Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulationReport as inadecuate




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Journal of Intensive Care

, 2:66

Recent advances in disseminated intravascular coagulation

Abstract

Antithrombin AT is known as an important physiological anticoagulant. AT inactivates thrombin and multiple other coagulation factors, thereby strongly inhibiting the over-activation of the coagulation system during disseminated vascular coagulation DIC. AT also suppresses the pro-inflammatory reactions that are promoted through protease-activated receptor-1 during sepsis. One of the unique characteristics of AT is the conformational change it undergoes when binding to heparin-like molecules. The anticoagulant function is greatly accelerated after AT binds to externally administered heparin in the circulating blood. Meanwhile, AT also binds to syndecan-4 on the cell surface under physiological conditions, thereby contributing to local antithrombogenicity. The binding of AT and syndecan-4 upregulates prostaglandin I2 production, downregulates pro-inflammatory cytokine production, and suppresses the leukocyte-endothelial interaction. Other than these activities, recent preclinical studies have reported that AT might inhibit neutrophil necrotic cell death and the ejection of neutrophil extracellular traps. Together, these effects may lead to the attenuation of inflammation by decreasing the level of damage-associated molecular patterns. Although a number of animal studies have demonstrated a survival benefit of AT, the clinical benefit has long been argued since the effect of high-dose AT was denied in 2001 in a large-scale randomized controlled trial targeting patients with severe sepsis. However, recent clinical studies examining the effects of a supplemental dose of AT in patients with sepsis-associated DIC have revealed that AT is potentially effective for DIC resolution and survival improvement without increasing the risk of bleeding. Since DIC is still a major threat during sepsis, the optimal method of identifying this promising drug needs to be identified.

KeywordsAntithrombin Sepsis Disseminated intravascular coagulation Thrombin Neutrophil extracellular traps Damage-associated molecular pattern Necrosis Syndecan-4 Heparin Protease-activated receptor AbbreviationsAPCactivated protein C

ATantithrombin

AUCarea under the receiver operating characteristic curve

DAMPsdamage-associated molecular patterns

DICdisseminated vascular coagulation

FDPfibrin-fibrinogen degradation products

GAGsglycosaminoglycans

ICAM-1intercellular adhesion molecule-1

ISTHInternational Society on Thrombosis and Haemostasis

JAAMJapanese Association for Acute Medicine

LPSlipopolysaccharide

NETsneutrophil extracellular traps

PARprotease-activated receptor

PTprothrombin time

RCTsrandomized controlled trials

RRrelative risk

TATthrombin-antithrombin complex

TFtissue factor

Electronic supplementary materialThe online version of this article doi:10.1186-s40560-014-0051-6 contains supplementary material, which is available to authorized users.

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Author: Toshiaki Iba - Daizoh Saitoh

Source: https://link.springer.com/



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