Dataset Information

Are Baseline Levels of Gas6 and Soluble Mer Predictors of Mortality and Organ Damage in Patients with Sepsis? The Need-Speed Trial Database.

ABSTRACT: Soluble tyrosine kinase receptor Mer (sMer) and its ligand Growth arrest-specific protein 6 (Gas6) are predictors of mortality in patients with sepsis. Our aim is to clarify whether their measurement at emergency department (ED) presentation is useful in risk stratification. We re-analyzed data from the Need-Speed trial, evaluating mortality and the presence of organ damage according to baseline levels of sMer and Gas6. 890 patients were eligible; no association with 7- and 30-day mortality was observed for both biomarkers (p > 0.05). sMer and Gas6 levels were significantly higher in acute kidney injury (AKI) patients compared to non-AKI ones (9.8 [4.1-17.8] vs. 7.9 [3.8-12.9] ng/mL and 34.8 [26.4-47.5] vs. 29.8 [22.1-41.6] ng/mL, respectively, for sMer and Gas6), and Gas6 also emerged as an independent AKI predictor (odds ratio (OR) 1.01 [1.00-1.02]). Both sMer and Gas6 independently predicted thrombocytopenia in sepsis patients not treated with anticoagulants (OR 1.01 [1.00-1.02] and 1.04 [1.02-1.06], respectively). Moreover, sMer was an independent predictor of both prothrombin time-international normalized ratio (PT-INR) > 1.4 (OR 1.03 [1.00-1.05]) and sepsis-induced coagulopathy (SIC) (OR 1.05 [1.02-1.07]). An early measurement of the sMer and Gas6 plasma concentration could not predict mortality. However, the biomarkers were associated with AKI, thrombocytopenia, PT-INR derangement and SIC, suggesting a role in predicting sepsis-related organ damage.

SUBMITTER: Gavelli F

PROVIDER: S-EPMC8869255 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Are Baseline Levels of Gas6 and Soluble Mer Predictors of Mortality and Organ Damage in Patients with Sepsis? The Need-Speed Trial Database.

Gavelli Francesco F Molinari Luca L Baldrighi Marco M Salmi Livia L Mearelli Filippo F Fiotti Nicola N Patrucco Filippo F Airoldi Chiara C Bellan Mattia M Sainaghi Pier Paolo PP Di Somma Salvatore S Lupia Enrico E Colonetti Efrem E Muiesan Maria Lorenza ML Biolo Gianni G Avanzi Gian Carlo GC Castello Luigi Mario LM

Biomedicines 20220118 2

Soluble tyrosine kinase receptor Mer (sMer) and its ligand Growth arrest-specific protein 6 (Gas6) are predictors of mortality in patients with sepsis. Our aim is to clarify whether their measurement at emergency department (ED) presentation is useful in risk stratification. We re-analyzed data from the Need-Speed trial, evaluating mortality and the presence of organ damage according to baseline levels of sMer and Gas6. 890 patients were eligible; no association with 7- and 30-day mortality was ...[more]

PMID: 35203408

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Project description:Background: Microglia are well known key regulators of neuroinflammation which feature in multiple neurodegenerative disorders. These cells survey the CNS and, under inflammatory conditions, become "activated" through stimulation of toll-like receptors (TLRs), resulting in changes in morphology and production and release of cytokines. In the present study, we examined the roles of the related TAM receptors, Mer and Axl, and of their ligand, Gas6, in the regulation of microglial pro-inflammatory TNF-α production and microglial morphology. Methods: Primary cultures of murine microglia of wild-type (WT), Mer-/- and Axl-/- backgrounds were stimulated by the TLR4 agonist, lipopolysaccharide (LPS) with or without pre-treatment with Gas6. Gene expression of TNF-α, Mer, and Axl was examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) was used to measure TNF-α release from microglia. Immunofluorescence staining of β-actin and the microglial marker Iba1 was performed to reveal microglial morphological changes, with cellular characteristics (area, perimeter, Feret's diameter, minimum Feret, roundness, and aspect ratio) being quantified using ImageJ software. Results: Under basal conditions, TNF-α gene expression was significantly lower in Axl-/- microglia compared to WT cells. However, all microglial cultures robustly responded to LPS stimulation with the upregulation of TNF-α expression to similar degrees. Furthermore, Mer receptor expression was less responsive to LPS stimulation when in Axl knockout cells. The presence of Gas6 consistently inhibited the LPS-induced upregulation of TNF-α in WT, Mer-/- and Axl-/- microglia. Moreover, Gas6 also inhibited LPS-induced changes in the microglial area, perimeter length, and cell roundness in wild-type cells. Conclusion: Gas6 can negatively regulate the microglial pro-inflammatory response to LPS as well as via stimulation of other TLRs, acting through either of the TAM receptors, Axl and Mer. This finding indicates an interaction between TLR and TAM receptor signaling pathways and reveals an anti-inflammatory role for the TAM ligand, Gas6, which could have therapeutic potential.

Project description:ObjectivesTo assess the effects of recombinant human soluble thrombomodulin treatment on 28-day all-cause mortality in subgroups categorized by baseline coagulation biomarker levels (prothrombin fragment 1.2, thrombin-antithrombin complex, D-dimer) in patients with sepsis-associated coagulopathy in the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin trial (SCARLET) (NCT01598831).DesignPost hoc, subgroup analysis of a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study.SettingICUs at 159 sites in 26 countries.PatientsEight-hundred adults with sepsis-associated coagulopathy defined as international normalized ratio greater than 1.40 and platelet count between 30 × 10/L and 150 × 10/L or greater than 30% decrease within 24 hours with concomitant cardiovascular and/or respiratory failure.InterventionsPatients randomized and treated with recombinant human soluble thrombomodulin (0.06 mg/kg/d; n = 395) or equivalent placebo (n = 405) for 6 days.Measurements and main resultsRecombinant human soluble thrombomodulin did not significantly reduce 28-day all-cause mortality in the Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin trial: absolute risk reduction was 2.55% (p = 0.32) in patients with sepsis-associated coagulopathy. In this post hoc analysis, mortality steadily increased with increasing baseline prothrombin fragment 1.2 and thrombin-antithrombin complex levels in the placebo group; for those values exceeding the upper limit of normal, the mortality increases in the recombinant human soluble thrombomodulin group were lower or negligible with increasing baseline prothrombin fragment 1.2 and thrombin-antithrombin complex. Consequently, absolute risk reductions were greater in subgroups with higher baseline prothrombin fragment 1.2 or thrombin-antithrombin complex. Absolute risk reductions were also greater in subgroups with baseline coagulation biomarker levels at or above median of the entire study population, ranging from 4.2% (95% CI, -5.0% to 13.4%) to 5.5% (95% CI, -4.0% to 14.9%).ConclusionsCompared with patients receiving placebo, patients treated with recombinant human soluble thrombomodulin having higher baseline thrombin generation biomarker levels had lower mortality. Further research regarding the predictive role of coagulation biomarkers for recombinant human soluble thrombomodulin treatment response in sepsis-associated coagulopathy is warranted to evaluate clinical relevance.

Dataset Information

Are Baseline Levels of Gas6 and Soluble Mer Predictors of Mortality and Organ Damage in Patients with Sepsis? The Need-Speed Trial Database.

Publications

Are Baseline Levels of Gas6 and Soluble Mer Predictors of Mortality and Organ Damage in Patients with Sepsis? The Need-Speed Trial Database.

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