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

IF 3.8 2区 医学 Q1 CRITICAL CARE MEDICINE Journal of Intensive Care Pub Date : 2014-12-31 eCollection Date: 2014-01-01 DOI:10.1186/s40560-014-0051-6
Toshiaki Iba, Daizoh Saitoh
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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.

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抗凝血酶在败血症相关弥散性血管内凝血的临床前和临床应用中的疗效。
抗凝血酶是一种重要的生理性抗凝剂。AT使凝血酶和多种其他凝血因子失活,从而强烈抑制弥散性血管凝固(DIC)过程中凝血系统的过度激活。AT还抑制脓毒症期间通过蛋白酶激活受体-1促进的促炎反应。AT的独特特征之一是它与肝素样分子结合时发生的构象变化。AT与循环血液中外用肝素结合后,抗凝功能大大加快。同时,AT在生理条件下也与细胞表面的syndecan-4结合,从而起到局部抗血栓形成的作用。AT和syndecan-4的结合上调前列腺素I2的产生,下调促炎细胞因子的产生,抑制白细胞与内皮细胞的相互作用。除了这些活性外,最近的临床前研究报道,AT可能抑制中性粒细胞坏死细胞死亡和中性粒细胞胞外陷阱的排出。总之,这些作用可能通过降低与损伤相关的分子模式的水平而导致炎症的衰减。尽管许多动物研究已经证明了AT的生存益处,但自2001年在一项针对严重脓毒症患者的大规模随机对照试验中否认大剂量AT的作用以来,临床益处一直存在争议。然而,最近的临床研究检查了补充剂量AT对脓毒症相关DIC患者的影响,表明AT对DIC的缓解和生存改善有潜在的效果,而不会增加出血的风险。由于DIC仍然是脓毒症期间的主要威胁,因此需要确定识别这种有前途的药物的最佳方法。
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来源期刊
Journal of Intensive Care
Journal of Intensive Care Medicine-Critical Care and Intensive Care Medicine
CiteScore
11.90
自引率
1.40%
发文量
51
审稿时长
15 weeks
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.
期刊最新文献
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