Department of Biomedical Sciences and Human Oncology, Section of General, Experimental and Clinical Pathology, University of Bari, Bari, Italy.
Thromb Res. 2012 Mar;129(3):290-5. doi: 10.1016/j.thromres.2011.10.013. Epub 2011 Nov 5.
Sepsis is often associated with haemostatic changes ranging from subclinical activation of blood coagulation (hypercoagulability), which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), characterized by widespread microvascular thrombosis and subsequent consumption of platelets and coagulation proteins, eventually causing bleeding manifestations. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. The latter, along with the micro-organism and its derivatives are now believed to drive the major changes responsible for massive thrombin formation and fibrin deposition, namely 1) the aberrant expression of the TF by different cells (especially monocytes-macrophages), 2) the impairment of physiological anticoagulant pathways, orchestrated mainly by dysfunctional endothelial cells (ECs) and 3) the suppression of fibrinolysis due to overproduction of plasminogen activator inhibitor-1 (PAI-1) by ECs and likely also to thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor (TAFI). The ensuing microvascular thrombosis and ischemia are thought to contribute to tissue injury and multiple organ dysfunction syndrome (MODS). Recent evidence indicates that extracellular nuclear materials released from activated and especially apoptotic or necrotic cells, e.g. High Mobility Group Box-1 (HMGB-1) and histones, are endowed with cell toxicity, proinflammatory and clot-promoting properties and thus, during sepsis, they may represent late mediators that propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenesis of DIC and MODS may have implications for the development of new therapeutic agents potentially useful for the management of severe sepsis.
败血症常伴有止血变化，范围从亚临床的血液凝固激活（高凝状态），这可能导致局部静脉血栓形成，到急性弥散性血管内凝血（DIC），其特征是广泛的微血管血栓形成和随后的血小板和凝血蛋白消耗，最终导致出血表现。这种危及生命的并发症的关键事件是宿主对感染因子的过度炎症反应，导致炎症介质的过度表达。后者，以及微生物及其衍生物，现在被认为是驱动导致大量凝血酶形成和纤维蛋白沉积的主要变化的原因，即 1）不同细胞（特别是单核细胞-巨噬细胞）TF 的异常表达，2）生理抗凝途径的损害，主要由功能失调的内皮细胞（ECs）协调，3）纤溶抑制由于 ECs 过量产生纤溶酶原激活物抑制剂-1（PAI-1），可能还由于凝血酶介导的凝血酶可激活纤溶抑制物（TAFI）的激活。由此产生的微血管血栓形成和缺血被认为有助于组织损伤和多器官功能障碍综合征（MODS）。最近的证据表明，从活化的特别是凋亡或坏死细胞释放的细胞外核材料，如高迁移率族框-1（HMGB-1）和组蛋白，具有细胞毒性、促炎和促凝性质，因此，在败血症中，它们可能代表传播进一步炎症、凝血、细胞死亡和 MODS 的晚期介质。这些对 DIC 和 MODS 发病机制的深入了解可能对开发新的治疗剂具有重要意义，这些治疗剂可能对严重败血症的治疗有用。
