Abstract
(1) Background: The endothelial glycocalyx is a primary target during the early phase of sepsis. We previously reported a newly developed recombinant non-fucosylated antithrombin has protective effects in vitro. We further evaluated the effects of this recombinant antithrombin on the glycocalyx damage in an animal model of sepsis. (2) Methods: Following endotoxin injection, in Wistar rats, circulating levels of hyaluronan, syndecan-1 and other biomarkers were evaluated in low-dose or high-dose recombinant antithrombin-treated animals and a control group (n = 7 per group). Leukocyte adhesion and blood flow were evaluated with intravital microscopy. The glycocalyx was also examined using side-stream dark-field imaging. (3) Results: The activation of coagulation was inhibited by recombinant antithrombin, leukocyte adhesion was significantly decreased, and flow was better maintained in the high-dose group (both p < 0.05). Circulating levels of syndecan-1 (p < 0.01, high-dose group) and hyaluronan (p < 0.05, low-dose group; p < 0.01, high-dose group) were significantly reduced by recombinant antithrombin treatment. Increases in lactate and decreases in albumin levels were significantly attenuated in the high-dose group (p < 0.05, respectively). The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05). (4) Conclusions: Recombinant antithrombin maintained vascular integrity and the microcirculation by preserving the glycocalyx in this sepsis model, effects that were more prominent with high-dose therapy.
Highlights
Coagulation activation in sepsis is recognized as a natural event for host-defense that prevents pathogen dissemination and localizes infection [1,2]
The glycocalyx thickness was reduced over time in control animals, but the derangement was attenuated and microvascular perfusion was better maintained in the high-dose group recombinant antithrombin group (p < 0.05)
Following injection of LPS, multiple structural changes in the endothelium were observed including disruption, irregularities, and thickening as well as loss of the glycocalyx layer and an increase in leukocytes adhering to the endothelium
Summary
Coagulation activation in sepsis is recognized as a natural event for host-defense that prevents pathogen dissemination and localizes infection [1,2]. Antithrombin is one of the most important physiological anticoagulants. It provides host protection as an anticoagulant, and through inhibiting acute inflammatory proteases such as thrombin and elastase [4,5,6]. Antithrombin is known to increase its anticoagulant activity by binding to heparan sulfate on the endothelial glycocalyx [7]. Antithrombin reportedly binds to heparan sulfate and contributes to glycocalyx stabilization [8,9]. Since antithrombin levels decrease dramatically in sepsis with coagulopathy [10], the supplementation of antithrombin for septic-associated disseminated intravascular coagulation (DIC) is a potential therapeutic approach [11]. Despite the lack of robust evidence, the antithrombin repletion in sepsis-associated DIC empirically administered in Japan is based on guidelines [12]. It has been suggested that the dose (intended to recover 80% of the activity) used in Japan is insufficient [13]
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