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Chapter 12 : Coagulation and Innate Immunity

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Abstract:

This chapter summarizes the current information on the linkage between the regulation of the coagulation and inflammatory responses to infection. Inflammation can affect coagulation status in less overt fashions. Inflammatory mediators such as interleukin-6 (IL-6) can not only increase platelet production, but the platelets that are generated are more thrombogenic, demonstrating an increased sensitivity to platelet agonists like thrombin. Among the major anticoagulant mechanisms, the protein C anticoagulant pathway is the most complex and appears to be the most impacted by acute inflammatory responses. Both antithrombin and protein C inhibitor play major roles in inactivating thrombomodulin (TM)-bound thrombin, resulting in a half-life for the bound thrombin of about 1 to 2 s. The difference in efficacy in modulating the host response to bacterial and endotoxin infusion between artificial anticoagulants and the natural anticoagulants suggests that the anti-inflammatory activities of the natural anticoagulants may be very important aspects of their physiological functions. The role of cleavage of the protease-activated receptors in activated protein C (APC) function remains to be fully elucidated. Most of the downstream events following activation of these receptors enhance inflammation. TM accelerates thrombin activation of a plasma procarboxypeptidase B, often named thrombin-activatable fibrinolysis inhibitor (TAFI). It is now recognized that even the statins thought originally to function by lowering cholesterol have important anti-inflammatory effects as well. Further identification of the links between inflammation and thrombosis should provide novel approaches to new diagnostics and therapeutics.

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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FIGURE 1

A simplified view of the regulation of blood coagulation by the protein C pathway. Factor VIIa binds to tissue factor (TF) to activate factor X, generating factor Xa. Factor Xa then binds to factor Va. The complex of factors Xa and V converts prothrombin (Pro) to thrombin (T).Thrombin can then either bind to TM or carry out procoagulant reactions like fibrin formation or platelet activation. When bound to TM, thrombin can activate protein C (PC) to APC. This process is enhanced when protein C is bound to EPCR. APC bound to EPCR cleaves substrates other than factor Va. APC dissociates from EPCR and can then interact with protein S to inactivate factor Va. The middle row shows inactivation of the factor IXa (IXa)-factor VIIIa complex by APC. In this case, factor V participates with APC and protein S in the inactivation of factor VIIIa. In the bottom row, the plasma proteinase inhibitors that regulate the protein C activation complex and the anticoagulant complex of APC and protein S are illustrated. α-AT, α-antitrypsin; α-Mac, α-macroglobulin; PCI, protein C inhibitor; and AT, antithrombin. TAFI is activated (TAFIa) by the thrombin-TM complex. TAFIa then inactivates C5a. For simplicity, the activation of factors VII,V, and VIII is not shown. Figure modified with permission from Esmon, 1999, copyright F. K. Schattauer.

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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Image of FIGURE 2
FIGURE 2

Thrombin is a multifunctional enzyme and generates the procoagulant, anticoagulant, inflammatory, and mitogenic responses. These responses serve to shift the hemostatic balance. EC, endothelial cell; PMNs, polymorphonucleocytes; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; CD40L, CD40 ligand; MCP-1, macrophage chemotactic protein-1. (From Esmon, 1993, with permission from the vol. 9, copyright by Annual Reviews.)

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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Image of FIGURE 3
FIGURE 3

Impact of inflammation on coagulation.

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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