Download PDF
Thromb Haemost 2000; 84(05): 764-769
DOI: 10.1055/s-0037-1614112
Review Article
Schattauer GmbH

Pentoxifylline Prevents Upregulation of Monocyte Tissue Factor in Renal Transplant Recipients Undergoing Post-graft Complications

Sophie Susen
1   From the Laboratoire d’Hématologie, Lille, France
,
Marc Hazzan
2   Service de Néphrologie-Hémodialyse-Transplantation, Lille, France
,
Myriam Labalette
3   Laboratoire d’Immunologie, Centre Hospitalier Regional Universitaire, Lille, France
,
Christophe Zawadzki
1   From the Laboratoire d’Hématologie, Lille, France
,
Jean Paul Dessaint
3   Laboratoire d’Immunologie, Centre Hospitalier Regional Universitaire, Lille, France
,
Gaston Lelièvre
2   Service de Néphrologie-Hémodialyse-Transplantation, Lille, France
,
Brigitte Jude
1   From the Laboratoire d’Hématologie, Lille, France
,
Christian Noël
2   Service de Néphrologie-Hémodialyse-Transplantation, Lille, France
› Author AffiliationsThe authors thank Dr. Alain Duhamel (Laboratory of Biostatistics, CHRU of Lille) for his help in statistical analysis. This work was supported by grants from Direction de la Recherche et des Etudes Doctorales (EA 2693 and 2686), the Centre Hospitalier Regional Universitaire of Lille, and Region Nord Pas de Calais.
Further Information

Publication History

Received 21 October 1999

Accepted after resubmission 23 May 2000

Publication Date:
13 December 2017 (online)

    Permissions and Reprints

Summary

Pentoxifylline (PTX) has been demonstrated to improve graft survival in renal transplant recipients undergoing post graft complications. As activated monocytes are possible initiators of vascular damage through tissue factor (TF) expression, we evaluated the monocyte TF expression and endothelium activation markers in 140 consecutive patients receiving cadaveric kidney grafts, randomized in a double-blind study comparing PTX versus placebo. Monocyte TF expression and plasma von Willebrand factor, tissue plasminogen activator, thrombomodulin and tumor necrosis factor-α (TNF-α) levels were determined before transplantation and each month after. Additional samplings were realized in case of acute rejection. TF and TNF-α expression were significantly modified after graft. In patients with complications, PTX prevented the increase of TF expression at month one, and after rejection episodes. Endothelium activation markers were significantly modified after graft and in patients with complications but PTX had no significant effect on their plasma levels. These results suggest that the protective effect of PTX on graft survival could be related to the prevention of monocyte TF upregulation associated with complications.

Key words

Pentoxyfilline - tissue factor - renal transplantation - endothelium
 

  • References

  • 1 Nemerson Y. Tissue factor and hemostasis. Blood 1988; 71: 71-8.
    PubMedGoogle Scholar
  • 2 Taylor FBJ, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, Blick K, Edgington TS. Letahl E. Coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-34.
    PubMedGoogle Scholar
  • 3 Rao LVM. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev 1992; 11: 249-66.
    CrossrefPubMedGoogle Scholar
  • 4 Jude B, Agraou B, McFadden EP, Susen S, Bauters C, Lepelley P, Vanhaesbroucke C, Devos P, Cosson A, Asseman P. Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina. Circulation 1994; 90: 1662-8.
    CrossrefPubMedGoogle Scholar
  • 5 Edgington TS, Mackman N, Ruf W. The structural biology of expression and function of tissue factor. Thromb Haemost 1991; 66: 67-79.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Helin H, Edgington TS. Allogeneic induction of the human T cell-instructed monocyte procoagulant response is rapid and is elicited by HLA-DR. J Exp Med 1983; 158: 962-75.
    CrossrefPubMedGoogle Scholar
  • 7 Rothberger H, Barringer M, Meredith J. Increased tissue factor activity of monocytes/macrophages isolated from canine renal allografts. Blood 1984; 63: 623-8.
    PubMedGoogle Scholar
  • 8 Hancock WW, Gee D, De MP, Rickles FR, Ewan VA, Atkins RC. Immunohistological analysis of serial biopsies taken during human renal allograft rejection. Changing profile of infiltrating cells and activation of the coagulation system. Transplantation 1985; 39: 430-8.
    CrossrefPubMedGoogle Scholar
  • 9 Cole EH, Cardella CJ, Schulman J, Levy GA. Monocyte procoagulant activity and plasminogen activator. Role in human allograft rejection. Transplantation 1985; 40: 363-71.
    CrossrefPubMedGoogle Scholar
  • 10 Rothberger H, Meredith J, Mutton T, Brown J, Mc Gee MP. Increased tissue factor activity generation in vitro by canine blood leukocytes associated with allogeneic kidney transplantation and rejection. Thromb Haemost 1985; 53: 1-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Halloran P, Aprile M, Haddad G, Robinette M. The significance of elevated procoagulant activity in the monocytes of renal allograft. Transplant Proc 1982; 14: 669-72.
    PubMedGoogle Scholar
  • 12 Faulk WP, Gargiulo P, McIntyre JA, Bang NU. Hemostasis and fibrinolysis in renal transplantation. Semin Thromb Hemost 1989; 15: 88-98.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Fellstrom B, Siegbahn A, Liljenberg G, Haglund O, Wallin R, Tufveson G, Bagge L. Primary haemostasis, plasmatic coagulation and fibrinolysis in renal transplantation. Thromb Res 1990; 59: 97-104.
    CrossrefPubMedGoogle Scholar
  • 14 Torry RJ, Labarrere CA, Gargiulo P, Faulk WP. Natural anticoagulant and fibrinolytic pathways in renal allograft failure. Transplantation 1994; 58: 926-31.
    CrossrefPubMedGoogle Scholar
  • 15 Weill D, Wautier JL, Dosquet C, Wautier MP, Carreno MP, Boval B. Monocyte modulation of endothelial leukocyte adhesion molecules. J Lab Clin Med 1995; 125: 768-74.
    PubMedGoogle Scholar
  • 16 de Prost D. Pentoxifylline: a potential treatment for thrombosis associated with abnormal tissue factor expression by monocytes and endothelial cells. J Cardiovasc Pharmacol 1995; 25: 114-8.
    CrossrefPubMedGoogle Scholar
  • 17 Archipoff G, Beretz A, Brisson C. et al. Effects of pentoxifylline on the modulation by cytokines of thrombomodulin and tissue factor activities on the surface of human endothelial cells in culture. In: Hakim J, Mandell GL, Novick Jr WJ. eds. Pentoxifylline and analogues: effects on leucocyte function. Basel: Karger; 1990: 48-52.
    Google Scholar
  • 18 Noël C, Hazzan M, Labalette M, Coppin MC, Jude B, Dessaint JP, Lelievre G. Improvement in the outcome of rejection with pentoxifylline in renal transplantation. Transplantation 1998; 65: 385-9.
    CrossrefPubMedGoogle Scholar
  • 19 Carson SD, Archer PG. Tissue factor activity in HeLa cells measured with a continuous chromogenic assay and ELISA reader. Thromb Res 1986; 15; 41: 185-95.
    CrossrefPubMedGoogle Scholar
  • 20 Bottles KD, Morrissey JH. Dexamethasone enhances agonist induction of tissue factor in monocytes but not in endothelial cells. Blood Coag Fibrinol 1993; 04: 405-13.
    CrossrefPubMedGoogle Scholar
  • 21 Gregory SA, Edgington TS. Tissue factor induction in human monocytes. Two distinct mechanisms displayed by different alloantigen-responsive T cell clones. J Clin Invest 1985; 76: 2440-5.
    CrossrefPubMedGoogle Scholar
  • 22 Carlsen E, Flatmark A, Prydz H. Cytokine-induced procoagulant activity in monocytes and endothelial cells. Transplantation 1988; 46: 575-80.
    CrossrefPubMedGoogle Scholar
  • 23 Iitaka M, Iwatani Y, Row VV, Volpe R. Induction of monocyte procoagulant activity with OKT3 antibody. J Immunol 1987; 139: 1617-23.
    PubMedGoogle Scholar
  • 24 Pradier O, Surquin M, Stordeur P, De Pauw L, Kinnaert P, Vereerstraeten P, Capel P, Goldman M, Abramowicz D. Monocyte procoagulant activity induced by in vivo administration of the OKT3 monoclonal antibody. Blood 1996; 87: 3768-74.
    PubMedGoogle Scholar
  • 25 Ollivier V, Ternisien C, Vu T, Hakim J, de Prost D. Pentoxifylline inhibits the expression of tissue factor mRNA in endotoxin-activated human monocytes. FEBS Lett 1993; 322: 231-4.
    CrossrefPubMedGoogle Scholar
  • 26 Ramani M, Khechai F, Ollivier V, Ternisien C, Bridey F, Hakim J, de Prost D. Interleukin-10 and pentoxifylline inhibit C reactive protein-induced tissue factor gene expression in peripheral human monocytes. FEBS Lett 1994; 356: 86-8.
    CrossrefPubMedGoogle Scholar
  • 27 Amirkhosravi A, Meyer T, Warnes G, Amaya M, Malik Z, Biggerstaff JP, Siddiqui FA, Sherman P, Francis JL. Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelal growth factor. Thromb Haemost 1998; 80: 598-602.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Kopp CW, Robson SC, Siegel JB, Anrather J, Winkler H, Grey S, Kaczmarek E, Bach FH, Geczy CL. Regulation of monocyte tissue factor activity by allogeneic and xenogeneic endothelial cells. Thromb Haemost 1998; 79: 529-38.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Shulman H, Striker G, Deeg HJ, Kennedy M, Strob R, Thoma ED. Nephrotoxicity of cyclosporine A after allogenic marrow transplantation: glomerular thrombosis and tubular injury. N Engl J Med 1981; 305: 1392-4.
    CrossrefPubMedGoogle Scholar
  • 30 Neild GH, Reuben R, Hartley RB, Cameron JS. Glomerular thrombi in renal allografts associated with cyclosporine treatment. J Clin Pathol 1985; 38: 253-8.
    CrossrefPubMedGoogle Scholar
  • 31 Chouhury M, Neild GH, Brown Z, Cameron JS. Thromboembolic complications in cyclosporine treated kidney allograft recipients. Lancet 1985; 02: 606-7.
    PubMedGoogle Scholar
  • 32 Carlsen E, Gaudernack G, Filion-Myklebust C, Pettersen KS, Prydz H. Allogenic induction of thromboplastin synthesis in monocytes and endothelial cells. Biphasic effect of cyclosporin A. Clin Exp Immunol 1989; 76: 428-33.
    PubMedGoogle Scholar
  • 33 Hölschermann H, Kohl O, Maus U, Dürfeld F, Bierhaus A, Nawroth PD, Lohmeyer J, Tillmans H, Haberbosch W. Cyclosporin A inhibits monocyte tissue factor activation in cardiac transplant recipients. Circulation 1997; 96: 4232-8.
    CrossrefPubMedGoogle Scholar
  • 34 Noël C, Hazzan M, Coppin MC, Codaccioni MX, Pruvot FR, Labalette M, Lelievre G. A randomized controlled trial of pentoxifylline for the prevention of the delayed graft function in cadaveric kidney graft. Clin Transplantation 1997; 11: 169-73.
    PubMedGoogle Scholar
  • 35 Mannucci PM. von Willebrand Factor a marker of endothelial damage?. Arterioscler Thomb Vasc Biol 1998; 18: 1359-62.
    CrossrefPubMedGoogle Scholar
  • 36 Ridker PM, Vaughan DE, Stampfer MS, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
    CrossrefPubMedGoogle Scholar
  • 37 Ridker PM, Hennekens CH, Stampfer MS, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-3.
    CrossrefPubMedGoogle Scholar
  • 38 Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost 1991; 65: 618-23.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 van den Eijden-Schrauwen Y, Kooistra T, de Vries RE, Emeis JJ. Studies on the acute release of tissue-type plasminogen activator from human endothelial cells in vitro and in rats in vivo: evidence for a dynamic storage pool. Blood 1995; 85: 3510-7.
    PubMedGoogle Scholar
  • 40 Huser B, Lammle B, Landmann J, Tran TH, Oberholzer M, Marbet GA, Thiel G, Mihatsch MJ, Duckert F. von Willebrand factor and factor VIII in renal transplant recipients under immunosuppression with cyclosporine and steroids. Sequential measurements over 4 months in 17 patients. Clin Nephrol 1990; 34: 214-22.
    PubMedGoogle Scholar
  • 41 Wang Y, Pratt JR, Hartley B, Evans B, Zhang L, Sacks SH. Expression of tissue type plasminogen activator and type 1 plasminogen activator inhibitor, and persistent fibrin deposition in chronic renal allograft failure. Kidney Int 1997; 52: 371-7.
    CrossrefPubMedGoogle Scholar
  • 42 Deira J, Alberca I, Lerma JL, Martin B, Tabernero JM. Changes in coagulation and fibrinolysis in the postoperative period immediately after kidney transplantation in patients receiving OKT3 or cyclosporine A as induction therapy. Am J Kidney Dis 1998; 32: 575-81.
    CrossrefPubMedGoogle Scholar
  • 43 Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M. The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients. Transplantation 1996; 27; 62: 828-30.
    CrossrefPubMedGoogle Scholar
  • 44 Hergesell O, Andrassy K, Geberth S, Nawroth P, Gabath S. Plasma thrombomodulin levels are dependent on renal function. Thromb Res 1993; 72: 455-8.
    CrossrefPubMedGoogle Scholar
  • 45 Tomura S, Nakamura Y, Deguchi F, Chida Y, Ohno Y, Kodama S, Hayashi T, Suzuki K, Marumo F. Plasma von Willebrand factor and thrombomodulin as markers of vascular disorders in patients undergoing regular hemodialysis therapy. Thromb Res 1990; 58: 413-9.
    CrossrefPubMedGoogle Scholar
  • 46 Himmelreich G, Riewald M, Rosch R, Blumhard G, Neuhaus P, Roissant R, Riess H. Thrombomodulin: a marker for endothelial damage during orthotopic liver transplantation. Am J Hematol 1994; 47: 1-5.
    CrossrefPubMedGoogle Scholar
  • 47 Haznedaroglu IC, Erdem Y, Yalcin AU, Sayinalp NM, Yasavul U, Turgan C, Caglar S, Dundar S, Kirazli S. Circulating thrombomodulin as a molecular marker of endothelium damage in renal transplant recipients. Nephron 1996; 73: 486-7.
    CrossrefPubMedGoogle Scholar
  • 48 Vischer UM, Wollheim CB. Purine nucleotides induce regulated secretion of von Willebrand factor: involvement of cytosolic Ca2+ and cyclic adenosine monophosphate-dependent signaling in endothelial exocytosis. Blood 1998; 91: 118-27.
    PubMedGoogle Scholar
  • 49 Hegeman RJ, van den Eijnden-Schrauwen Y, Emeis JJ. Adenosine 3’:5’-cyclic monophosphate induces regulated secretion of tissue-type plasminogen activator and von Willebrand factor from cultured human endothelial cells. Thromb Haemost 1998; 79: 853-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Ishii H, Kizaki K, Uchiyama H, Horie S, Kazama M. Cyclic AMP increases thrombomodulin expression on membrane surface of cultured human umbilical vein endothelial cells. Thromb Res 1990; 59: 841-50.
    CrossrefPubMedGoogle Scholar
  • 51 Seigneur M, Dufourcq P, Belloc F, Lenoble M, Renard M, Boisseau MR. Influence of pentoxifylline on membrane thrombomodulin levels in endothelial cells submited to hypoxic conditions. J Cardiovasc Pharmacol 1995; 25: 85-7.
    CrossrefPubMedGoogle Scholar
  • 52 Ohdama S, Takano S, Ohashi K, Miyake S, Aoki N. Pentoxifylline prevents tumor necrosis factor-induced suppression of endothelial cell surface thrombomodulin. Thromb Res 1991; 62: 745-55.
    CrossrefPubMedGoogle Scholar