Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation

Iba, Toshiaki; Saitoh, Daizoh

doi:10.1186/s40560-014-0051-6

Cited by 47 publications

(43 citation statements)

References 64 publications

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“…LPS treatment led to marked dysregulation of parameters of blood coagulation akin to that seen in disseminated intravascular coagulation [35]. A pro-thrombotic state was evident at 18 h post LPS with elevation of fibrinogen levels in serum [36], and decrease in levels of antithrombin [37] and protein C [38] (Fig 7, upper panel).…”

Section: Coagulopathy Fibrinolysis and Low Platelet Count And Their mentioning

confidence: 92%

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

et al. 2020

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We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component. Female C57 BL/6 mice, 6-8 weeks old, were administered a single i.p. injection of LPS at a dose of 10 mg/Kg or 20 mg/Kg with or without concurrent treatment with the above cfCh inactivating agents. Administration of cfCh inactivating agents concurrently with LPS resulted in prevention of following pathological parameters: 1) release of cfCh in extra-cellular spaces of brain, lung and heart and in circulation; 2) release of inflammatory cytokines in circulation; 3) activation of DNA damage, apoptosis and inflammation in cells of thymus, spleen and in PBMCs; 4) DNA damage, apoptosis and inflammation in cells of lung, liver, heart, brain, kidney and small intestine; 5) liver and kidney dysfunction and elevation of serum lactate; 6) coagulopathy, fibrinolysis and thrombocytopenia; 7) lethality. We conclude that cfCh that are released from dying host cells in response to bacterial endotoxin represents a global instigator of sepsis. cfCh inactivation may provide a novel approach to management of sepsis in humans.

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Section: Coagulopathy Fibrinolysis and Low Platelet Count And Their mentioning

confidence: 92%

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

et al. 2020

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“…Although the study did not have enough power to prove with statistical significance that AT supplementation was associated with a reduction in 28-day mortality, the results did suggest that AT supplementation improved outcomes in DIC patients (28-day mortality: 13% vs. 10%, n ¼ 60, P ¼ 1.0) (16). Furthermore, several studies have indicated that AT supplementation does not increase bleeding complications in patients with sepsis-induced DIC (16)(17)(18).…”

Section: Introductionmentioning

confidence: 91%

Antithrombin Supplementation and Mortality in Sepsis-Induced Disseminated Intravascular Coagulation

Hayakawa¹,

Kudo²,

Saito

et al. 2016

Shock

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ABSTRACT-Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of ATsupplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n ¼ 715, AT group; n ¼ 1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (n ¼ 1,784, odds ratio [95% confidence intervals]: 0.748 [0.572-0.978], P ¼ 0.034). However, quintile-stratified propensity score analysis (n ¼ 1,784, odds ratio: 0.823 [0.646-1.050], P ¼ 0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649-1.125], P ¼ 0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (P ¼ 0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

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“…As a result, although the denuded endothelial surface could be more prothrombotic, shedding heparan into the plasma itself is antithrombotic. Syndecan-4 is known as a binding site of antithrombin, and its derangement decreases the activity of antithrombin [47]. Strand et al [53] reported that the shedding of syndecan-4 promotes leukocyte recruitment after a lipopolysaccharide challenge in mice.…”

Section: Measurement Of Glycocalyx In Plasma and Urinementioning

confidence: 99%

Derangement of the endothelial glycocalyx in sepsis

Iba

Levy

2019

Journal of Thrombosis and Haemostasis

223

296

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Summary The vascular endothelial surface is coated by the glycocalyx, a ubiquitous gel‐like layer composed of a membrane‐binding domain that contains proteoglycans, glycosaminoglycan side‐chains, and plasma proteins such as albumin and antithrombin. The endothelial glycocalyx plays a critical role in maintaining vascular homeostasis. However, this component is highly vulnerable to damage and is also difficult to examine. Recent advances in analytical techniques have enabled biochemical, visual and computational investigation of this vascular component. The glycocalyx modulates leukocyte–endothelial interactions, thrombus formation and other processes that lead to microcirculatory dysfunction and critical organ injury in sepsis. It also acts as a regulator of vascular permeability and contains mechanosensors as well as receptors for growth factors and anticoagulants. During the initial onset of sepsis, the glycocalyx is damaged and circulating levels of glycocalyx components, including syndecans, heparan sulfate and hyaluronic acid, can be measured and are reportedly useful as biomarkers for sepsis. Also, a new methodology using side‐stream dark‐field imaging is now clinically available for assessing the glycocalyx. Multiple factors including hypervolemia and hyperglycemia are toxic to the glycocalyx, and several agents have been proposed as therapeutic modalities, although no single treatment has been proven to be clinically effective. In this article, we review the derangement of the glycocalyx in sepsis. Despite the accumulated knowledge regarding the important roles of the glycocalyx, the relationship between derangement of the endothelial glycocalyx and severity of sepsis or disseminated intravascular coagulation has not been adequately elucidated and further work is needed.

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Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation

Cited by 47 publications

References 64 publications

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice

Antithrombin Supplementation and Mortality in Sepsis-Induced Disseminated Intravascular Coagulation

Derangement of the endothelial glycocalyx in sepsis

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