Download PDF
Thromb Haemost 1997; 77(05): 0905-0910
DOI: 10.1055/s-0038-1656076
Coagulation
Schattauer GmbH Stuttgart

The Coagulation and Fibrinolytic Responses of Baboons after In Vivo Thrombin Generation – Effect of Interleukin 6

Egbert K O Kruithof
1   The Division of Angiology and Hemostasis, University Hospital, Geneva, Switzerland; Ares Serono, Geneva, Switzerland
,
Jean Claude Mestries
2   The Department of Radiobiology, CRSSA, La Tronche, France
,
Marie-Paule Gascon
3   The Preclinical Pharmacology Department, Ares Serono, Geneva, Switzerland
,
Arnaud Ythier
3   The Preclinical Pharmacology Department, Ares Serono, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

Received 17 September 1996

Accepted after resubmission 10 January 1997

Publication Date:
11 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Disseminated intravascular coagulation (DIC) may lead to severe thrombotic or hemorrhagic complications. The present work was undertaken to study the effect of interleukin 6 (IL-6) on variations of key coagulation and fibrinolytic parameters in plasma in a baboon model of experimental DIC induced by injection of factor Xa and phospholipids at dosages leading to partial (48%) or complete fibrinogen depletion. Transient increases of D-dimer, fibrinopeptide A, thrombin-antithrombin and the activated partial thromboplastin time were observed. Each parameter had a particular (time and Xa/phospho- lipid dose dependent) pattern of changes. The principal effect of IL-6 was a more rapid restoration of fibrinogen concentrations and of overall coagulation tests. Injection of factor Xa/phospholipids led also to a rapid increase of tissue-type plasminogen activator (t-PA) the extent of which was dependent on Xa/phospholipid dose. Pretreatment with IL-6 induced a threefold increase of basal t-PA and a corresponding increase of the t-PA response. Plasminogen activator inhibitor type 1 (PAI-1) concentrations did not change after low dose Xa/phospholipids, but increased eightfold after high dose Xa/phospholipids. IL-6 pretreatment induced within 8 h a twentyfold increase of PAI-1 but no further increase was observed after injection of factor Xa/phospholipids.

Thus, in vivo thrombin generation leads to dynamic modifications of the coagulation and fibrinolytic systems. The principal effect of IL-6 is a more rapid normalization of overall coagulation tests, due to normalization of fibrinogen, and an increased t-PA release response which is partially counteracted by increased PAI-1 concentrations.

 

  • References

  • 1 Hardaway RM. Organ damage in shock, disseminated intravascular coagulation, and stroke. Compr Ther 1992; 18: 17-21
    PubMedGoogle Scholar
  • 2 Levi M, Ten CateH, Van derPoll T, Van DeventerSJH. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270: 975-979
    CrossrefPubMedGoogle Scholar
  • 3 Taylor FB, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in baboons. J Clin Invest 1987; 79: 918-925
    CrossrefPubMedGoogle Scholar
  • 4 Emerson TE, Fournel MA, Redens TB, Taylor FB. Efficacy of antithrombin 111 supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia. Am J Med 1989; 87 (Suppl. 03) 27-35
    CrossrefPubMedGoogle Scholar
  • 5 Creasey AA, Chang ACK, Feigen L, Wun TC, Taylor FB, Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-2860
    CrossrefPubMedGoogle Scholar
  • 6 Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E, Yamazaki M, Matsuda T. Changes in plasma levels of tissue-plasminogen activator/inhibitor complex and active plasminogen activator inhibitor in patients with disseminated intravascular coagulation. Am J Hematol 1991; 36: 176-183
    CrossrefPubMedGoogle Scholar
  • 7 Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E, Yamazaki M, Aoshima K, Matsuda T. Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers. Blood Coagul Fibrinolysis 1994; 5: 829-832
    CrossrefPubMedGoogle Scholar
  • 8 Giles AR, Nesheim ME, Herring SW, Hoogendoom H, Stump DC, Heldebrant CM. The fibrinolytic potential of the normal primate following the generation of thrombin in vivo. Thromb Haemost 1990; 63: 476-481
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Wada H, Tanigawa M, Wakita Y, Nakase T, Minamikawa K, Kaneko T, Ohiwa M, Kageyama S, Kobayashi T, Noguchi T, Deguchi K, Shirakawa S. Increased plasma level of interleukin-6 in disseminated intravascular coagulation. Blood Coagul Fibrinolysis 1993; 4: 583-590
    CrossrefPubMedGoogle Scholar
  • 10 Van derPoll T, Büller HR, Ten CateH, Wortel CH, Bauer KA, Van DeventerSJH, Hack CE, Sauerwein HP, Rosenberg RD, Ten CateJW. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990; 322: 1622-1627
    CrossrefPubMedGoogle Scholar
  • 11 Van derPoll T, Levi M, Hack CE, Ten CateH, Van DeventerSJH, Eerenberg AJM, De GrootER, Jansen J, Gallati H, Biiller HR, Ten CateJW, Aarden LA. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179: 1253-1259
    CrossrefPubMedGoogle Scholar
  • 12 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
    PubMedGoogle Scholar
  • 13 Jansen PM, Boermeester MA, Fischer E, De JongIW, Van derPoll T, Moldawer LL, Hack CE, Lowry SF. Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation and the release of secretory type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin 1 alpha adminstration and during lethal bacteremia. Blood 1995; 86: 1027-1034
    CrossrefPubMedGoogle Scholar
  • 14 Biemond BJ, Levi M, Ten CateH, Van derPoll T, Büller HR, Hack CE, Ten CateJW. Plasminogen activator and plasminogen activator inhibitor 1 release during experimental endotoxaemia in chimpanzees: Effect of interventions in the cytokine and coagulation cascades. Clin Sci 1995; 88: 587-594
    CrossrefPubMedGoogle Scholar
  • 15 Podor TJ, Hirsh J, Gelehrter TD, Zeheb R, Torry D, Guigoz Y, Sierra F, Gauldie J. Type 1 plasminogen activator inhibitor is not an acute phase reactant in rats. Lack of IL-6-and hepatocyte-dependent synthesis. J Immunol 1993; 150: 225-235
    PubMedGoogle Scholar
  • 16 Rubin N, Colman RW. Disseminated intravascular coagulation. Approach to treatment. Drugs 1992; 44: 963-971
    CrossrefPubMedGoogle Scholar
  • 17 Bauer KA, Weitz Jl. Laboratory markers of coagulation and fibrinolysis. In: Hemostasis and Thrombosis. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds Lippincott Company; Philadelphia: 1994. 3. pp 1197-1202
    Google Scholar
  • 18 Mirshahi M, Soria J, Soria C, Faivre R, Lu H, Courtney M, Roitsch C, Tripier D, Caen JP. Evaluation of the inhibition by heparin and hirudin of coagulation activation during r-tPA-induced thrombolysis. Blood 1989; 74: 1025-1030
    PubMedGoogle Scholar
  • 19 Weitz Jl, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin 111 but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J Clin Invest 1990; 86: 385-391
    CrossrefPubMedGoogle Scholar
  • 20 Van denEijnden-Schrauwen Y, Kooistra T, De VriesREM, Emeis JJ. Studies on the acute release of tissue-type plasminogen activator from human endothelial cells in vitro and rats in vivo: evidence for a dynamic storage pool. Blood 1995; 85: 3510-3517
    CrossrefPubMedGoogle Scholar
  • 21 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1994; 342: 1076-1079
    PubMedGoogle Scholar
  • 22 Thompson SG, Kienast J, Pyke SD, Haverkate F, Van DeLoo JC. the ECAT study group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-641
    CrossrefPubMedGoogle Scholar
  • 23 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-1168
    CrossrefPubMedGoogle Scholar