Effect of a platelet activating factor antagonist and antithrombin III on septicemia and endotoxemia in rats.

Inoue, Yuuichi; Kohno, Shigeru; Miyazaki, Tatsuya; Yamaguchi, Keiko

doi:10.1620/tjem.163.175

Cited by 10 publications

(4 citation statements)

References 20 publications

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“…Since it was modified and popularized by Wichterman in 1980 [33], the CLP model has been considered the gold standard for sepsis research. Initially, CLP was not as widely used as lipopolysaccharide (LPS) as an inducer of DIC in animal models, probably because of its low reproducibility [34-36]. However, since its standardization by Rittirsch in 2009 [26], it has been possible to reproduce CLP exactly.…”

Section: Discussionmentioning

confidence: 99%

Novel biomarkers for early prediction of sepsis-induced disseminated intravascular coagulation in a mouse cecal ligation and puncture model

Song

et al. 2013

J Inflamm

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IntroductionThe objective of this study was to identify biomarkers of sepsis-induced disseminated intravascular coagulation (DIC) among platelet-derived factors using biotin label-based custom protein microarray technology in a mouse cecal ligation and puncture (CLP) model.MethodsKM mice were randomized into sham-operated and CLP groups. Blood samples were obtained immediately and at 1 h, 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after establishment of the CLP for platelet count, coagulation assay and blood chemistry. Lung and mesentery tissues were examined histologically at all corresponding time points, looking for microthrombus formation. Serial protein microarray analysis was performed to detect platelet-derived factors.ResultsThe survival rate 72 h post-CLP was 15%, but there was no mortality among the sham-operated mice. Compared with the sham group, the platelet count (n = 5, p < 0.05), fibrinogen concentration (n = 5, p < 0.05) and alanine aminotransferase level of the CLP group began to decrease significantly at 6 h post-CLP. Significant prolongation of prothrombin time (n = 5, p < 0.05) and activated partial thromboplastin time (n = 5, p < 0.05) and elevation of D-dimer (n = 5, p < 0.05) occurred after 6 h post-CLP. On histology, microthrombus formation in lung and mesentery tissue was observed in the CLP groups 6 h post-CLP and had become significant and extensive 12 h post-CLP (n = 5, p < 0.05). On protein microarray analysis and ELISA, thrombospondin (TSP), tissue inhibitor of metalloproteinase 1 (TIMP-1) and thymus chemokine-1 (TCK-1) all increased during the first 2 h post-CLP, then remained at a higher level than in the sham group for 72 h post-CLP (n = 5, p < 0.05).ConclusionsTSP, TIMP-1 and TCK-1 are elevated in the early stage of sepsis-induced DIC in a mouse CLP model and may be considered early markers for sepsis-induced DIC.

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Section: Discussionmentioning

confidence: 99%

Novel biomarkers for early prediction of sepsis-induced disseminated intravascular coagulation in a mouse cecal ligation and puncture model

Song

et al. 2013

J Inflamm

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“…After CLP, animals develop hypercoagulability with mild fibrinolysis. Only a few reports have studied thrombi formation in this model and these typically show fibrin deposition or microthrombi formation in organs such as kidney and liver (51, 52), highlighting the impact of coagulopathy during severe infections. Indeed, the development of thrombi rich in platelets in the microvasculature of kidney, lung, and liver has been observed 48 h after CLP, correlating with organ dysfunction due to ischemic complications such as kidney failure and respiratory distress syndrome (53).…”

Section: Models To Study Thrombosis Induced By Infectionmentioning

confidence: 99%

Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models

Beristain‐Covarrubias

et al. 2019

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Thrombosis is a common consequence of infection that is associated with poor patient outcome. Nevertheless, the mechanisms by which infection-associated thrombosis is induced, maintained and resolved are poorly understood, as is the contribution thrombosis makes to host control of infection and pathogen spread. The key difference between infection-associated thrombosis and thrombosis in other circumstances is a stronger inflammation-mediated component caused by the presence of the pathogen and its products. This inflammation triggers the activation of platelets, which may accompany damage to the endothelium, resulting in fibrin deposition and thrombus formation. This process is often referred to as thrombo-inflammation. Strikingly, despite its clinical importance and despite thrombi being induced to many different pathogens, it is still unclear whether the mechanisms underlying this process are conserved and how we can best understand this process. This review summarizes thrombosis in a variety of models, including single antigen models such as LPS, and infection models using viruses and bacteria. We provide a specific focus on Salmonella Typhimurium infection as a useful model to address all stages of thrombosis during infection. We highlight how this model has helped us identify how thrombosis can appear in different organs at different times and thrombi be detected for weeks after infection in one site, yet largely be resolved within 24 h in another. Furthermore, we discuss the observation that thrombi induced to Salmonella Typhimurium are largely devoid of bacteria. Finally, we discuss the value of different therapeutic approaches to target thrombosis, the potential importance of timing in their administration and the necessity to maintain normal hemostasis after treatment. Improvements in our understanding of these processes can be used to better target infection-mediated mechanisms of thrombosis.

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“…Combination of AT III (about 1000 U/kg) and a platelet aggregation factor antagonist in a rat model of cecal ligation and puncture (CLP) was described by Inoue et al 33 The combination therapy significantly reduced glomerular fibrin deposition and survival.…”

Section: Combination Therapy In Sepsismentioning

confidence: 99%

Antithrombin III in Animal Models of Sepsis and Organ Failure

Dickneite¹

1998

Semin Thromb Hemost

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Antithrombin III (AT III) is the physiological inhibitor of thrombin and other serine proteases of the clotting cascade. In the development of sepsis, septic shock and organ failure, the plasma levels of AT III decrease considerably, suggesting the concept of a substitution therapy with the inhibitor. A decrease of AT III plasma levels might also be associated with other pathological disorders like trauma, burns, pancreatitis or preclampsia. Activation of coagulation and consumption of AT III is the consequence of a generalized inflammation called SIRS (systemic inflammatory response syndrome). The clotting cascade is also frequently activated after organ transplantation, especially if organs are grafted between different species (xenotransplantation). During the past years AT III has been investigated in numerous corresponding disease models in different animal species which will be reviewed here. The bulk of evidence suggests, that AT III substitution reduces morbidity and mortality in the diseased animals. While gaining more experience with AT III, the concept of substitution therapy to maximal baseline plasma levels (100%) appears to become insufficient. Evidence from clinical and preclinical studies now suggests to adjust the AT III plasma levels to about 200%, i.e., doubling the normal value. During the last few years several authors proposed that AT III might not only be an anti-thrombotic agent, but to have in addition an anti-inflammatory effect.

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Effect of a platelet activating factor antagonist and antithrombin III on septicemia and endotoxemia in rats.

Cited by 10 publications

References 20 publications

Novel biomarkers for early prediction of sepsis-induced disseminated intravascular coagulation in a mouse cecal ligation and puncture model

Novel biomarkers for early prediction of sepsis-induced disseminated intravascular coagulation in a mouse cecal ligation and puncture model

Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models

Antithrombin III in Animal Models of Sepsis and Organ Failure

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