Esmon Charles T
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
Ann Med. 2002;34(7-8):598-605. doi: 10.1080/078538902321117823.
The goals of this chapter are to provide a brief review of the biology of the protein C pathway and some of the features of the pathway that make it uniquely positioned to control microvascular coagulation and control the acute inflammatory response. Activated protein C works as an antithrombotic agent by inactivating factors Va and VIIIa. It is particularly effective at preventing microvascular thrombosis. Platelets may provide a margin of safety for activated protein C as an antithrombotic. Approximately 25% of the factor V/Va in plasma is contained within the platelet and hence resistant to time dependent inactivation by activated protein C. In addition, factor Va bound to the platelet surface is relatively resistant to inactivation by activated protein C. Activated protein C also facilitates clot lysis by inhibiting plasminogen activator inhibitor 1, a process that is accelerated markedly by vitronectin. Inflammatory cytokines like tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) downregulate two key components of the protein C activation complex, thrombomodulin and the endothelial cell protein C receptor resulting in decreased protein C activation. Activated protein C in turn has been shown in several animal models and in vitro to inhibit TNF elaboration in response to endotoxin. This inhibition appears to be due to diminished nuclear factor kappaB (NF kappaB) expression and nuclear translocation. Activated protein C has been shown to reduce the rate of death due to severe sepsis. This reduction may be due to both the anticoagulant effects as demonstrated by a reduction in D-dimer and inflammatory effects as demonstrated by a reduction in interleukin 6.
本章的目标是简要回顾蛋白C途径的生物学特性以及该途径的一些特点，这些特点使其在控制微血管凝血和急性炎症反应方面具有独特的地位。活化蛋白C通过灭活因子Va和VIIIa发挥抗血栓作用。它在预防微血管血栓形成方面特别有效。血小板可能为活化蛋白C作为抗血栓剂提供一定的安全边际。血浆中约25%的因子V/Va存在于血小板内，因此对活化蛋白C的时间依赖性灭活具有抗性。此外，结合在血小板表面的因子Va对活化蛋白C的灭活也相对具有抗性。活化蛋白C还通过抑制纤溶酶原激活物抑制剂1促进凝块溶解，这一过程在玻连蛋白的作用下会显著加速。肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β）等炎性细胞因子会下调蛋白C激活复合物的两个关键成分，即血栓调节蛋白和内皮细胞蛋白C受体，导致蛋白C活化减少。反过来，在多个动物模型和体外实验中已证明，活化蛋白C可抑制对内毒素产生的TNF。这种抑制作用似乎是由于核因子κB（NFκB）表达和核转位减少所致。已证明活化蛋白C可降低严重脓毒症导致的死亡率。这种降低可能是由于抗凝作用（如D-二聚体减少所示）和炎症作用（如白细胞介素6减少所示）。
