# Inflammation: What's There and What's New?
## 2 Inflammatory Mechanisms
### Initiation of the Inflammatory Response
#### 2.1.2. Coagulation Cascade Profile in Inflammatory Processes  
During an infection, a coagulation cascade occurs, and it can be split into two pathways that eventually converge, resulting in thrombin activation and fibrinogen division into fibrin. The intrinsic pathway is a collection of plasma proteins controlled by Hageman factor (factor XII), a liver-produced protein that regulates collagen, basement membranes, and activated platelets by attaching to them [15]. When the Hageman effect is switched on, it causes a series of events that contribute to the development of thrombin. The intrinsic pathway is most frequently stimulated by directed tissue pain. The production of tissue factor, on the other hand, stimulates the extrinsic pathway [16]. Tissue factor acts on tissues that are not normally accessible to the vascular compartment, such as subcutaneous tissues and blood vessel adventitial layers. Moreover, during inflammatory processes, endothelial cells and stimulated monocytes generate tissue factor in response to TNF-a, IL-1, IL-6, and C-reactive protein [17]. The presence of tissue factor activates factor VII, forming a complex with tissue factor and eventually inducing the production of thrombin through the stimulation of coagulating agents. The activation of the coagulation cascade is relevant to the development of fibrin clots and to pro-inflammatory processes. Pro-inflammatory activity has been linked to factor Xa, thrombin, and the tissue factor-VIIa complex. Thrombin and the tissue factor-VIIa complex, in particular, cause mononuclear and endothelial cells to release pro-inflammatory cytokines, such as TNF-a [18]. Such an effect is usually regulated through the linking of particular factors on the membrane of target cells to protease-activated receptors. The inflammatory process then initiates coagulation, which will further amplify the immune process. During inflammation, the clotting cascade is activated, but is restricted by many factors. It inhibits pro-coagulant pathways from unregulated induction. Anti-thrombin, the C protein system, and tissue factor pathway inhibitor (TFPI) are the main well-defined factors. After formation in the liver, anti-thrombin immediately establishes bonds with inactivated thrombin. Heparin, as well as glycosaminoglycans, greatly potentiate this bonding. The association of anti-thrombin with the endothelial cell surface in rodents stimulates the release of PGI2, which inhibits monocyte production of TNF-\(\alpha\) by inhibiting the activation of the nuclear factor-kB (NF-kB) transcription factor. Thus, besides coagulation control, anti-thrombin also presents anti-inflammatory effects [18]. Protein C is a circulating protein that activates endothelial cells through the thrombin-thrombomodulin complex. Through the inactivation of Va and VIIIa, the activation of protein C decelerates the clotting cascade. The induction of thrombin synthesis by TNF-a through monocytes is also inhibited due to the activation of protein C by the inhibition of the activation of NF-kB and AP-1. Thus, protein C acts as an anti-coagulant and as an anti-inflammatory agent. During a sepsis situation, because of the intake and the induction of inflammation and down-regulation of thrombomodulin, the depletion of activated protein C may occur. This contributes to unregulated thrombin production, leading to rapid coagulation and elevated pro-inflammatory activity. Increased mortality in septic patients with low activated protein C levels has shown the significance of protein C in controlling thrombin production during sepsis [19]. TFPI is the third critical element in the regulation of thrombin production. On endothelial cells, TFPI is present and bonded to lipoproteins. Through the formation of a quaternary structure with tissue factor and factor VIIa, TFPI inactivates tissue factor. During inflammation, the induction of tissue factor activity inhibits the extrinsic clotting pathway.