Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation.
Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation.
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DOI：
10.1186/s40560-014-0050-7
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发表时间：
2015
影响因子：
7.1
通讯作者：
Ikezoe T
中科院分区：
文献类型：
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作者：
Ikezoe T
血栓调节蛋白(TM)/活化蛋白C(APC)系统在体内维持血栓形成和止血的动态平衡以及维持血管完整性方面起着重要作用。表达于血管内皮细胞的TM与凝血酶结合，形成1：1的复合体，起到抗凝血剂的作用。此外，凝血酶-TM复合体激活蛋白C产生APC，在S蛋白存在的情况下，APC灭活因子VIIIa和Va，从而抑制进一步的凝血酶形成。耐人寻味的是，APC具有抗炎和细胞保护作用。此外，TM的胞外区还具有APC非依赖的抗炎和细胞保护活性。值得注意的是，在脓毒症引起的弥漫性血管内凝血(DIC)中，TM/APC系统由于各种机制而受到损害，包括细胞表面TM被激活的炎症细胞产生的细胞因子和蛋白酶裂解。因此，有理由认为重组蛋白重组TM/APC系统可以缓解脓毒症和DIC。在蛋白C全球评估严重脓毒症(PROWESS)试验成功的基础上，FDA于2002年批准重组人APC(RhAPC)用于严重脓毒症患者。然而，随后的临床试验未能显示出rhAPC的临床益处，并注意到与出血相关的不良事件的发生率增加，这促使该行业将rhAPC撤出市场。另一方面，自2008年以来，重组人可溶性TM(RTM)已在日本用于治疗DIC患者，目前正在美国、南美、亚洲、澳大利亚、欧盟和其他国家进行评估RTM对伴有凝血障碍的严重脓毒症患者的疗效的III期临床试验。本文综述了TM/APC系统在感染性DIC患者中产生抗凝、抗炎和细胞保护作用的分子机制。
The thrombomodulin (TM)/activated protein C (APC) system plays an important role in maintaining the homeostasis of thrombosis and hemostasis and maintaining vascular integrity in vivo. TM expressed on vascular endothelium binds to thrombin, forming a 1:1 complex and acts as an anticoagulant. In addition, the thrombin-TM complex activates protein C to produce APC, which inactivates factors VIIIa and Va in the presence of protein S, thereby inhibiting further thrombin formation. Intriguingly, APC possesses anti-inflammatory as well as cytoprotective activities. Moreover, the extracellular domain of TM also possesses APC-independent anti-inflammatory and cytoprotective activities. Of note, the TM/APC system is compromised in disseminated intravascular coagulation (DIC) caused by sepsis due to various mechanisms, including cleavage of cell-surface TM by exaggerated cytokines and proteases produced by activated inflammatory cells. Thus, it is reasonable to assume that reconstitution of the TM/APC system by recombinant proteins would alleviate sepsis and DIC. On the basis of the success of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (rhAPC) for severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for rhAPC, and an increased incidence of hemorrhage-related adverse events was noted, which prompted the industry to withdraw rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. This review article discusses the molecular mechanisms by which the TM/APC system produces anticoagulant as well as anti-inflammatory and cytoprotective activities in septic DIC patients.