Fig. 3

Mechanisms of intravascular coagulation in sepsis. Sepsis-induced coagulopathy involves both intrinsic and extrinsic coagulation pathways. After vessel damage, the fibers directly activate plasma clotting factor XI (FXI). Injury to the vascular wall also allows FVIIa to come into contact with fibroblasts that carry the TF receptor. The FVIIa/TF complex then activates FX and FIX. Thrombin is generated, and FV, FVIII, FXI and thrombocytes are activated. This pathway serves to propagate coagulation, resulting in the generation of large amounts of thrombin and fibrin. When thrombin binds to the endothelial cell surface protein thrombomodulin (TM), the substrate specificity of the enzyme is altered, resulting in loss of its procoagulant activity. The thrombin–TM complex acts as an anticoagulant by activating protein C (PC) and subsequent thrombin-activatable fibrinolysis inhibitor (TAFI), which attenuates the coagulation cascade by inactivating activated cofactors V and VIII. Endothelial cells have heparan sulfate proteoglycans that bind and enhance plasma coagulation proteins, including tissue factor pathway inhibitor (TFPI) and antithrombin (AT) (synthesized in the liver). Thrombomodulin (TM), which promotes thrombin-mediated activation of protein C (PC), is also expressed on endothelial cells. This reaction is amplified by the endothelial protein C receptor (EPCR). Activated protein C (APC) inactivates FVa and FVIIIa, thereby limiting coagulation. Endothelial cells synthesize and release tissue-type plasminogen activator (tPA), which promotes plasminogen (Plg) to plasmin (Pln) conversion. TM/thrombin interacts with the coagulation–fibrolysis system to act as a negative feedback loop in the presence of APC–EPCR. The interaction between APC and EPCR also enables the switching of the PAR-1 signal to an anti-inflammatory pattern and enhances the integrity of the endothelium via S1P- and Ang/Tie-mediated activities. Fibrinolytic inhibitors, such as plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolytic inhibitor (TAFI), are upregulated under septic conditions and aggravate microvascular thrombosis by preventing fibrin degradation. PAI-1 is produced by ECs, megakaryocytes, smooth muscle cells, fibroblasts, monocytes, adipocytes, hepatocytes, and other cell types. Platelets store a pool of PAI-1, which accounts for more than half of its availability and helps deliver it to the clot. TAFI circulates in the plasma and may be activated by the thrombin-thrombomodulin complex. Thrombin-induced conversion of TAFI to activated TAFI (TAFIa) supports the important role of the coagulation cascade in regulating fibrinolysis. In the context of sepsis, the stimulation of inflammatory cytokines, coagulation factors or VEGF allows the secretion of Ang2 from the WPB. Through an autocrine loop mechanism, Ang2 itself acts as a fast-acting regulator of the endothelium. Thrombomodulin is an endothelial cell surface molecule that plays an essential role as an anticoagulant by acting as a cofactor in the thrombin-mediated activation of protein C and thrombin-activated fibrinolysin inhibitor (TAFI). Ang-1 and Ang-2 are effective in inhibiting the generation of activated protein C and TAFI by thrombin and TM in cultured endothelial cells and in inhibiting the binding of thrombin to TM in vitro. Ang2 appears to be a more potent inhibitor of TM function, binding to TM with higher affinity than Ang1. ↑: activation, ┫: inhibition