Untitled

Abstract

23 APC = activated protein C; CRP = C-reactive protein; EPCR = endothelial protein C receptor; IL = interleukin; LBP = lipopolysaccharide-binding protein; LPS = lipopolysaccharide; MAPK = mitogen-activated protein kinase; NF-κB = nuclear factor-κB; PAI = plasminogen activator inhibitor; PAR = protease-activated receptor; TAFI = thrombin activatable fibrinolysis inhibitor; TF = tissue factor; TFPI = tissue factor pathway inhibitor; TLR = Toll-like receptor; TNF = tumor necrosis factor. Available online http://ccforum.com/content/7/1/23Humoral and cellular elements of the innate immune system (complement components, mannose binding lectins, soluble CD14, defensins, antimicrobial peptides, neutrophils, monocyte/macrophage cell lines, natural killer cells) are recognized as the principal early responders following microbial infection. Perturbations of the clotting system frequently accompany systemic inflammatory states, and at least some of the elements of the coagulation system are almost invariably activated in patients with septic shock [1][2][3]. The simultaneous activation of the inflammatory response and the clotting cascade following tissue injury is a phylogenetically ancient survival strategy. The linkage between coagulation and inflammation can be traced back to the earliest events in eukaryotic evolution before the separation of plants and invertebrate animals from the evolutionary pathway that led toward vertebrate animal development.Homologous structures of the Toll and IL-1 receptor domain are found in plants, where they function to activate antimicrobial peptides within plant cells in response to microbial invasion (for review [4,5]). The evolutionary linkage between coagulation and inflammation is perhaps best exemplified by the study of host defenses of the horseshoe crab (Limulus polyphemus). This ubiquitous crab commonly inhabits coastal marine waters in the temperate regions of the Northern Hemisphere. This animal has been invaluable in the study of ancestry of the coagulation cascades and antimicrobial defense mechanisms of the innate immune response. AbstractThe innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a...

The Multifunctional Protein C System

“…These trials looked for agents that could provide anticoagulant, antiinflammatory, and anti-endotoxin activity. However, plasmaderived antithrombin [152,153] and recombinant tissue factor pathway inhibitor (tifacogin trial) did not show any clinical efficacy. Only APC was able to show beneficial clinical outcomes [154][155][156][157][158].…”

Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy

“…One important feature of monocytes in HIV pathogenesis is their capacity to produce TF (8-10). TF is expressed in response to inflammatory stimuli such as toll-like receptors (TLR) (11-13) and cytokine-driven signals (14, 15) and initiates the extrinsic coagulation cascade by cleaving coagulation factors leading to formation of Factor Xa, thrombin and fibrin, which when degraded forms the coagulation biomarker D-dimer (16, 17). For these reasons, augmented TF expression is associated with increased levels of D-dimer (18) and thus may be associated with an increased risk for cardiovascular complications in HIV-infected individuals (19).…”

Lactobacillus casei: influence on the innate immune response and haemostatic alterations in a liver-injury model

“…Unfortunately, in the liver, as in other organs, an excessive inflammatory response bears the risk of additional tissue damage (Chandra 2004). In addition, an inflammatory state leads invariably to the activation of the coagulation system and to the inhibition of anticoagulatory and fibrinolytic mechanisms (Opal and Esmon 2003). Alterations in the synthesis of coagulation factors during hepatic injury contributes to the modifications of haemostasis observed in some liver diseases.…”