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Critical Care
Published in: Critical Care 1/2017

Open Access 01-12-2017 | Research

Dual inhibition of thrombin and activated factor X attenuates disseminated intravascular coagulation and protects organ function in a baboon model of severe Gram-negative sepsis

Authors: Herbert Schöchl, Martijn van Griensven, Stefan Heitmeier, Volker Laux, Ulrike Kipman, Jan Roodt, Soheyl Bahrami, Heinz Redl

Published in: Critical Care | Issue 1/2017

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Abstract

Background

Inhibition of procoagulant pathways may improve outcome in sepsis. We examined whether a dual short-acting thrombin (factor II) and factor X (FX)a inhibitor (SATI) ameliorates sepsis-induced disseminated intravascular coagulation (DIC) and is organ-protective.

Methods

Escherichia coli were infused for 2 h in 22 anesthetized baboons. The control (CO) group (n = 8) received sterile isotonic solution only. In the treatment groups, SATI was administered starting 15 minutes after the end of the bacterial exposure. In the low-dose group (LD-SATI, n = 8), SATI was infused with 75 μg/kg/h for the first hour, followed by 23 μg/kg/h until the end of the study. In the high-dose SATI group (HD-SATI, n = 6), 225 μg/kg/h was administered for the first hour followed by continuous infusion of 69 μg/kg/h until termination of the study.

Results

Sepsis-induced DIC was attenuated, as reflected by lower peak thrombin-antithrombin complexes (threefold) and D-dimer levels (twofold) in both SATI groups compared to the CO. This coincided with strongly improved cell/organ protection assessed by decreased levels of lactate dehydrogenase (threefold), creatinine (twofold), aspartate aminotransferase (threefold), and amylase (twofold) compared to the CO group. Anuria, which started at 8 h in the CO group, was prevented in both SATI groups. Peak interleukin-6 release at 12 h was prevented in the treatment groups. In both SATI groups, fewer catecholamines were necessary and no bleeding complications were observed.

Conclusions

Dual inhibition of thrombin and FXa preserved activation of coagulation, protected organ function and ameliorated inflammation in severe Gram-negative sepsis in baboons. SATI could be a novel therapeutic agent against sepsis-induced DIC.
Literature
1.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.CrossRefPubMed
2.
Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima S, McGinley E, et al. Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators. Nationwide trends of severe sepsis in the 21st century (2000–2007). Chest. 2011;140:1223–31.CrossRefPubMed
3.
4.
Angus DC, van der Poll T. Severe sepsis and septic shock. New Engl J Med. 2013;29(369):840–51.CrossRef
5.
6.
7.
Fourrier F. Severe sepsis, coagulation, and fibrinolysis: dead end or one way? Crit Care Med. 2012;40:2704–8.CrossRefPubMed
8.
9.
van der Poll T, de Jonge E, Levi M. Regulatory role of cytokines in disseminated intravascular coagulation. Semin Thromb Hemost. 2001;27:639–51.CrossRefPubMed
10.
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637.CrossRefPubMed
11.
Dhainaut JF, Yan SB, Joyce DE, Pettilä V, Basson B, Brandt JT, et al. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost. 2004;2:1924–33.CrossRefPubMed
12.
Simon S, Light B, Spapen H, Stone J, Seibert A, Peckelsen C, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290:238–47.CrossRefPubMed
13.
Eid A, Wiedermann CJ, Kinasewitz GT. Early administration of high-dose antithrombin in severe sepsis: single center results from the KyberSept-trial. Anesth Analg. 2008;107:1633–8.CrossRefPubMed
14.
Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–78.CrossRefPubMed
15.
Wunderink RG, Laterre PF, Francois B, Perrotin D, Artigas A, Vidal LO, et al. Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2011;183:1561–8.CrossRefPubMed
16.
Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–64.CrossRefPubMed
17.
Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, et al. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost. 2006;4:90–7.CrossRefPubMed
18.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. New Engl J Med. 2001;344:699–709.CrossRefPubMed
19.
Iba T, Saitoh D, Wada H, Asakura H. Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a secondary survey. Crit Care. 2014;18:497.CrossRefPubMedPubMedCentral
20.
Pernerstorfer T, Hollenstein U, Hansen JB, Stohlawetz P, Eichler HG, Handler S, et al. Lepirudin blunts endotoxin-induced coagulation activation. Blood. 2000;95:1729–34.PubMed
21.
Hollenstein UM, Pernerstorfer T, Homoncik M, Hansen JB, Finzen H, Handler S, Jilma B. Effect of factor X inhibition on coagulation activation and cytokine induction in human systemic inflammation. J Infect Dis. 2002;186:1270–6.CrossRefPubMed
22.
Giardino EC, Haertlein BJ, de Garavilla L, Costanzo MJ, Damiano BP, Andrade-Gordon P, Maryanoff BE. Cooperative antithrombotic effect from the simultaneous inhibition of thrombin and factor Xa. Blood Coagul Fibrinolysis. 2010;21:128–34.CrossRefPubMed
23.
Agnelli G, Gallus A, Goldhaber SZ, Haas S, Huisman MV, Hull RD, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral direct factor Xa inhibitor BAY 59-7939 in patients with acute symptomatic deep-vein thrombosis) study. Circulation. 2007;116:180–7.CrossRefPubMed
24.
Redl HR, Martin U, Khadem A, Pelinka LE, van Griensven M. Anti-L-selectin antibody therapy does not worsen the post septic course in a baboon model. Crit Care. 2005;9:R735.CrossRefPubMedPubMedCentral
25.
Schlag G, Redl H, Davies J. Live Escherichia coli sepsis models in baboons. In: Schlag G, Redl H, editors. Pathophysiology of shock, sepsis, and organ failure. Berlin, Heidelberg: Springer; 1993. p. 1076–107.CrossRef
26.
Schlag G, Redl H, Hallström S, Radmore K, Davies J. Hyperdynamic sepsis in baboons: I. Aspects of hemodynamics. Circ Shock. 1991;34:311–8.PubMed
27.
Fourrier F. Clinical trial results with antithrombin III in sepsis. Crit Care Med. 2000;28:S38–43.CrossRefPubMed
28.
Martin NB, Jamieson A, Tuffin DP. The effect of interleukin-4 on tumour necrosis factor-alpha induced expression of tissue factor and plasminogen activator inhibitor-1 in human umbilical vein endothelial cells. Thromb Haemost. 1993;70:1037–42.PubMed
29.
Raeven P, Drechsler S, Weixelbaumer KM, Bastelica D, Peiretti F, Klotz A, et al. Systemic inhibition and liver-specific over-expression of PAI-1 failed to improve survival in all-inclusive populations or homogenous cohorts of CLP mice. J Thromb Haemost. 2014;12:958–69.CrossRefPubMed
30.
Lorente L, Martín MM, Borreguero-León JM, Solé-Violán J, Ferreres J, Labarta L, Diaz C, et al. Sustained high plasma plasminogen activator inhibitor-1 levels are associated with severity and mortality in septic patients. Thromb Res. 2014;134:182–6.CrossRefPubMed
31.
Benes J, Chvojka J, Sykora R, Radej J, Krouzecky A, Novak I, Matejovic M. Searching for mechanisms that matter in early septic acute kidney injury: an experimental study. Crit Care. 2011;15:R256.CrossRefPubMedPubMedCentral
32.
Seymour CW, Rosengart MR. Septic Shock. Advances in diagnosis and treatment. JAMA. 2015;18(314):708–17.CrossRef
33.
Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41.CrossRefPubMed
34.
Wada H, Matsumoto T, Yamashita Y, Hatada T. Disseminated intravascular coagulation: testing and diagnosis. Clin Chim Acta. 2014;436:130–4.CrossRefPubMed
35.
Redl H, Schlag G, Bahrami S, Schade U, Ceska M, Stütz P. Plasma neutrophil-activating peptide-1/interleukin-8 and neutrophil elastase in a primate bacteremia model. J Infect Dis. 1991;164:383–8.CrossRefPubMed
36.
Waage A, Redl H, Schlag G, Schade U. The cytokine network in sepsis II: IL-1 and IL-6. In: Schlag G, Redl H, editors. Pathophysiology of shock, sepsis, and organ failure. Berlin, Heidelberg: Springer; 1993. p. 491–8.CrossRef
Metadata
Title
Dual inhibition of thrombin and activated factor X attenuates disseminated intravascular coagulation and protects organ function in a baboon model of severe Gram-negative sepsis
Authors
Herbert Schöchl
Martijn van Griensven
Stefan Heitmeier
Volker Laux
Ulrike Kipman
Jan Roodt
Soheyl Bahrami
Heinz Redl
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2017
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-017-1636-y

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