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

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. Escherichia coli were infused for 2 h i...

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Published in:Critical care (London, England) England), 2017-03, Vol.21 (1), p.51-51, Article 51
Main Authors: Schöchl, Herbert, van Griensven, Martijn, Heitmeier, Stefan, Laux, Volker, Kipman, Ulrike, Roodt, Jan, Bahrami, Soheyl, Redl, Heinz
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Anticoagulants
Antithrombins - pharmacology
Antithrombins - therapeutic use
Blood clots
Blood Coagulation - physiology
Blood pressure
Catheters
Clinical trials
Critical care
Cytokines
Disseminated Intravascular Coagulation - drug therapy
E coli
Escherichia coli - metabolism
Escherichia coli - pathogenicity
Escherichia coli Infections - complications
Escherichia coli Infections - drug therapy
Factor Xa - adverse effects
Factor Xa - agonists
Factor Xa Inhibitors - pharmacology
Factor Xa Inhibitors - therapeutic use
Laboratory animals
Mortality
Neutrophils
Papio - metabolism
Papio - microbiology
Pulmonary arteries
Sepsis
Sepsis - complications
Sepsis - drug therapy
South Africa
Thrombin - adverse effects
Thrombin - antagonists & inhibitors
Thrombosis
Veins & arteries
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Summary: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. 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. 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. 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.
ISSN:1364-8535
1466-609X
1364-8535
1366-609X
DOI:10.1186/s13054-017-1636-y