Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.

Creasey, Abla A.; Chang, Alvin; Feigen, Larry P.; Wun, TC; Taylor, Fletcher B.; Hinshaw, Lerner B.

doi:10.1172/jci116529

Cited by 539 publications

(340 citation statements)

References 25 publications

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“…However, delayed treatment cannot be tested in high-load bacteremic challenge studies because the LD100 challenge leads to early, rapid, and irreversible organ damage as a result of shock, DIC, and capillary leak. We also know from other therapies tested in the LD100 model (28,29) that the chance of success decreases rapidly when the treatment is delayed longer than 1 h postinfection. Experiments testing delayed treatment with C5 inhibitor will likely require the use of a less-severe challenge, such as an LD50 model, and will also require a larger number of animals to achieve statistical significance in determining survival benefit.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

Keshari

Silasi‐Mansat

Popescu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9. RA101295 reduced the E. coliinduced "oxidative burst," as well as leukocyte activation, without affecting host phagocytosis of E. coli. RA101295 treatment reduced plasma LPS content in E. coli-challenged baboons, implying reduced complement-mediated bacteriolysis, whereas treated animals showed slightly improved bacterial clearance during the bacteremic stage compared with controls. Treatment with RA101295 also improved consumptive coagulopathy and preserved endothelial anticoagulant and vascular barrier functions. RA101295 abolished sepsis-induced surges in proinflammatory cytokines and attenuated systemic circulatory and febrile responses, likely reflecting decreased systemic levels of LPS and C5a. Overall, RA101295 treatment was associated with significant organ protection and markedly reduced mortality compared with nontreated controls (four of five animals survived in a 100% lethal model). We therefore conclude that inhibition of C5 cleavage during the bacteremic stage of sepsis could be an important therapeutic approach to prevent sepsis-induced inflammation, consumptive coagulopathy, and subsequent organ failure and death. complement | coagulation | sepsis | Escherichia coli | organ failure

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Section: Discussionmentioning

confidence: 99%

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

Keshari

Silasi‐Mansat

Popescu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This positive result was reduced by 60% when the TFPI was administered 4 h after the lethal dose of E. coli. The effects on coagulation and inflammation were reduced, as indicated by the lower levels of circulating interleukin 6 [76]. However, the infusion of TFPI did not cause haemodynamic instability.…”

Section: Tissue Factor and Tissue Factor Pathway Inhibitor -Clinical mentioning

confidence: 97%

Tissue factor and tissue factor pathway inhibitor

Price

Thompson²,

Kam

2004

Anaesthesia

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SummaryThe classical 'cascade ⁄ waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways. Recent molecular biology and clinical data indicate that tissue factor ⁄ factor-VII interaction is the primary cellular initiator of coagulation in vivo. The process of blood coagulation is divided into an initiation phase followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence has shown that blood-borne tissue factor has an important procoagulant function in sepsis, atherosclerosis and cancer, and other functions beyond haemostasis such as immune function and metastases.

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“…These findings have led to many approaches for attempting to control the multiple septic responses, and replacement of natural endogenous anti-coagulants was believed to offer potential benefits. However, although clinical trials in severe sepsis with anti-thrombin-III and tissue factor pathway inhibitor replacement therapies have proved disappointing, [12][13][14] suppression of thrombin generation by recombinant human activated PC (aPC) may indeed correlate with improved survival, 15 at least in cases of severe sepsis coupled with DIC.…”

mentioning

confidence: 99%

A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

Ganopolsky

Castellino

2004

The American Journal of Pathology

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During the systemic inflammatory state induced by sepsis, the potential for coagulopathy exists because of up-regulation of natural procoagulants and antifibrinolytics, and down-regulation of natural anti-coagulants, with protein C (PC) being a critical example of the latter case. PC functions as an anti-coagulant, profibrinolytic, and anti-inflammatory agent, and, thus, its administration or deficiency may affect the course and outcome of sepsis in patients. In this study, a cecal ligation and puncture model of septic peritonitis was applied to wild-type mice and littermates with a targeted heterozygous deficiency of PC (PC ؉/؊ ) to characterize the importance of a PC-deficiency on polymicrobial sepsis. An enhanced mortality rate was found to accompany a PC deficiency. Plasma cytokines, as well as organ-specific expression of cytokine transcripts, were elevated in PC ؉/؊ mice. No signs of severe disseminated intravascular coagulation (DIC) were observed in wild-type or PC ؉/؊ mice, as indicated by an increase in fibrinogen levels and the invariability of platelet counts after cecal ligation and puncture. Consumption of coagulation factors was similar in both genotypes and a decrease in the PC mRNA and protein levels was more prominent in PC ؉/؊ mice. Renal and organ muscle damage was enhanced in PC ؉/؊ mice, as shown by increases in plasma blood urea nitrogen, creatinine, and creatinine kinase. Hypotension and bradycardia were more enhanced in PC ؉/؊ mice than in wild-type mice, thus provoking a more severe septic shock response. Thus, the hemodynamic role of PC during sepsis is of critical importance to the outcome of the

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Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.

Cited by 539 publications

References 25 publications

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

Tissue factor and tissue factor pathway inhibitor

A Protein C Deficiency Exacerbates Inflammatory and Hypotensive Responses in Mice During Polymicrobial Sepsis in a Cecal Ligation and Puncture Model

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