor (TNF-α) and endotoxin in 47 patients with bacterial infection (22 patients presented with positive blood cultures). Results were compared with those observed in 30 healthy subjects. There was a significant increase in PAI-1 and TNF-α in patients as compared to controls (p <0.0001), whereas no differences for PAI-2 were observed. PAI-1 and TNF-α were significantly higher in 18 patients with gram-negative bacteremia as compared to all other patients (p <0.0001). However, no correlation between the analyzed parameters and either endotoxin or clinical outcome was observed. We conclude that there is an increase of PAI-1 and TNF-α in patients with sepsis, which is not related to the endotoxin concentration. Our results suggest that PAI-1, but not PAI-2, is the main plasminogen activator inhibitor in human sepsis.

Dedicated to Professor M. Verstraete on the occasion of his 65th birthday

• References

• 1 McGovern VJ. Shock revisited. Pathol Annu 1984; 19: 15-36
• 2 Collen D. On the regulation and control of fibrinolysis. Thromb Haemostas 1980; 43: 77-89
• 3 Sprengers ED, Kluft TC. Plasminogen activator inhibitors. Blood 1987; 69: 381-387
• 4 Loskutoff DJ. Type 1 plasminogen activator inhibitor and its potential influence on thrombolytic therapy. Sem Thromb Hemostas 1988; 14: 100-109
• 5 Páramo JA, De Boer A, Colucci M, Jonker JJ C, Collen D. Plasminogen activator inhibitor (PA-inhibitor) in the blood of patients with deep venous thrombosis. Thromb Haemostas 1985; 54: 725
• 6 Páramo JA, Colucci M, Collen D, Van De Werf F. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573-574
• 7 Colucci M, Paramo JA, Collen D. Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 1985; 75: 818-824
• 8 Páramo JA, Fernández DíazJ, Rocha E. Plasminogen activator inhibitor activity in bacterial infection. Thromb Haemostas 1988; 59: 451-454
• 9 Holmberg L, Lecander I, Persson B, Asted B. An inhibitor from placenta specifically binds urokinase and inhibits plasminogen activator released from ovarian carcinoma in tissue culture. Biochim Biophys Acta 1978; 544: 128-137
• 10 Lecander I, Astedt B. Isolation of a new specific plasminogen activator inhibitor from pregnancy plasma. Br J Haematol 1986; 62: 221-228
• 11 Kruithof EK O, Vassalli JD, Schleuning WD, Mattaliano RH, Bachmann F. Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U937. J Biol Chem 1986; 261: 11207-11213
• 12 Kruithof EK O, Tran-Thang C, Gudinchet A, Hauert J, Nicoloso G, Genton C, Welti H, Bachmann F. Fibrinolysis in pregnancy. A study of plasminogen activator inhibitors. Blood 1987; 69: 460-466
• 13 Schwartz BS, Monroe MC, Levin EC. Increased release of plasminogen activator inhibitor type 2 accompanies the human mononuclear cell tissue factor response to lipopolysaccharide. Blood 1988; 71: 734-741
• 14 Old LJ. Tumor necrosis factor (TNF). Science 1985; 230: 630-632
• 15 Beutler B, Cerami A. Cachectin: more than tumor necrosis factor. N Engl J Med 1987; 316: 379-385
• 16 Schleef RR, Bevilacqua MP, Sawdey M, Gimbrone MA, Loskutoff DJ. Citokine activation of vascular endothelium. Effects on tissue type plasminogen activator and type 1 plasminogen activator inhibitor. J Biol Chem 1988; 263: 5797-5803
• 17 Van Hinsbergh VW M, Kooistra T, Van den Berg EA, Princen HM G, Fiers W, Emeis JJ. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 1988; 72: 1467-1473
• 18 Páramo JA, Alfaro MJ, Rocha E. Postoperative changes in the plasmatic levels of tissue-type plasminogen activator and its fast-acting inhibitor. Relationship to deep vein thrombosis and influence of prophylaxis. Thromb Haemostas 1985; 54: 713-716
• 19 Leroux-Roels G, Offner F, Philippe J, Vermeulen A. Influence of blood-collecting systems on concentrations of tumor necrosis factor in serum and plasma. Clin Chem 1988; 34: 2373-2374
• 20 Engebretsen LF, Kierulf P, Brandtzaeg P. Extreme plasminogen activator inhibitor and endotoxin values in patients with meningococcal disease. Thromb Res 1986; 42: 713-716
• 21 Pralong G, Calandra T, Glauser M-P, Schellekens J, Verhoef J, Bachmann F, Kruithof EK O. Plasminogen activator inhibitor 1: A new prognostic marker in septic shock. Thromb Haemostas 1989; 61: 459-462
• 22 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320: 1165-1172
• 23 Crutchley DJ, Conanan LB. Endotoxin induction of an inhibitor of plasminogen activator in bovine pulmonary artery endothelial cells. J Biol Chem 1986; 261: 154-159
• 24 Emeis JJ, Kooistra T. Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 1986; 163: 1260-1266
• 25 Lecander I, Astedt B. Occurrence of a specific plasminogen activator inhibitor of placental type, PAI-2, in men and non-pregnant women. Fibrinolysis 1989; 3: 27-30
• 26 Phillips LL, Margaretten W, McKay DG. Changes in the fibrinolytic enzyme system following intravascular coagulation induced by thrombin and endotoxin. Am J Obst Gynecol 1968; 100: 319-326
• 27 Waage A, Espevik T, Lamvik J. Detection of tumour necrosis factorlike cytoxicity in serum from patients with septicaemia but not from untreated cancer patients. Scand J Immunol 1986; 24: 739-743
• 28 Scuderi P, Sterling KE, Lam KS, Finley PR, Ryan KJ, Ray CG, Petersen E, Slymen DJ, Salmon SE. Raised serum levels of tumor necrosis factor in parasitic infections. Lancet 1986; 2: 1364-1365
• 29 Waage A, Halstensen A, Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1987; 2: 355-7
• 30 Girardin E, Grau GE, Dayer J-M, Roux-Lombard P. The J5 Study Group, Lambert P H. Tumour necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 1988; 319: 397-400
• 31 Michie HR, Manogue KR, Spriggs DR, Revhaug A, O’Dwyer S, Dinarello CA, Cerami A, Wolff SM, Wilmore DW. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481-1486
• 32 De Groote MA, Martin MA, Densen P, Pfaller MA, Wenzel RP. Plasma tumor necrosis factor levels in patients with presumed sepsis. Results in those treated with antilipid A antibody vs placebo. JAMA 1989; 262: 249-251
• 33 Medina R, Socher SH, Han JH, Friedman PA. Interleukin-1, endotoxin or tumor necrosis factor/cachectin enhance the level of plasminogen activator inhibitor messenger RNA in bovine aortic endothelial cells. Thromb Res 1989; 54: 41-52
• 34 Ziegler EJ. Tumor necrosis factor in humans. N Engl J Med 1988; 318: 1533-1535
• 35 Gómez C, Páramo JA, Colucci M, Rocha E. Effect of heparin and/or antithrombin III on the generation of endotoxin-induced plasminogen activator inhibitor. Thromb Haemostas 1989; 62: 694-698
• 36 Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985; 269: 869-871
• 37 Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330: 662-664