Fibrinolytic Response to lnterferon-a in Healthy Human Subjects

Summary

Interferons (IFNs) are used for a variety of disorders. It has been postulated that part of the effects of IFN may be mediated by IFN-induced modulation of endothelial cells. Since the principal activating and inhibiting factors of the fibrinolytic system are synthesized and stored in endothelial cells, we have studied the effects on fibrinolysis and coagulation of the administration of recombinant IFN-α (5 × 10⁶U/m²) to healthy human subjects (n = 8) in a randomized controlled cross-over study. IFN-α significantly increased plasma levels of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Simultaneously, plasma levels of the inhibitor of plasminogen activation, PAI-1, sharply increased. The net effect on plasma plasminogen activator activity (PA-activity) was a modest increase to 116% of baseline, however without a significant effect on plasmin generation, as reflected by plasma levels of plasmin-α₂-antiplasmin complexes. IFN-α had no effect on the plasma levels of thrombin-antithrombin III (TAT) complexes.

We conclude that despite considerable effects on endothelial cells, IFN-α does not significantly alter the coagulant-fibrinolytic balance, although the occurrence of such changes under pathological circumstances is not excluded.

• References

• 1 Baron S, Tyring SK, Fleischmann R, Coppenhaver DH, Niesei DW, Klimpel GR, Stanton J, Hughes TK. The interferons. Mechanism of action and clinical applications. JAMA 1991; 266: 1375-1381
• 2 Taylor JR, Grossberg SE. Recent progress in interferon research: molecular mechanisms of regulation, action, and virus circumvention. Virus Res 1990; 15: 01-25
• 3 Weil J, Epstein CJ, Epstein LB. A unique set of polypeptides is induced by y interferon in addition to those induced in common with α and β interferons. Nature 1983; 301: 437-439
• 4 Doukas J, Pober JS. Gamma interferon enhances endothelial cell activation induced by tumor necrosis factor but not interleukin 1. J Immunol 1990; 145: 1727-1733
• 5 Stolpen AH, Guinan EC, Fiers W, Pober JS. Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am J Pathol 1986; 123: 16-24
• 6 Levin EG, Loskutoff DJ. Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activator. J Cell Biol 1982; 94: 631-636
• 7 Loskutoff DJ, van Mourik JA, Erickson LA, Lawrence D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci USA 1983; 80: 2956-2960
• 8 Gyetko MR, Shollenberger SB, Sitrin RG. Urokinase expression in mononuclear phagocytes: cytokine-specific modulation by interferon-γ and tumor necrosis factor-α. J Leucoc Biol 1992; 51: 256-260
• 9 Smith TJ, Ahmed A, Hogg MG, Higgins PJ. Interferon is an inducer of plasminogen activator type 1 in human orbital fibroblasts. Am J Physiol 1992; 263: C24-C29
• 10 Murphy P, Hart DA. Modulation of plasminogen activator and plasminogen activator inhibitor expression in the human U373 glioblastoma/astrocytoma cell line by inflammatory mediators. Exp Cell Res 1992; 198: 093-100
• 11 Sirén V, Immonen I, Cantell K, Vaheri A. Alpha- and gamma interferon inhibit plasminogen activator inhibitor-1 gene expression in human retinal pigment epithelial cells. Ophthalm Res 1964; 26: 1-7
• 12 Verheijen JH, Mullaart E, Chang GTG, Kluft C, Wijngaards G. A simple sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemost 1982; 48: 266-269
• 13 Van Zonneveld AJ, Veerman H, Brakenhoff JPJ, Aarden LA, Cajot JF, Pannekoek H. Mapping of epitopes on human tissue-type plasminogen activator with recombinant deletion mutant proteins. Thromb Haemost 1987; 57: 82-86
• 14 Binnema DJ, van Iersel JJL, Dooijewaard G. Quantitation of urokinase antigen in plasma and culture media by use of an ELISA. Thromb Res 1986; 43: 569-573
• 15 De Boer JP, Abbink JJ, Brouwer MC, Meijer C, Roem D, Voom GP, Lambers WJ, van Mourik JA, Hack CE. PAI-1 synthesis in the human hepatoma cell line Hep G2 is increased by cytokines - Evidence that the liver contributes to acute phase behaviour of PAI-1. Thromb Haemost 1991; 65: 181-185
• 16 Verheijen JH, Chang GTG, Kluft C. Evidence for the occurrence of a fast-acting inhibitor for tissue-type plasminogen activator in human plasma. Thromb Haemost 1984; 51: 392-395
• 17 Levi M, de Boer JP, Roem D, ten Cate JW, Hack CE. Plasminogen activation in vivo upon intravenous infusion of DDAVP. Quantitative assessment of plasmin-α₂-antiplasmin complex with a novel monoclonal antibody based radioimmunoassay. Thromb Haemost 1992; 67: 111-116
• 18 Niedbala MJ, Picarella MS. Tumor necrosis factor induction of endothelial cell urokinase-type plasminogen activator mediated proteolysis of extracellular matrix and its antagonism by γ-interferon. Blood 1992; 79: 678-687
• 19 Wojta J, Zoellner H, Gallicchio M, Hamilton JA, McGrath K. Interferon counteracts interleukin-la stimulated expression of urokinase-type plasminogen activator in human endothelial cells in vitro. Biochem Biophys Res Comm 1992; 188: 463-469
• 20 Zuchella M, Pacchiarini L, Meloni F, Ballabio P, Saporiti A, Brocchieri A, Grignani G. Effect of interferon alpha, interferon gamma and tumor necrosis factor on the procoagulant activity of human cancer cells. Haematologica 1993; 78: 282-286
• 21 Biemond BJ, Levi M, ten Cate H, van der Poll T, Büller H, Hack CE, ten Cate JW. Endotoxin-induced activation and inhibition of the fibrinolytic system: effects of various interventions in the cytokine and coagulation cascades in experimental endotoxemia in chimpanzees. Clin Science 1995 in press
• 22 van der Poll T, Levi M, Büller HR, van Deventer SJH, de Boer JP, Hack CE, ten Cate JW. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991; 174: 729-732
• 23 Jansen P, Boermeester MA, Fischer E, de Jong IW, van der Poll T, Moldawer LL, Hack CE, Lowry SF. Contribution of interleukin-1 to activation of coagulation and fibrinolysis, to neutrophil degranulation and the release of sPLA2 in sepsis. Blood 1995 in press
• 24 Baars JW, de Boer JP, Wagstaff J, Roem D, Eerenberg-Belmer AJM, Nauta J, Pinedo HM, Hack CE. Interleukin-2 induces activation of coagulation and fibrinolysis: resemblance to the changes seen during experimental endotoxaemia. Br J Haematol 1992; 82: 295-301
• 25 Mestries JC, Kruithof EKO, Gascon MP, Herodin F, Agay D, Ythier A. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw 1994; 5: 275-281
• 26 Juhan Vague I, Alessi MC. Plasminogen activator inhibitor-1 and athero-thrombosis. Thromb Haemost 1993; 70: 138-143
• 27 Levi M, Wilmink JM, Büller HR, Surachno J, ten Cate JW. Impaired fibrinolysis in cyclosporin-treated renal transplant patients. Transplantation 1992; 54: 978-983