{"title":"Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation.","authors":"Toshiaki Iba, Daizoh Saitoh","doi":"10.1186/s40560-014-0051-6","DOIUrl":null,"url":null,"abstract":"<p><p>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. </p>","PeriodicalId":16123,"journal":{"name":"Journal of Intensive Care","volume":"2 1","pages":"66"},"PeriodicalIF":3.8000,"publicationDate":"2014-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40560-014-0051-6","citationCount":"39","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Intensive Care","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40560-014-0051-6","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2014/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
引用次数: 39
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.
期刊介绍:
"Journal of Intensive Care" is an open access journal dedicated to the comprehensive coverage of intensive care medicine, providing a platform for the latest research and clinical insights in this critical field. The journal covers a wide range of topics, including intensive and critical care, trauma and surgical intensive care, pediatric intensive care, acute and emergency medicine, perioperative medicine, resuscitation, infection control, and organ dysfunction.
Recognizing the importance of cultural diversity in healthcare practices, "Journal of Intensive Care" also encourages submissions that explore and discuss the cultural aspects of intensive care, aiming to promote a more inclusive and culturally sensitive approach to patient care. By fostering a global exchange of knowledge and expertise, the journal contributes to the continuous improvement of intensive care practices worldwide.