Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Jan;93(1):114–120. doi: 10.1172/JCI116934

Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees.

M Levi 1, H ten Cate 1, K A Bauer 1, T van der Poll 1, T S Edgington 1, H R Büller 1, S J van Deventer 1, C E Hack 1, J W ten Cate 1, R D Rosenberg 1
PMCID: PMC293743  PMID: 8282778

Abstract

Knowledge of the pathogenetic mechanisms responsible for the activation of the coagulation system associated with endotoxemia is important for the development of improved modalities for prevention and treatment. We analyzed the appearance in plasma of TNF, IL-6, and indices of coagulation and fibrinolytic system activation in normal chimpanzees after intravenous infusion of endotoxin. Endotoxin infusion elicited reproducible and dose-dependent elevations in serum TNF and IL-6, as well as marked increases in thrombin generation in vivo as measured by immunoassays for prothrombin activation fragment F1 + 2, thrombin-antithrombin III complexes, and fibrinopeptide A. Activation of the fibrinolytic mechanism was monitored with assays for plasminogen activator activity and plasmin-alpha 2-antiplasmin complexes. To potentially intervene in the molecular pathways elicited by endotoxin, pentoxifylline, an agent that interrupts "immediate early" gene activation by monocytes, or a potent monoclonal antibody that neutralizes tissue factor-mediated initiation of coagulation, were infused shortly before endotoxin. Pentoxifylline markedly inhibited increases in the levels of TNF and IL-6, as well as the effects on coagulation and fibrinolysis. In contrast, the monoclonal antibody to tissue factor completely abrogated the augmentation in thrombin generation, but had no effect on cytokine levels or fibrinolysis. We conclude that the endotoxin-induced activation of coagulation appears to be mediated by the tissue factor-dependent pathway, the fibrinolytic response triggered by endotoxin is not dependent on the generation of thrombin, and that the release of cytokines may be important in mediating the activation of both the coagulation and the fibrinolytic mechanisms in vivo.

Full text

PDF
114

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bauer K. A., Kass B. L., ten Cate H., Bednarek M. A., Hawiger J. J., Rosenberg R. D. Detection of factor X activation in humans. Blood. 1989 Nov 1;74(6):2007–2015. [PubMed] [Google Scholar]
  2. Bauer K. A., Kass B. L., ten Cate H., Hawiger J. J., Rosenberg R. D. Factor IX is activated in vivo by the tissue factor mechanism. Blood. 1990 Aug 15;76(4):731–736. [PubMed] [Google Scholar]
  3. Bauer K. A., ten Cate H., Barzegar S., Spriggs D. R., Sherman M. L., Rosenberg R. D. Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans. Blood. 1989 Jul;74(1):165–172. [PubMed] [Google Scholar]
  4. Bevilacqua M. P., Pober J. S., Majeau G. R., Fiers W., Cotran R. S., Gimbrone M. A., Jr Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4533–4537. doi: 10.1073/pnas.83.12.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Colucci M., Balconi G., Lorenzet R., Pietra A., Locati D., Donati M. B., Semeraro N. Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest. 1983 Jun;71(6):1893–1896. doi: 10.1172/JCI110945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Conway E. M., Bach R., Rosenberg R. D., Konigsberg W. H. Tumor necrosis factor enhances expression of tissue factor mRNA in endothelial cells. Thromb Res. 1989 Feb 1;53(3):231–241. doi: 10.1016/0049-3848(89)90098-4. [DOI] [PubMed] [Google Scholar]
  7. GREENWOOD F. C., HUNTER W. M., GLOVER J. S. THE PREPARATION OF I-131-LABELLED HUMAN GROWTH HORMONE OF HIGH SPECIFIC RADIOACTIVITY. Biochem J. 1963 Oct;89:114–123. doi: 10.1042/bj0890114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grabarek J., Timmons S., Hawiger J. Modulation of human platelet protein kinase C by endotoxic lipid A. J Clin Invest. 1988 Sep;82(3):964–971. doi: 10.1172/JCI113705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gregory S. A., Morrissey J. H., Edgington T. S. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol Cell Biol. 1989 Jun;9(6):2752–2755. doi: 10.1128/mcb.9.6.2752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Han J., Thompson P., Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med. 1990 Jul 1;172(1):391–394. doi: 10.1084/jem.172.1.391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hawiger J., Hawiger A., Steckley S., Timmons S., Cheng C. Membrane changes in human platelets induced by lipopolysaccharide endotoxin. Br J Haematol. 1977 Feb;35(2):285–299. doi: 10.1111/j.1365-2141.1977.tb00585.x. [DOI] [PubMed] [Google Scholar]
  12. Helle M., Boeije L., de Groot E., de Vos A., Aarden L. Sensitive ELISA for interleukin-6. Detection of IL-6 in biological fluids: synovial fluids and sera. J Immunol Methods. 1991 Apr 8;138(1):47–56. doi: 10.1016/0022-1759(91)90063-l. [DOI] [PubMed] [Google Scholar]
  13. Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
  14. Moore K. L., Andreoli S. P., Esmon N. L., Esmon C. T., Bang N. U. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest. 1987 Jan;79(1):124–130. doi: 10.1172/JCI112772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nawroth P. P., Stern D. M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986 Mar 1;163(3):740–745. doi: 10.1084/jem.163.3.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nosslin B. Analysis of disappearance time-curves after single injection of labelled proteins. Ciba Found Symp. 1972;9:113–130. doi: 10.1002/9780470719923.ch7. [DOI] [PubMed] [Google Scholar]
  17. Nuijens J. H., Huijbregts C. C., Eerenberg-Belmer A. J., Abbink J. J., Strack van Schijndel R. J., Felt-Bersma R. J., Thijs L. G., Hack C. E. Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(-)-inhibitor complexes in sepsis. Blood. 1988 Dec;72(6):1841–1848. [PubMed] [Google Scholar]
  18. Ollivier V., Houssaye S., Ternisien C., Léon A., de Verneuil H., Elbim C., Mackman N., Edgington T. S., de Prost D. Endotoxin-induced tissue factor messenger RNA in human monocytes is negatively regulated by a cyclic AMP-dependent mechanism. Blood. 1993 Feb 15;81(4):973–979. [PubMed] [Google Scholar]
  19. Pixley R. A., De La Cadena R., Page J. D., Kaufman N., Wyshock E. G., Chang A., Taylor F. B., Jr, Colman R. W. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons. J Clin Invest. 1993 Jan;91(1):61–68. doi: 10.1172/JCI116201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ruf W., Edgington T. S. An anti-tissue factor monoclonal antibody which inhibits TF.VIIa complex is a potent anticoagulant in plasma. Thromb Haemost. 1991 Nov 1;66(5):529–533. [PubMed] [Google Scholar]
  21. Schleef R. R., Bevilacqua M. P., Sawdey M., Gimbrone M. A., Jr, Loskutoff D. J. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. J Biol Chem. 1988 Apr 25;263(12):5797–5803. [PubMed] [Google Scholar]
  22. Suffredini A. F., Harpel P. C., Parrillo J. E. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med. 1989 May 4;320(18):1165–1172. doi: 10.1056/NEJM198905043201802. [DOI] [PubMed] [Google Scholar]
  23. Taylor F. B., Jr, Chang A., Ruf W., Morrissey J. H., Hinshaw L., Catlett R., Blick K., Edgington T. S. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock. 1991 Mar;33(3):127–134. [PubMed] [Google Scholar]
  24. Teitel J. M., Bauer K. A., Lau H. K., Rosenberg R. D. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1 + 2 fragment and thrombin--antithrombin complex. Blood. 1982 May;59(5):1086–1097. [PubMed] [Google Scholar]
  25. Verheijen J. H., Mullaart E., Chang G. T., Kluft C., Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemost. 1982 Dec 27;48(3):266–269. [PubMed] [Google Scholar]
  26. Zabel P., Wolter D. T., Schönharting M. M., Schade U. F. Oxpentifylline in endotoxaemia. Lancet. 1989 Dec 23;2(8678-8679):1474–1477. doi: 10.1016/s0140-6736(89)92929-2. [DOI] [PubMed] [Google Scholar]
  27. de Smet B. J., de Boer J. P., Agterberg J., Rigter G., Bleeker W. K., Hack C. E. Clearance of human native, proteinase-complexed, and proteolytically inactivated C1-inhibitor in rats. Blood. 1993 Jan 1;81(1):56–61. [PubMed] [Google Scholar]
  28. ten Cate H., Bauer K. A., Levi M., Edgington T. S., Sublett R. D., Barzegar S., Kass B. L., Rosenberg R. D. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest. 1993 Sep;92(3):1207–1212. doi: 10.1172/JCI116691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. van Deventer S. J., Büller H. R., ten Cate J. W., Aarden L. A., Hack C. E., Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990 Dec 15;76(12):2520–2526. [PubMed] [Google Scholar]
  30. van Hinsbergh V. W., Bauer K. A., Kooistra T., Kluft C., Dooijewaard G., Sherman M. L., Nieuwenhuizen W. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. Blood. 1990 Dec 1;76(11):2284–2289. [PubMed] [Google Scholar]
  31. van Hinsbergh V. W., Kooistra T., van den Berg E. A., Princen H. M., Fiers W., Emeis J. J. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood. 1988 Nov;72(5):1467–1473. [PubMed] [Google Scholar]
  32. van der Poll T., Büller H. R., ten Cate H., Wortel C. H., Bauer K. A., van Deventer S. J., Hack C. E., Sauerwein H. P., Rosenberg R. D., ten Cate J. W. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med. 1990 Jun 7;322(23):1622–1627. doi: 10.1056/NEJM199006073222302. [DOI] [PubMed] [Google Scholar]
  33. van der Poll T., Levi M., Büller H. R., van Deventer S. J., de Boer J. P., Hack C. E., ten Cate J. W. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med. 1991 Sep 1;174(3):729–732. doi: 10.1084/jem.174.3.729. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES