Abstract
Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.
Highlights
Materials and methodsInfection is known as one of the risk factors of thromboembolic diseases such as venous thrombosis and arterial thrombosis [1,2,3]
We evaluated the effects of edoxaban, which is one of the direct oral anticoagulants (DOACs) with the mechanism of the direct inhibition of factor Xa (FXa), on blood coagulation parameters, microvascular thrombus formation, organ damage parameters, and inflammatory cytokines in rats injected with LPS
LPS is the most frequently used inducer to mimic coagulopathy associated with infection in animal models [3]
Summary
Materials and methodsInfection is known as one of the risk factors of thromboembolic diseases such as venous thrombosis (deep vein thrombosis and pulmonary embolism) and arterial thrombosis (myocardial infarction and stroke) [1,2,3]. There are several types of pathogens (bacteria and viruses) and symptoms (pneumonia, urinary tract infection, and systemic infection etc.), all types of infections can elevate the risk of thrombosis. Over-activation of coagulation can lead to thrombosis and result in poor outcome [4]. Typical animal models are induced by intravenous or intraperitoneal injection of a single product derived from pathogens. LPS is a major component of the outer cell membrane of gram-negative bacteria like Escherichia coli and is recognized by host cells [5]. Binding of LPS to host cells such as monocytes/macrophages, platelets and endothelial cells results in a procoagulant state through directly activating pro-inflammatory responses simultaneously with coagulation factors like monocyte-derived tissue factor [6]. Inflammatory cytokines produced in the LPS model upregulate the coagulation factors such as tissue factor [7]
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