Sequential transcriptomic alterations in the cerebral cortex of mice after cerebral venous sinus thrombosis
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PROVIDER: PRJNA1028538 | ENA |
REPOSITORIES: ENA
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Project description:Arterial and venous (A/V) thrombosis constitutes the greatest source of morbidity and mortality worldwide. Long considered as distinct entities, accumulating evidence indicates that A/V thrombosis can occur in the same populations suggesting that common mechanisms are likely operative. Although hyperactivation of the immune system is a common forerunner to the genesis of thrombotic events in both vascular systems, the key molecular control points remain poorly understood. Consequently, anti-thrombotic therapies targeting the immune system for therapeutic gain are lacking. Here we show that neutrophils are key effectors of both A/V thrombosis and can be targeted via novel immunoregulatory nanoparticles. Using antiphopholipid antibody syndrome (APS) as a model for devastating A/V thrombosis, we identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of neutrophil activation. Upon activation via genetic loss of KLF2 or administration of antiphospholipid antibodies, neutrophils cluster P-selectin glycoprotein ligand 1 (PSGL-1) via cortical actin remodeling, thereby increasing adhesion potential at thrombosis sites. Targeting clustered PSGL-1 using designer nanoparticles attenuates neutrophil-mediated A/V thrombosis in APS and KLF2 knockout models, illustrating the importance and feasibility of targeting activated neutrophils to prevent pathological thrombosis. Together, our results demosntrate a role for activated neutrophils to prevent pathological thrombosis. Together, our results demonstrate a role for activated neutorphils in both arterial and venous thrombosis and identify key molecular events that serve as potential targets for therapeutics against diverse causes of immunothrombosis.
2022-09-12 | GSE208336 | GEO
Project description:The prognosis of cerebral venous sinus thrombosis (CVST) is variable, and outcome may range from complete recovery to death. Prognostic factors to predict outcome in the acute phase of CVST have not been analysed in a prospective study. Prognostic factors in patients enrolled in a clinical treatment trial were prospectively investigated. Poor outcome after 12 weeks, defined as death or dependency (Oxford handicap score > or =3), was used as the principle outcome measure. Univariate relations between possible prognostic factors and outcome at 12 weeks were analyzed with chi(2) tests. Treatment and all factors associated with prognosis (p< or = 0.25) were forced into a logistic regression model with a forward selection procedure. Fifty nine patients (50 women, nine men) were studied, with a mean age of 37 years (range 18 to 80 years). After 12 weeks 10 patients (17%) had a poor outcome. The univariate identified factors related to poor outcome were papilloedema, altered consciousness, coma, age older than 33 years, diagnostic delay < or =10 days, intracerebral haemorrhage, and involvement of the straight sinus. Isolated intracranial hypertension and a delta sign on CT were associated with good outcome. In the multivariate analysis coma and cerebral haemorrhage were significantly associated with a poor outcome, with odds ratios of 8.2 (95% confidence interval (95% CI) 1. 3-50.1) and 20.7 (95% CI 1.6-264.3) respectively. Involvement of the straight sinus was also weakly, but not significantly, associated with poor outcome. In conclusion, coma and intracerebral haemorrhage are independent predictors for poor outcome of CVST.
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Project description:BackgroundNeutrophil extracellular traps (NETs) contribute to the creation of a coagulation state in various diseases. Currently, it is not clear whether NETs are present in the thrombi and plasma of patients with cerebral venous sinus thrombosis (CVST). This study aimed to investigate the presence of NETs in thrombi and blood samples from CVST patients and the procoagulant activity (PCA) of NETs during the progression of CVST.ResultsThrombi obtained from CVST patients undergoing thrombectomy were examined by immunochemistry using neutrophil elastase (NE), CD66b and citrullinated histone H3(citH3). The presence of NET markers in samples from 37 CVST patients and 32 healthy people was evaluated by ELISA. NET-producing neutrophils and neutrophil-platelet (PLT) aggregates were examined in samples obtained from CVST patients and healthy people by flow cytometry. The TAT complex in plasma sample from each group was detected by ELISA to evaluate the procoagulant activity of NETs in CVST patients. Neutrophils from healthy subjects were treated with PLT-rich plasma in the presence of anti-PF4 antibodies or an autophagy inhibitor and analyzed by flow cytometry and confocal microscopy. After treatment with NETs, the expression of von Willebrand factor (VWF), tissue factor (TF) and CD31 in human brain microvascular endothelial cells (HBMECs) was measured by confocal microscopy and western blotting. Our results showed that NETs were abundant in the plasma and thrombi from CVST patients. Platelet factor 4 (PF4) from CVST PLTs induced NET generation through autophagy. NETs could induce PCA by modulating TF and phosphatidylserine (PS) in CVST. NETs also disrupted the endothelial barrier and transformed ECs into a procoagulant phenotype to exacerbate thrombogenicity.ConclusionsNET generation was mediated by PF4 from PLTs through autophagy and contribute to thrombosis in CVST patients.
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Project description:Protein C (PC) deficiency increases the risk of venous thrombosis (VT) among members of Kindred Vermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 with weaker support on chromosomes 10p12 and 18p11.2-q11. Preliminary data from Affimetrix microarray expression analysis of Blood Outgrowth Endothelial Cells of 3 members of Kindred Vermont II compared to a well established normal control group indicated that IgsF4 was decreased in patients versus controls. In addition, both statistical and pathway analysis results suggested that these genes are associated protein C. Further studies indicated that Cell Adhesion Molecule 1 (CADM1), a member of the IgsF4 superfamily, may be associated with VT.
2009-07-15 | GSE17078 | GEO
Project description:A targetable pathway in neutrophils mitigates both arterial and venous thrombosis
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Project description:Deep vein thrombosis (DVT) is a common clinical problem, but its cellular and molecular mechanisms remain incompletely understood. We performed single-cell RNA sequencing (scRNA-seq) on the vein wall of mouse inferior vena cava (IVC) ligation model of deep vein thrombosis (DVT), to analyze the transcriptomic changes in the vein wall during acute venous thrombosis.
2023-02-10 | GSE221978 | GEO
Project description:IntroductionCOVID-19 vaccines became available after being carefully monitored in clinical trials with safety and efficacy on the human body. However, a few recipients developed unusual side effects, including cerebral venous sinus thrombosis (CVST). We aim to systematically review the baseline features, clinical characteristics, treatment, and outcomes in patients developing CVST post-COVID-19 vaccination.MethodsThis study was conducted according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) 2020 guideline. Investigators independently searched PubMed, Embase, and Google Scholar for English language articles published from inception up until September 10, 2021, reporting the incidence of CVST post-COVID-19 vaccines. We analyzed CVST patients' baseline data, type of vaccines, clinical findings, treatment, and outcomes. Our systematic review process yielded patient-level data.ResultThe final analysis included 25 studies that identified 80 patients who developed CVST after the COVID-19 vaccination. Of the 80 CVST cases, 31 (39.24%) patients died. There was no significant relationship between mortality and age (P = .733), sex (P = .095), vaccine type (P = .798), platelet count (P = .93), and comorbidities such as hypertension (P = .734) and diabetes mellitus (P = .758). However, mortality was associated with the duration of onset of CVST symptoms after vaccination (P = .022). Patients with CVST post-COVID-19 vaccination were more likely to survive if treated with an anticoagulant (P = .039). Patients who developed intracranial hemorrhage (P = .012) or thrombosis in the cortical vein (P = .021) were more likely to die.ConclusionCOVID-19 vaccine-associated CVST is associated with high mortality rate. Timely diagnosis and management can be lifesaving for patients.
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