scholarly journals Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4762-4768 ◽  
Author(s):  
Erik I. Tucker ◽  
Norah G. Verbout ◽  
Philberta Y. Leung ◽  
Sawan Hurst ◽  
Owen J. T. McCarty ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Inflammatory Responses ◽  
Bowel Perforation ◽  
Multiple Organ ◽  
Factor Xii ◽  
Contact Activation ◽  
Factor Xi ◽  
Intravascular Coagulation ◽  
Vehicle Treatment ◽  
Severe Infections

Abstract Severe bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- antithrombin complex formation, IL-6, and TNF-α levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibiting FXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks.

Induction of Disseminated Intravascular Coagulation in the Factor XII-deficient Fowl

1973 ◽  
Vol 30 (01) ◽  
pp. 025-035 ◽  
Author(s):  
Fredrik Skjørten ◽  
Stein A. Evensen
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Plasma Proteins ◽  
Coagulation Factors ◽  
Factor Xii ◽  
Contact Activation ◽  
Intravascular Coagulation ◽  
Fibrillar Material ◽  
Ultrastructural Appearance ◽  
Tissue Thromboplastin ◽  
Homologous Tissue

SummaryBirds are naturally deficient in the coagulation factors responsible for the contact activation reactions in mammalian plasma. In the present study, fowl lungs were examined for evidence of disseminated intravascular coagulation (DIC) 5 min or 4 hours after injection of either Liquoid or bacterial endotoxin. These substances are potent initiators of DIC in mammals, and activation of factor XII is believed to be essential for their triggering effect.Liquoid injection produced intravascular deposits with the light microscopical staining properties of fibrin. However these deposits had a purely granular ultra-structure; their formation was not prevented by adequate anticoagulation, and there was no concomitant thrombocyte aggregation. It is suggested that the deposits represent precipitates of plasma proteins, including fibrinogen.Endotoxin failed to produce clinical reactions, intravascular deposits or thrombocyte aggregates. In contrast, animals injected with homologous tissue thromboplastin died, and fibrillar material with the ultrastructural appearance of fibrin, as well as thrombocyte aggregates were found in small pulmonary vessels. These effects were completely prevented by anticoagulation.We conclude that both Liquoid and endotoxin failed to trigger DIC in the factor XII-deficient fowl, suggesting that these substances depend on the contact activation reactions for the generation of thrombin.

Disseminated intravascular coagulation in meningococcal sepsis

2003 ◽  
Vol 23 (03) ◽  
pp. 125-130 ◽  
Author(s):  
S. Zeerleder ◽  
R. Zürcher Zenklusen ◽  
C. E. Hack ◽  
W. A. Wuillemin
Keyword(s):  
Organ Dysfunction ◽  
Disseminated Intravascular Coagulation ◽  
Skin Necrosis ◽  
Multiple Organ ◽  
Meningococcal Sepsis ◽  
Multiple Organ Dysfunction ◽  
Intravascular Coagulation ◽  
Therapeutic Concepts ◽  
New Therapeutic Concepts ◽  
Coagulation And Fibrinolysis

SummaryWe report on a man (age: 49 years), who died from severe meningococcal sepsis with disseminated intravascular coagulation (DIC), multiple organ dysfunction syndrome and extended skin necrosis. We discuss in detail the pathophysiology of the activation of coagulation and fibrinolysis during sepsis. The article discusses new therapeutic concepts in the treatment of disseminated intravascular coagulation in meningococcal sepsis, too.

scholarly journals Simvastatin improves the prognosis of endotoxin-induced disseminated intravascular coagulation by regulating the intestinal microenvironment

2020 ◽  
Author(s):  
Min Xu ◽  
Lili Luo ◽  
Mengyi Du ◽  
Lu Tang ◽  
Jie Zhou ◽  
...  
Keyword(s):  
Bacterial Translocation ◽  
Disseminated Intravascular Coagulation ◽  
Intestinal Barrier ◽  
Plasminogen Activator Inhibitor ◽  
Coagulation Factors ◽  
Organ Damage ◽  
Multiple Organ ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intravascular Coagulation ◽  
Coagulation Dysfunction

Abstract Background: Disseminated intravascular coagulation (DIC) is characterized by extensive endothelial injury and coagulation activation that is primarily caused by infection and can be aggravated by the gut due to increased permeability and bacterial translocation. Studies have shown that statins play an important role in reducing inflammation, protecting the endothelium and improving coagulation. In addition, statins regulate tight junction (TJ) proteins and gut microbes. Therefore, we aimed to investigate whether simvastatin improves DIC prognosis by regulating the intestinal microenvironment. Methods: Mice were administered 20 mg/kg simvastatin by gavage for 2 weeks and then intraperitoneally injected with 50 mg/kg endotoxin. Twelve hours later, cytokine release, coagulation dysfunction, multiple organ damage and survival were assessed. In addition, intestinal barrier and permeability and bacteria and bacteria translocation were evaluated. Results: We found that the severity of endotoxin-induced DIC was significantly improved in simvastatin-pretreated mice, who showed attenuated depletion of coagulation factors and platelets, decreased plasminogen activator inhibitor-1 (PAI-1) expression, reduced organ fibrin deposition and an improved survival rate. In addition, simvastatin reduced epithelial apoptosis, increased TJ gene expression, and upregulated antimicrobial peptides, lysozyme and mucins. Simvastatin-pretreated mice showed increased Lactobacillales counts, while the LPS group had increased numbers of Desulfovibrio and Mucispirillum, which produce harmful toxins and damage the intestinal epithelium and mucosa. Finally, with the decreased intestinal permeability in the simvastatin group, bacterial translocation in the organs and blood was significantly reduced, both in quantity and species. Conclusions: Simvastatin improves DIC prognosis, and the intestinal microenvironment participates in this process.

Coagulation factor XI improves host defence during murine pneumonia-derived sepsis independent of factor XII activation

2017 ◽  
Vol 117 (08) ◽  
pp. 1601-1614 ◽  
Author(s):  
Ingrid Stroo ◽  
Sacha Zeerleder ◽  
Chao Ding ◽  
Brenda Luken ◽  
Joris Roelofs ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Klebsiella Pneumoniae ◽  
Inflammatory Responses ◽  
Coagulation Factor ◽  
Host Defence ◽  
Human Neutrophils ◽  
Factor Xii ◽  
Factor Xi ◽  
Phagocytic Capacity ◽  
Bacterial Outgrowth

SummaryBacterial pneumonia, the most common cause of sepsis, is associated with activation of coagulation. Factor XI (FXI), the key component of the intrinsic pathway, can be activated via factor XII (FXII), part of the contact system, or via thrombin. To determine whether intrinsic coagulation is involved in host defence during pneumonia and whether this is dependent on FXII activation, we infected in parallel wild-type (WT), FXI knockout (KO) and FXII KO mice with two different clinically relevant pathogens, the Gram-positive bacterium Streptococcus pneumoniae and the Gram-negative bacterium Klebsiella pneumoniae, via the airways. FXI deficiency worsened survival and enhanced bacterial outgrowth in both pneumonia models. This was accompanied with enhanced inflammatory responses in FXI KO mice. FXII KO mice were comparable with WT mice in Streptococcus pneumoniae pneumonia. On the contrary, FXII deficiency improved survival and reduced bacterial outgrowth following infection with Klebsiella pneumoniae. In both pneumonia models, local coagulation was not impaired in either FXI KO or FXII KO mice. The capacity to phagocytose bacteria was impaired in FXI KO neutrophils and in human neutrophils where activation of FXI was inhibited. Deficiency for FXII or blocking activation of FXI via FXIIa had no effect on phagocytosis. Taken together, these data suggest that FXI protects against sepsis derived from Streptococcus pneumoniae or Klebsiella pneumoniae pneumonia at least in part by enhancing the phagocytic capacity of neutrophils by a mechanism that is independent of activation via FXIIa.Supplementary Material to this article is available online at www.thrombosis-online.com.

Septic Shock, Multiple Organ Failure, and Disseminated Intravascular Coagulation

CHEST Journal ◽  
1992 ◽  
Vol 101 (3) ◽  
pp. 816-823 ◽  
Author(s):  
Francois Fourrier ◽  
Claude Chopin ◽  
Jenny Goudemand ◽  
Sylvie Hendrycx ◽  
Claudine Caron ◽  
...  
Keyword(s):  
Septic Shock ◽  
Multiple Organ Failure ◽  
Organ Failure ◽  
Disseminated Intravascular Coagulation ◽  
Multiple Organ ◽  
Intravascular Coagulation
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