Plasminogen Activator Inhibitor 1 for Predicting Sepsis Severity and Mortality Outcomes: A Systematic Review and Meta-Analysis

Tipoe, Timothy L.; Wu, William; Chung, Lilianna; Gong, Mengqi; Dong, Mei; Liu, Tong; Roever, Leonardo; Ho, Jeffery; Wong, Martin Cs; Chan, Matthew T. V.; Tse, Gary; Wu, Justin C. Y.; Wong, Sunny H.

doi:10.3389/fimmu.2018.01218

Cited by 61 publications

(56 citation statements)

References 40 publications

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“…UFH has been indicated to exert an anticoagulant effect by binding to the lysine site on AT, which is also modulated by platelets, fibrin, thrombin, factors Xa, IXa, XIa and XIIa and TF (30,31). Tipoe (8) demonstrated that high levels of PAI-1 may predict an adverse outcome in severe sepsis, and suppressed fibrinolysis has been suggested to be one the most important predictors of multiple organ dysfunction during DIC. The results of the present study identified that preconditioning UFH attenuated the level of PAI-1.…”

Section: Discussionmentioning

confidence: 99%

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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%

“…The initiation of fibrinolysis is mediated by plasminogen activators and is regulated by plasminogen activator inhibitor-1 (PAI-1). PAI-1, which indicates poor patient prognosis in sepsis-induced DIC, mediates the inhibition of endogenous fibrinolysis during sepsis (8).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…However, the presence of PAI-1 was found in cells in the heart tissue samples, suggesting that a reduced removal of fibrin may occur, leading to a deposition of fibrin clots in small blood vessels and inadequate tissue perfusion and organ failure (Brandtzaeg et al, 1990;Madoiwa et al, 2006). Previous studies indicate that elevated PAI-1 in plasma or serum is a significant predictor of disease severity and mortality, first discovered in plasma samples from meningococcal sepsis patients (Brandtzaeg et al, 1990;Kornelisse et al, 1996;Tipoe et al, 2018).…”

Section: Transcriptional Profiles In Heart Tissue Samplesmentioning

confidence: 99%

Extensive Changes in Transcriptomic “Fingerprints” and Immunological Cells in the Large Organs of Patients Dying of Acute Septic Shock and Multiple Organ Failure Caused by Neisseria meningitidis

Brusletto

Løberg

Hellerud

et al. 2020

Front. Cell. Infect. Microbiol.

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Background: Patients developing meningococcal septic shock reveal levels of Neisseria meningitidis (10 6-10 8 /mL) and endotoxin (10 1-10 3 EU/mL) in the circulation and organs, leading to acute cardiovascular, pulmonary and renal failure, coagulopathy and a high case fatality rate within 24 h. Objective: To investigate transcriptional profiles in heart, lungs, kidneys, liver, and spleen and immunostain key inflammatory cells and proteins in post mortem formalin-fixed, paraffin-embedded (FFPE) tissue samples from meningococcal septic shock patients. Patients and Methods: Total RNA was isolated from FFPE and fresh frozen (FF) tissue samples from five patients and two controls (acute non-infectious death). Differential expression of genes was detected using Affymetrix microarray analysis. Lung and heart tissue samples were immunostained for T-and B cells, macrophages, neutrophils and the inflammatory markers PAI-1 and MCP-1. Inflammatory mediators were quantified in lysates from FF tissues. Results: The transcriptional profiles showed a complex pattern of protein-coding and non-coding RNAs with significant regulation of pathways associated with organismal death, cell death and survival, leukocyte migration, cellular movement, proliferation of cells, cell-to-cell signaling, immune cell trafficking, and inflammatory responses in an organ-specific clustering manner. The canonical pathways including acute phase response-, EIF2-, TREM1-, IL-6-, HMBG1-, PPAR signaling, and LXR/RXR activation were associated with acute heart, pulmonary, and renal failure. Fewer genes were regulated in the liver and particularly in the spleen. The main upstream regulators were TNF, IL-1β, IL-6, RICTOR, miR-6739-3p, and CD3. Increased numbers of inflammatory cells (CD68+, MPO+, CD3+, and CD20+) were found in lungs and heart. PAI-1 inhibiting Brusletto et al. Transcriptional Profiles in MSS Organs fibrinolysis and MCP-1 attracting leukocyte were found significantly present in the septic tissue samples compared to the controls. Conclusions: FFPE tissue samples can be suitable for gene expression studies as well as immunostaining of specific cells or molecules. The most pronounced gene expression patterns were found in the organs with highest levels of Neisseria meningitidis DNA. Thousands of protein-coding and non-coding RNA transcripts were altered in lungs, heart and kidneys. We identified specific biomarker panels both protein-coding and non-coding RNA transcripts, which differed from organ to organ. Involvement of many genes and pathways add up and the combined effect induce organ failure.

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“…Because the occurrence and development of sepsis is closely related to the immune function of the body (Tipoe et al 2018), we compared the immune function related indicators of the patients. CD4+ expression in MG and SG patients was lower than that in CG patients, whereas CD8+ expression was higher.…”

Section: Discussionmentioning

confidence: 99%

Expression and significance of HMGB1 in patients with sepsis and effects on prognosis

et al. 2020

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This study explored the expression of high mobility group box 1 protein (HMGB1) expression in patients with sepsis and its effects on immune function and prognosis. Patients with sepsis (n = 112) were divided into the mild group (MG, n = 59) and severe group (SG, n = 53) according to the disease severity of sepsis. Fifty healthy people who came to our hospital for physical examination at the same time served as the control group (CG). Serum HMGB1, CD4+, and CD8+ expression levels and CD4+/CD8+ ratios were compared between the three groups. The correlation between serum HMGB1 expression, APACHE II score, and MODS score was analyzed. Serum HMGB1 and CD8+ expressions were lower in the CG group than the values in the MG and SG groups, whereas the CD4+ expression and CD4+/CD8+ ratio were higher. Serum HMGB1 expression in sepsis patients was positively correlated with the APACHEII and MODS scores. In addition, the 28-day survival rate of the MG was higher than that of the SG. HMGB1 was highly expressed in the serum of patients with sepsis. HMGB1 expression was positively associated with the severity of sepsis. In addition, HMGB1 was closely related to the immune function and prognosis of patients with sepsis. ARTICLE HISTORY

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Plasminogen Activator Inhibitor 1 for Predicting Sepsis Severity and Mortality Outcomes: A Systematic Review and Meta-Analysis

Cited by 61 publications

References 40 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

Extensive Changes in Transcriptomic “Fingerprints” and Immunological Cells in the Large Organs of Patients Dying of Acute Septic Shock and Multiple Organ Failure Caused by Neisseria meningitidis

Expression and significance of HMGB1 in patients with sepsis and effects on prognosis

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