Download PDF
Thromb Haemost 1993; 69(02): 098-102
DOI: 10.1055/s-0038-1651562
Original Article
Clinical Studies
Schattauer GmbH Stuttgart

Reduction of Mortality with Antithrombin III in Septicemic Rats: A Study of Klebsiella pneumoniae Induced Sepsis

Gerhard Dickneite
The Research Laboratories of Behringwerke AG, Marburg/Lahn, Germany
,
Eric-Paul Pâques
The Research Laboratories of Behringwerke AG, Marburg/Lahn, Germany
› Author Affiliations
Further Information

Publication History

Received 10 March 1992

Accepted after revision 23 September 1992

Publication Date:
03 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Experimental gram-negative sepsis was induced in the rat by Klebsiella pneumoniae. Although bacteria are susceptible to the treatment with the antibiotic Tobramycin, DIC could not be prevented. DIC was manifested by a leuko- and thrombocytopenia, decreases in fibrinogen and AT III and an increase of the aPTT. In this model the therapeutic treatment with human AT III was evaluated. To determine the optimal concentration of AT III a prestudy in a LPS induced DIC in the rat was performed. It was shown that a bolus i. v. injection of 500 U/kg improved survival and DIC, and was thus chosen for the Klebsiella sepsis model. The infectious load was adjusted to yield a mortality rate of 90-100% in the untreated Klebsiella group and a reduction to about 40-50% of the mortality rate by Tobramycin. It was found that AT III reduced mortality in the Klebsiella induced sepsis not only when given prophylactically but was effective even when administrated in a late stage of the DIC, i. e. 3 or 5 h post infection.

 

  • References

  • 1 Weinstein L. Gram-negative bacterial infections: A look at the past, a view of the present, and a glance at the future. Rev Infect Dis 1985; 7: 538-544
    CrossrefPubMedGoogle Scholar
  • 2 Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740-745
    CrossrefPubMedGoogle Scholar
  • 3 McKay DG. Clinical significance of intravascular coagulation. In: Bibliotheca Haematologica, No. 49: Disseminated Intravascular Coagulation. Takeshi A, Yamanaka M. (eds). Basel: Karger; 1983: 63-78
    Google Scholar
  • 4 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
    CrossrefPubMedGoogle Scholar
  • 5 van Deventer SJH, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: Analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520-2526
    PubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 Nordenman B, Nyström C, Björk I. The size and shape of human and bovine antithrombin III. Eur J Biochem 1977; 78: 195-203
    CrossrefPubMedGoogle Scholar
  • 8 Soons H, Tans G, Hemker HC. The heparin-catalysed inhibition of human factor XIa by antithrombin III is dependent on the heparin type. Biochem J 1988; 256: 815-820
    CrossrefPubMedGoogle Scholar
  • 9 Pieters J, Willems G, Hemker HC, Lindhout T. Inhibition of factor IXa and factor Xa by antithrombin III/heparin during factor X activation. J Biol Chem 1988; 263: 15313-15318
    PubMedGoogle Scholar
  • 10 Stead N, Kaplan AP, Rosenberg RD. Inhibition of activated factor XII by antithrombin-heparin cofactor. J Biol Chem 1976; 251: 6481-6488
    PubMedGoogle Scholar
  • 11 Venneröd AM, Laake K, Solberg AK, Strömland S. Inactivation and binding of human plasma kallikrein by antithrombin III and heparin. Thromb Res 1976; 9: 457-466
    CrossrefPubMedGoogle Scholar
  • 12 Rosenberg RD. Actions and interactions of antithrombin and heparin. N Engl J Med 1975; 292: 146-151
    CrossrefPubMedGoogle Scholar
  • 13 Craig PA, Olson StT, Shore JD. Transient kinetics of heparin-catalyzed protease inactivation by antithrombin III. J Biol Chem 1989; 264: 5452-5461
    PubMedGoogle Scholar
  • 14 Brandtzaeg P, Sandset PM, Joo GB, Ovstebo R, Abildgaard U, Kierulf P. The quantitative association of plasma endotoxin, Antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. Thromb Res 1989; 55: 459-470
    CrossrefPubMedGoogle Scholar
  • 15 De Stefano V, Triolo L, De Martini D, Ferrelli R, Mori R, Leone G. Antithrombin III loss in patients with nephrotic syndrome or receiving continuous ambulatory peritoneal dialysis. Evidence of inactive antithrombin III in urine of patients with nephrotic syndrome. J Lab Clin Med 1987; 109: 550-555
    PubMedGoogle Scholar
  • 16 Castaman G, Ruggeri M, Rodeghiero F. Increased proteolysis of antithrombin III vicenza during disseminated intravascular coagulation in acute leukemia. Thromb Res 1989; 55: 661-664
    CrossrefPubMedGoogle Scholar
  • 17 Ono I, Ohura T, Hamamoto J, Umeda T, Ogura T. Clinical observations of coadministration of antithrombin III preparation with heparin in burned patients. J Burn Care Rehabil 1984; 5: 25-29
    CrossrefPubMedGoogle Scholar
  • 18 Blauhut B, Kramar H, Vinazzer H, Bergmann H. Substitution of antithrombin III in shock and DIC: a randomized study. Thromb Res 1985; 39: 81-89
    CrossrefPubMedGoogle Scholar
  • 19 Jochum M, Lander St, Heimburger N, Fritz H. Effect of human granulocytic elastase on isolated human antithrombin III. Hoppe-Seyler's Z Physiol Chem 1981; 362: 103-112
    PubMedGoogle Scholar
  • 20 Lämmle B, Tran TH, Ritz R, Duckert F. Plasma prekallikrein, factor XII, antithrombin III, Crinhibitor and α2-macroglobulin in critically III patients with suspected disseminated intravascular coagulation (DIC). Am J Clin Pathol 1984; 82: 396-404
    CrossrefPubMedGoogle Scholar
  • 21 Mammen EF, Miyakawa T, Phillipps TF, Assarian GS, Brown JM, Murano G. Human antithrombin concentrates and experimental disseminated intravascular coagulation. Semin Thromb Hemostas 1985; 11: 373-383
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Emerson. ThE Jr, Fornel WJ, Leach WJ, Redens ThB. Protection against disseminated intravascular coagulation and death by anti-thrombin-III in the Escherichia coli endotoxemic rat. Circ Shock 1987; 21: 1-13
    PubMedGoogle Scholar
  • 23 Triantaphyllopoulos DC. Effects of human antithrombin III on mortality and blood coagulation induced in rabbits by endotoxin. Thromb Haemostas 1984; 51: 232-235
    PubMedGoogle Scholar
  • 24 Taylor Jr FB, Emerson Jr TE, Jordan R, Chang AK, Blick KE. Antithrombin-III prevents the lethal effects of Escherichia coli infusion in baboons. Circ Shock 1988; 26: 227-235
    PubMedGoogle Scholar
  • 25 Mann Jr LT, Jensenius JC, Simonsen M, Abildgaard U. Antithrombin III: Protection against death after injection of thromboplastin. Science 1969; 166: 517-518
    CrossrefPubMedGoogle Scholar
  • 26 Brockmeier D, Lückel G, Hoerep-PC G. Interactive program package for the analysis of pharmacokinetic data. Frankfurt/Main: Internal Rep Hoechst AG. 1990
    PubMedGoogle Scholar
  • 27 Langner K, Lauffer L, Enßle K, Oquendo P, Kanzy EJ, Dickneite G, Kurrle R. Structural and functional analysis of a TNF receptor-immunoglobulin fusion protein. Florenz: Proceedingsband, 2nd Int Congress on Cytokines. 1992 22-6 March
    PubMedGoogle Scholar
  • 28 Rosenthal EJK. Causative organisms of septicaemia 1983–1985. Results of a multicentre study. Dtsch Med Wschr 1986; 111: 1874-1880
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Redens TB, Leach WJ, Bogdanoff DA, Emerson Jr. TE. Synergistic protection from lung damage by combining antithrombin-III and alpha1-proteinase inhibitor in the E. coli endotoxemic sheep pulmonary dysfunction model. Circ Shock 1988; 26: 15-26
    PubMedGoogle Scholar
  • 30 Maki M, Terao T, Ikenoue T, Takemura T, Sekiba K, Shirakawa K, Soma H. Clinical evaluation of antithrombin III concentrate (BI 6.013) for disseminated intravascular coagulation in obstetrics. Gynecol Obstet Invest 1987; 23: 230-240
    CrossrefPubMedGoogle Scholar
  • 31 Vinazzer H. Therapeutic use of antithrombin III in shock and disseminated intravascular coagulation. Semin Thromb Hemostas 1989; 15: 347-352
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Dihanich M, Monard D. cDNA sequence of rat prothrombin. Nucl Acids Res 1990; 18: 4251
    CrossrefPubMedGoogle Scholar