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Thromb Haemost 1998; 80(06): 1022-1026
DOI: 10.1055/s-0037-1615405
Letters to the Editor
Schattauer GmbH

Melagatran, a Low Molecular Weight Thrombin Inhibitor, Counteracts Endotoxin-induced Haemodynamic and Renal Dysfunctions in the Pig

Mats Eriksson
1   Departments of Anaesthesiology and Intensive Care
,
Anders Larsson
2   Clinical Chemistry
,
Tom Saldeen
3   Forensic Medicine, University Hospital, Uppsala
,
Christer Mattsson
4   Astra Hässle Preclinical Research and Development, Mölndal, Sweden
› Author Affiliations
Further Information

Publication History

Received 18 March 1998

Accepted after resubmission 28 August 1998

Publication Date:
07 December 2017 (online)

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Summary

Coagulation and fibrinolysis are crucial in septic shock and inhibition of thrombin may be beneficial in this circumstance. Since porcine endotoxaemia has been found to replicate severe septic shock, a low molecular weight thrombin inhibitor, melagatran, was infused during the first 3 out of 6 h of endotoxaemia in pigs. Plasma creatinine (p <0.01) and urinary output (p <0.05) were less affected in the melagatran + endotoxin group (n = 6) as compared to endotoxaemic controls (n = 9). The left ventricular stroke work index, systemic vascular resistance index and oxygen extraction were all less affected (p <0.05) by endotoxin during the infusion of melagatran. The plasma concentration of melagatran declined with an apparent plasma half-life of 5 h as soon as the infusion was stopped. APTT, however, continued to increase after the infusion of melagatran had stopped and reached a maximum of 113 s at 5 h (baseline 17 s). APTT in endotoxaemic control pigs reached a maximum of 22 s. Thus, melagatran may counteract some consequences of endotoxaemia.

 

  • References

  • 1 Griffin J. The thrombin paradox. Nature 1995; 378: 337-8.
    CrossrefPubMedGoogle Scholar
  • 2 Hoffman M, Cooper ST. Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms. Blood Cells 1995; 21: 156-67.
    PubMedGoogle Scholar
  • 3 Marks JD, Berman-Marks C, Luce JM, Montgomery AB, Turner J, Metz CA. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis 1990; 141: 94-7.
    CrossrefPubMedGoogle Scholar
  • 4 Hermann JP, Kutryk MJ, Serruys PW. Clinical trials of direct thrombin inhibitors during invasive procedures. Thromb Haemost 1997; 78: 367-76.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Verstraete M. Direct thrombin inhibitors: appraisal of the anti-thrombotic/hemorrhagic balance. Thromb Haemost 1997; 78: 357-63.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Stone R. Search for sepsis drugs goes on despite past failures. Science 1992; 264: 365-7.
    PubMedGoogle Scholar
  • 7 Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. The New England Journal of Medicine 1989; 321: 280-7.
    CrossrefPubMedGoogle Scholar
  • 8 Modig J. Adult respiratory distress syndrome. Comp Pathol Bull 1989; 21: 2-4.
    PubMedGoogle Scholar
  • 9 Eriksson M, Nelson D, Nordgren A, Larsson A. Increased platelet microvesicle formation is associated with mortality in a porcine model of endotoxaemia. Acta Anaesthesiol Scand 1998; 42: 551-7.
    CrossrefPubMedGoogle Scholar
  • 10 Bredengard C, Nordfang O, Wildgoose P, Svendsen O, Hedner U, Diness V. The effect of two-domain tissue factor pathway inhibitor on endotoxin-induced disseminated intravascular coagulation in rabbits. Blood Coagul Fibrinolysis 1993; 4: 699-706.
    CrossrefPubMedGoogle Scholar
  • 11 Yamazaki M, Asakura H, Aoshima K, Saito M, Jokaji H, Uotani C, Kumabashiri I, Morishita E, Ikeda T, Matsuda T. Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats. Thromb Haemost 1994; 72: 392-6.
    PubMedGoogle Scholar
  • 12 Spannagl M, Hoffmann H, Siebeck M, Weipert J, Schwarz HP, Schramm W. A purified antithrombin III-heparin complex as a potent inhibitor of thrombin in porcine endotoxin shock. Thromb Res 1991; 61: 1-10.
    PubMedGoogle Scholar
  • 13 Gustafsson D, Antonsson T, Bylund R, Erikson U, Gyzander E, Nilsson I, Elg M, Mattsson C, Deinum J, Persson S, Karlsson O, Nilsson A, Sörensen M. Effects of melagatran, a new low molecular weight thrombin inhibitor on thrombin and fibrinolytic enzymes. Thromb Haemost 1998; 79: 110-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Eriksson M, Larsson A, Lundkvist K, Lööf L. Endotoxaemic liver injury in a porcine model – Relation to tumor necrosis factor alfa release and survival. Scand J Inf Dis 1998; 30: 169-72.
    CrossrefPubMedGoogle Scholar
  • 15 Lichtwarck-Aschoff M, Nielsen JB, Sjöstrand UH, Edgren EL. An experimental randomized study of five different ventilatory modes in a piglet model of severe respiratory distress. Intensive Care Med 1992; 18: 339-47.
    CrossrefPubMedGoogle Scholar
  • 16 Clark CA, Harman EM. Hemodynamic Monitoring: Pulmonary Artery Catheters. In: Critical care. Civetta JM, Taylor RW, Kirby RR, eds. Philadelphia: J B Lippincott Co; 1988. pp 293-302.
    Google Scholar
  • 17 Nilsson IM, Olow B. Determination of fibrinogen and fibrinolytic activity. Thromb Diath Haemorrh 1962; 8: 297-10.
    PubMedGoogle Scholar
  • 18 Taylor FB, Chang AC, Peer G, Li A, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli. Blood 1998; 91: 1609-15.
    PubMedGoogle Scholar
  • 19 Park CT, Creasey AA, Wright SD. Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. Blood 1997; 89: 4268-74.
    PubMedGoogle Scholar
  • 20 Nowak G, Markwardt F. Hirudin in disseminated intravascular coagulation. Haemostasis 1991; 1: 142-8.
    PubMedGoogle Scholar
  • 21 Pearson JM, Schultze AE, Jean PA, Roth RA. Platelet participation in liver injury from gram-negative bacterial lipopolysaccharide in the rat. Shock 1995; 4: 178-86.
    CrossrefPubMedGoogle Scholar
  • 22 Myrvold HE, Brandberg Å, Lindquist O, Busch C, Lewis DH. The role of platelets and fibrinogen in experimental septic shock. Acta Chir Scand 1977; 143: 131-7.
    PubMedGoogle Scholar
  • 23 Colotta F, Sciacca FL, Sironi M, Luini W, Rabiet MJ, Mantovani A. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 1994; 144: 975-85.
    PubMedGoogle Scholar
  • 24 Cirino G, Cicala C, Bucci MR, Sorrentino L, Maraganore JM, Stone SR. Thrombin functions as an inflammatory mediator through activation of its receptor. J Exp Med 1996; 183: 821-7.
    CrossrefPubMedGoogle Scholar
  • 25 Bryan-Brown C. Gas transport and delivery. Uptake, solubility, and distribution of gases. In: Textbook of Critical Care. Shoemaker WC, Thompson W, Holbrook P, eds. Philadelphia: Saunders, W B.; 1994. pp 210-218.
    Google Scholar
  • 26 Mehta JL, Chen L, Mattson C, Gustafson D, Saldeen TGP. Melagatran, an oral active site inhibitor of thrombin, prevents or delays formation of electrically-induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol 1998; 31: 345-51.
    CrossrefPubMedGoogle Scholar
  • 27 Bucha E, Nowak G. The Ecarin Coagulation Time (ECT): the first specific method suited for quick determination of thrombin inhibitors in whole blood, plasma and body fluids. Int Angiol 1995; 14 (Suppl. 01) 174.
    PubMedGoogle Scholar
  • 28 Callas DD, Fareed J. Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Res 1996; 83: 463-8.
    CrossrefPubMedGoogle Scholar
  • 29 Berry CN, Lunven C, Girardot C, Lechaire I, Girand D, Charles M-C, Ferrari P, O’Brien DP. Ecarin Clotting Time: a predictive coagulation assay for the antithrombotic activity of argatraoban in rats. Thromb Haemost 1998; 79: 228-33.
    Article in Thieme ConnectPubMedGoogle Scholar