Metabolome of Cerebral Thrombi Reveals an Association between High Glycemia at Stroke Onset and Good Clinical Outcome

Suissa, Laurent; Guigonis, Jean-Marie; Graslin, Fanny; Doche, Emilie; Osman, Ophélie; Chau, Yves; Sédat, Jacques; Lindenthal, Sabine; Pourcher, Thierry

doi:10.3390/metabo10120483

Cited by 10 publications

(14 citation statements)

References 23 publications

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“…Though glucose is the substrate for sorbitol synthesis and is metabolized in the glycolytic pathway, this did not seem affected in these patients, as shown by proteomic analysis. Conversely, the excess of extracellular glucose in patients with AIS may be converted into sorbitol by the polyol pathway at stroke onset [ 26 ]. Regarding the predictive models, the authors applied the sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) to determine the relationship between relevant metabolites and favorable clinical outcomes.…”

Section: Multiomic Studiesmentioning

confidence: 99%

“…Methodologically, the performance of classical predictors of CE and omic signatures was evaluated using ROC curves and area under curves receiver operating characteristic (AUROC). Similarly to the previously discussed study by Suissa et al [ 26 ], the authors used sPLS-DA to discriminate between different origins of cerebral thrombi, applied logarithm transformations to the data, and analyzed untargeted proteomic and metabolomic results. The internal validity was checked using resampling methods and cross-validations.…”

Section: Multiomic Studiesmentioning

confidence: 99%

“…Recent studies [ 21 , 22 , 23 , 24 , 25 , 26 ] have evaluated omic techniques to assess thrombi composition. These refer to a variety of technologies enabling deep phenotyping of biological samples to define their molecular characteristics [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

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Corti

et al. 2023

IJMS

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Cerebrovascular diseases represent a leading cause of disability, morbidity, and death worldwide. In the last decade, the advances in endovascular procedures have not only improved acute ischemic stroke care but also conceded a thorough analysis of patients’ thrombi. Although early anatomopathological and immunohistochemical analyses have provided valuable insights into thrombus composition and its correlation with radiological features, response to reperfusion therapies, and stroke etiology, these results have been inconclusive so far. Recent studies applied single- or multi-omic approaches—such as proteomics, metabolomics, transcriptomics, or a combination of these—to investigate clot composition and stroke mechanisms, showing high predictive power. Particularly, one pilot studies showed that combined deep phenotyping of stroke thrombi may be superior to classic clinical predictors in defining stroke mechanisms. Small sample sizes, varying methodologies, and lack of adjustments for potential confounders still represent roadblocks to generalizing these findings. However, these techniques hold the potential to better investigate stroke-related thrombogenesis and select secondary prevention strategies, and to prompt the discovery of novel biomarkers and therapeutic targets. In this review, we summarize the most recent findings, overview current strengths and limitations, and present future perspectives in the field.

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Section: Multiomic Studiesmentioning

confidence: 99%

Section: Multiomic Studiesmentioning

confidence: 99%

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Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

Costamagna

Bonato

Corti

et al. 2023

IJMS

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“…Interestingly, increased glucose can lead to sorbitol production in erythrocytes, impairing the antioxidant function of red blood cells [ 22 ]. However, increased erythrocyte sorbitol levels have been associated with positive outcomes in stroke patients [ 23 ]. Although the mechanism explaining this discrepancy is not known, we can only speculate that NADPH consumption for sorbitol production may limit the pool of NADPH for NADPH oxidase, thus limiting the production of ROS.…”

Section: Red Blood Cells In Atherosclerosismentioning

confidence: 99%

Unexplored Roles of Erythrocytes in Atherothrombotic Stroke

Papadopoulos

Αναγνωστοπουλοσ

Tsiptsios

et al. 2023

Neurology International

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Stroke constitutes the second highest cause of morbidity and mortality worldwide while also impacting the world economy, triggering substantial financial burden in national health systems. High levels of blood glucose, homocysteine, and cholesterol are causative factors for atherothrombosis. These molecules induce erythrocyte dysfunction, which can culminate in atherosclerosis, thrombosis, thrombus stabilization, and post-stroke hypoxia. Glucose, toxic lipids, and homocysteine result in erythrocyte oxidative stress. This leads to phosphatidylserine exposure, promoting phagocytosis. Phagocytosis by endothelial cells, intraplaque macrophages, and vascular smooth muscle cells contribute to the expansion of the atherosclerotic plaque. In addition, oxidative stress-induced erythrocytes and endothelial cell arginase upregulation limit the pool for nitric oxide synthesis, leading to endothelial activation. Increased arginase activity may also lead to the formation of polyamines, which limit the deformability of red blood cells, hence facilitating erythrophagocytosis. Erythrocytes can also participate in the activation of platelets through the release of ADP and ATP and the activation of death receptors and pro-thrombin. Damaged erythrocytes can also associate with neutrophil extracellular traps and subsequently activate T lymphocytes. In addition, reduced levels of CD47 protein in the surface of red blood cells can also lead to erythrophagocytosis and a reduced association with fibrinogen. In the ischemic tissue, impaired erythrocyte 2,3 biphosphoglycerate, because of obesity or aging, can also favor hypoxic brain inflammation, while the release of damage molecules can lead to further erythrocyte dysfunction and death.

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“…116 Nevertheless, metabolomics analysis suggested clot sorbitol content as a surrogate marker reflecting blood glucose level at stroke onset. 117 PLT, RBC, and WBC content of AIS thrombi could be estimated through biochemical quantification of glycoprotein (GP) VI (immunoassay), heme (formic acid-based colorimetric assay), and DNA (dsDNA fluorescence assay kit) in thrombus homogenates. 118 Hemoglobin (ELISA) and heme content were highly correlated with RBC content determined by flow cytometry.…”

Section: Thrombus Composition: Molecular Biology Biochemical Assays and Flow Cytometrymentioning

confidence: 99%

Clot Composition Analysis as a Diagnostic Tool to Gain Insight into Ischemic Stroke Etiology: A Systematic Review

et al. 2021

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Mechanical thrombectomy renders the occluding clot available for analysis. Insights into thrombus composition could help establish the stroke cause. We aimed to investigate the value of clot composition analysis as a complementary diagnostic tool in determining the etiology of large vessel occlusion (LVO) ischemic strokes (International Prospective Register of Systematic Reviews [PROSPERO] registration # CRD42020199436). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we ran searches on Medline (using the PubMed interface) and Web of Science for studies reporting analyses of thrombi retrieved from LVO stroke patients subjected to mechanical thrombectomy (January 1, 2006 to September 21, 2020). The PubMed search was updated weekly up to February 22, 2021. Reference lists of included studies and relevant reviews were hand-searched. From 1,714 identified studies, 134 eligible studies (97 cohort studies, 31 case reports, and six case series) were included in the qualitative synthesis. Physical, histopathological, biological, and microbiological analyses provided information about the gross appearance, mechanical properties, structure, and composition of the thrombi. There were non-unanimous associations of thrombus size, structure, and composition (mainly proportions of fibrin and blood formed elements) with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) etiology and underlying pathologies, and similarities between cryptogenic thrombi and those of known TOAST etiology. Individual thrombus analysis contributed to the diagnosis, mainly in atypical cases. Although cohort studies report an abundance of quantitative rates of main thrombus components, a definite clot signature for accurate diagnosis of stroke etiology is still lacking. Nevertheless, the qualitative examination of the embolus remains an invaluable tool for diagnosing individual cases, particularly regarding atypical stroke causes.

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Metabolome of Cerebral Thrombi Reveals an Association between High Glycemia at Stroke Onset and Good Clinical Outcome

Cited by 10 publications

References 23 publications

Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

Unexplored Roles of Erythrocytes in Atherothrombotic Stroke

Clot Composition Analysis as a Diagnostic Tool to Gain Insight into Ischemic Stroke Etiology: A Systematic Review

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