28 Chapter 2 hemorrhage [22]. The most important initiator of coagulation in sepsis is tissue factor (TF). Indeed, inhibition of TF prevents DIC and improves survival in experimental sepsis [21]. TF is predominantly produced by macrophages and monocytes and its expression is enhanced by proinflammatory cytokines, exemplifying the close interaction between inflammation and coagulation [23]. Furthermore, TF can reside in micro particles that are formed by hematopoietic and endothelial cells. These micro particles play a significant role in both coagulation and inflammation [24]. In healthy hosts, coagulation is controlled by three main anticoagulant pathways: the antithrombin system, tissue factor pathway inhibitor (TFPI) and the protein C system. In septic patients all these pathways are impaired in their function, partially due to endothelial dysfunction, resulting in low levels of these coagulation inhibitors [25, 26]. The physiological function of the protein C system has been supported by investigations in which interventions inhibiting this pathway resulted in severe coagulopathy and death in otherwise nonlethal infection models. During the early stages of inflammation plasminogen activators are released to help breakdown fibrin. Sepsis is associated with high levels of plasminogen activator inhibitor type 1 (PAI-1), a main inhibitor of fibrinolysis, further facilitating microvascular thrombosis [27]. The interaction between inflammation and coagulation is not unilateral. Coagulation factors regulate inflammation in particular through proteolytic cleavage of protease activated receptors (PARs)[28]. Activated protein C (APC) influences inflammation, by reducing the expression of receptors for cytokines and chemokines [29], by downregulating the production of inflammatory mediators [30, 31] and by blockage of cytokine release and leukocyte activation [32]. During sepsis the vascular endothelium is involved in the disturbance of anticoagulant mechanisms. Glycosaminoglycans on the endothelial surface supports antithrombin mediated inhibition of thrombin formation and platelet adhesion. Sepsis reduces the production of glycosaminoglycans averting not only antithrombin function, but also that of TFPI with regard to inhibiting the main coagulation TF-factor VIIa complex. In healthy hosts endothelium generates APC from protein C through an interaction between thrombin and thrombomodulin (a receptor expressed by endothelial cells); formation of APC by the thrombomodulin-thrombin complex is accelerated by the endothelial protein C receptor (EPCR). APC inactivates coagulation cofactors Va and VIIIa by proteolysis, thereby inhibiting coagulation. In sepsis APC levels are reduced due to impaired production caused by downregulation of both thrombomodulin and EPCR on endothelial cells, as well as by increased consumption. Adhesion of cells to the endothelium is increased in sepsis. Physiologically, injured endothelium activates von Willebrand factor which forms multimers at the site of injury as a primary step in protective coagulation [25]. Von Willebrand multimers are cleaved by a proteolytic enzyme ADAMTS13 to control adhesion and prevent formation of large obstructive von Willebrand multimers. In sepsis there is a relative deficiency of ADAMTS13 leading to ultra-large von Willebrand multimers at injured sites, contributing to overwhelming platelet adhesion and microvascular thrombosis, and possibly eventually multiple organ dysfunction. Furthermore, activation of platelets because of vascular injury during sepsis starts a vicious cycle which leads to more activated endothelium and platelets which further increases coagulation [25].
RkJQdWJsaXNoZXIy MTk4NDMw