Activation of the protein C pathway in acute sepsis

Alcaraz, Antonio García; España, Francisco; Sánchez-Cuenca, J.M.; Zuazu, Isabel; Estellés, Amparo; Aznar, Justo; Vicente, Vicente

doi:10.1016/0049-3848(95)00093-7

Cited by 33 publications

(25 citation statements)

References 35 publications

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“…Cell surface-associated TM also serves as an important scavenging site for thrombin and loss of this function, in conjunction with very low levels of AT, may result in an increase in the availability of free thrombin in the bronchoalveolar space. In addition, low levels of PC and APC may have been caused in part by increased consumption, increased binding to protein C inhibitor (forming APC-PCI complexes) (44), and degradation of PC by the neutrophil degranulation product elastase (45), although in our investigation only LPS and not LTA elicited detectable neutrophil exocytosis in the lung. LTA and LPS similarly impacted bronchoalveolar fibrinolysis, whereby the LPS-induced effects were strictly in accordance with our earlier studies in healthy humans, characterized by an overall suppressed fibrinolytic activity as reflected by reduced PA levels and increased PAI-1 concentrations (11)(12)(13).…”

Section: Discussionmentioning

confidence: 95%

Activation of coagulation and inhibition of fibrinolysis in the human lung on bronchial instillation of lipoteichoic acid and lipopolysaccharide*

Hoogerwerf

Vos

Levi

et al. 2009

Critical Care Medicine

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Section: Discussionmentioning

confidence: 95%

Activation of coagulation and inhibition of fibrinolysis in the human lung on bronchial instillation of lipoteichoic acid and lipopolysaccharide*

Hoogerwerf

Vos

Levi

et al. 2009

Critical Care Medicine

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“…The ac tivation of the protein C pa thway w as evide nc ed by the appea rance of a nd/or increas e in APC:PCI and APC :α 1 AT c omple x levels in circ ula tion. A ll these obse rvations c onfirme d the involve me nt of the prote in C pa thw ay in huma n sepsis [151].…”

Section: Protein C System and Inflammationmentioning

confidence: 99%

“…Inflammation reduces free protein S (PS) in circulation by increasing C4b-binding protein (C4b-BP), leading to the formation of PS-C4b-BP without anticoagulant activity. fever experienced a generalized activation of the protein C pathway, which resulted in consumption of protein C and PCI, and in the appearance of APC:inhibitor complexes [30], suggesting that this pathway is intimately involved in vivo in the interaction of the coagulation and inflammatory system and highlighting the interest in screening the protein C system in clinical situations where the inflammatory process in a variety of vasculitides is involved [151]. Moreover, we also show ed that, in the course of se ps is, patients experie nce d a ge ne raliz ed ac tivation of the protein C pa thway w hic h is more promine nt in the ac ute phas e of the dis eas e, re sulting in the cons umption of protein C and PCI a nd in the inc re ase of APC:inhibitor c omple xe s [151].…”

Section: Protein C System and Inflammationmentioning

confidence: 99%

The Multifunctional Protein C System

España¹,

Medina²,

Navarro³

et al. 2005

CMCCHA

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The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.

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“…This profibrinolytic activity of APC is not shared by antithrombin [1, 2]. APC actually binds to the active site of PAI-1 and as such blocks the serine protease inhibitor actions of PAI-1 [2,100,101]. The reaction of APC with PAI-1 is relatively slow, but the rate is enhanced dramatically by vitronectin [102], raising the possibility that the profibrinolytic effects of APC might center around cells such as platelets that can release vitronectin.…”

Section: Endogenous Mechanisms To Prevent Thrombus Formationmentioning

confidence: 99%

“…The acute phase complement component C4b-binding protein is upregulated in inflammation, and binds and inactivates protein S. Protein S is an endogenous coagulation inhibitor that enhances the activity of APC as an inhibitor of factors Va and VIIIa [2,100]. A summary of some of the procoagulant effects that accompany the acute inflammatory response is provided in Table 3.…”

Section: The Mechanisms By Which Inflammatory Responses Promote Coagumentioning

confidence: 99%

Untitled

2002

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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...

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Activation of the protein C pathway in acute sepsis

Cited by 33 publications

References 35 publications

Activation of coagulation and inhibition of fibrinolysis in the human lung on bronchial instillation of lipoteichoic acid and lipopolysaccharide*

Activation of coagulation and inhibition of fibrinolysis in the human lung on bronchial instillation of lipoteichoic acid and lipopolysaccharide*

The Multifunctional Protein C System

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