Sepsis-associated disseminated intravascular coagulation and thromboembolic disease

Abstract

Sepsis is almost invariably associated with haemostatic abnormalities ranging from subclinical activation of blood coagulation (hypercoagulability), which may contribute to localized venous thromboembolism, to acute disseminated intravascular coagulation (DIC), characterized by massive thrombin formation and widespread microvascular thrombosis, partly responsible of the multiple organ dysfunction syndrome (MODS), and subsequent consumption of platelets and coagulation proteins causing, in most severe cases, bleeding manifestations. There is general agreement that the key event underlying this life-threatening sepsis complication is the overwhelming inflammatory host response to the infectious agent leading to the overexpression of inflammatory mediators. Mechanistically, the latter, together with the micro-organism and its derivatives, causes DIC by 1) up-regulation of procoagulant molecules, primarily tissue factor (TF), which is produced mainly by stimulated monocytes-macrophages and by specific cells in target tissues; 2) impairment of physiological anticoagulant pathways (antithrombin, protein C pathway, tissue factor pathway inhibitor), which is orchestrated mainly by dysfunctional endothelial cells (ECs); and 3) suppression of fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1) by ECs and likely also to thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor (TAFI). Notably, clotting enzymes non only lead to microvascular thrombosis but can also elicit cellular responses that amplify the inflammatory reactions. Inflammatory mediators can also cause, directly or indirectly, cell apoptosis or necrosis and recent evidence indicates that products released from dead cells, such as nuclear proteins (particularly extracellular histones), are able to propagate further inflammation, coagulation, cell death and MODS. These insights into the pathogenetic mechanisms of DIC and MODS may have important implications for the development of new therapeutic agents that could be potentially useful particularly for the management of severe sepsis.

Figure 1.

Up-regulation of Tissue Factor (TF) in Sepsis. Infectious agents, their products, and endogenous inflammatory mediators induce TF synthesis in various blood cells as well as the release of TF-bearing microparticles from activated or apoptotic cells. The latter may fuse with different cells and make them capable of activating coagulation. Available evidence point to monocytes-macrophages as the most important procoagulant cells in sepsis.

Figure 2.

Anticoagulant properties of endothelial cells. Heparan-sulphate (HS) is expressed on the endothelial surface and accelerates the interaction between antithrombin (AT) and its target enzymes, among which factor Xa and thrombin (IIa). Thrombomodulin (TM) and endothelial protein C receptor (EPCR) are also membrane proteins and are involved in protein C (PC) activation. Tissue factor pathway inhibitor (TFPI) and protein S (PS) are released into blood. TFPI, after combining with factor Xa, binds to and neutralizes the TF/VIIa complex on cell surfaces. Protein S is the cofactor of activated protein C (APC) which degrades factors Va and VIIIa. Micro-organisms and inflammatory mediators down-regulate the anticoagulant properties of the endothelium in different ways (see text).

Figure 3.

Fibrinolysis suppression in sepsis. Microorganisms, their products, and endogenous inflammatory mediators may lead to hypofibrinolysis by enhancing the release of plasminogen activator inhibitors (mainly PAI-1), particularly by endothelial cells. The same agents may variably influence the release of t-PA (see text for further details).