Coagulation abnormalities in sepsis

Tsao, Cheng Ming; Ho, Shung Tai; Wu, Chang‐Chieh

doi:10.1016/j.aat.2014.11.002

Cited by 32 publications

(26 citation statements)

References 99 publications

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“…During sepsis, pathogenic agents and inflammatory mediators regulate coagulation through at least 3 simultaneous pathways: The activation of pro-coagulation pathways, the downregulation of physiological anticoagulant production and the inhibition of fibrinolysis (29). F1+2 and TAT are regarded as the sensitive indicators of thrombin generation (6).…”

Section: Discussionmentioning

confidence: 99%

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS‑induced sepsis

et al. 2019

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Sepsis commonly progresses to disseminated intravascular coagulation and induces the activation of heparanase (HPA) and the shedding of endothelial glycocalyx constituents, including syndecan-1 (SDC-1) and heparan sulphate (HS). However, the degradation of glycocalyx and its association with coagulation disorders remains undetermined. The present study aimed to evaluate the effect of unfractionated heparin (UFH) and N-acetylheparin (NAH), which is a non-anticoagulant heparin derivative, on endothelial glycocalyx and coagulation function in a lipopolysaccharide (LPS)-induced sepsis rat model, and to compare the differences observed in coagulation function between UFH and NAH. Experimental rats were randomly assigned to four groups: Control; LPS; UFH + LPS; and NAH + LPS. Rats were administered UFH or NAH and subsequently, ~1 min later, administered LPS (10 mg/kg; intravenous). The blood and lung tissues of rats were collected 0.5, 2 and 6 h after LPS injection, and were used for subsequent analysis. The results demonstrated that HPA activity and SDC-1 and HS levels increased, and this increase was associated with inflammatory cytokines and coagulation/fibrinolysis markers in the sepsis rat model. Histopathological examination was performed, and the lung injury score and lung wet/dry ratio indicated that UFH and NAH also significantly improved lung tissue injury. The results of the ELISA analysis demonstrated that UFH and NAH treatment: i) significantly decreased the levels of inflammatory cytokines including tumor necrosis factor-α and interleukin-6; ii) inhibited HPA activity and protected the integrity of the glycocalyx, which was identified by decreased HS and SDC-1 levels; and iii) decreased the levels of prothrombin fragment 1+2, thrombin-antithrombin complex, and plasminogen activator inhibitor-1 and increased the levels of fibrinogen and antithrombin-III. Preconditioning with UFH decreased the plasma activated partial thromboplastin time. These results indicated that UFH and NAH may alleviate sepsis-induced coagulopathy, and this effect may have been due to an inhibition of HPA activity and decrease in the shedding of the endothelial glycocalyx.

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Section: Discussionmentioning

confidence: 99%

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS‑induced sepsis

et al. 2019

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“…As is well known, LPS itself is a strong inducer of coagulation, whether via tissue factor or otherwise [e.g., Ref. (1039–1048)], and will bind to fibrin strongly (259, 1049). The morphological methods have not yet, to our knowledge, been performed on blood from preeclamptics, whether as a diagnostic or a prognostic, although we note that clotting factors came top in one GWAS looking for gene–PE associations (117).…”

Section: Clotting Coagulopathies and Fibrinogen In Pementioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

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“…As is well known, LPS itself is a strong inducer of coagulation, whether via tissue factor or otherwise (e.g. [972–981]), and will bind to fibrin strongly [252; 982]. The morphological methods have not yet to our knowledge been performed on blood from pre-eclamptics, whether as a diagnostic or a prognostic, though we note that clotting factors came top in one GWAS looking for gene-PE associations [111].…”

Section: Clotting Coagulopathies and Fibrinogen In Pementioning

confidence: 99%

A Dormant Microbial Component in the Development of Pre-Eclampsia¹

Kell

Kenny

2016

Preprint

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Pre-eclampsia (PE) is a complex, multi-system disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE, and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused.We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is in fact microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “pre-eclampsia” that we assessed has in fact also been shown to be raised in response to infection. An infectious component to PE fulfils the Bradford Hill criteria for ascribing a disease to an environmental cause, and suggests a number of treatments, some of which have in fact been shown to be successful.PE was classically referred to as endotoxaemia or toxaemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the aetiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.Insight, innovation, integrationMany descriptors of pre-eclampsia are widely accepted (e.g. abnormal trophoblast invasion, oxidative stress, inflammation and altered immune response, and anti-angiogenic responses). However, without knowing what causes them, they do not explain the syndrome. The Biological Insight of this manuscript is that there is considerable evidence to the effect that each of these phenomena (hence PE) are caused by the resuscitation of dormant bacteria that shed (known and potent) inflammagens such as LPS, often as a consequence of iron availability. PE is thus seen as a milder form of sepsis. The Technological Innovations come from the use of molecular markers (of microbes and omics more generally, as well as novel markers of coagulopathies) to measure this. The Benefit of Integration comes from bringing together a huge number of disparate observations into a unifying theme.

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Coagulation abnormalities in sepsis

Cited by 32 publications

References 99 publications

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS‑induced sepsis

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS‑induced sepsis

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Pre-Eclampsia¹

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Coagulation abnormalities in sepsis

Cited by 32 publications

References 99 publications

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS‑induced sepsis

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS‑induced sepsis

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Pre-Eclampsia1

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A Dormant Microbial Component in the Development of Pre-Eclampsia¹