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Sökning: WFRF:(Munsch Gaëlle)

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1.
  • Diaz, Rocio Vacik, et al. (författare)
  • Plasma levels of complement components C5 and C9 are associated with thrombin generation
  • 2024
  • Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 22:9, s. 2531-2542
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The thrombin generation assay (TGA) evaluates the potential of plasma to generate thrombin over time, providing a global picture of an individual's hemostatic balance. Objectives: This study aimed to identify novel biological determinants of thrombin generation using a multiomics approach. Methods: Associations between TGA parameters and plasma levels of 377 antibodies targeting 236 candidate proteins for cardiovascular risk were tested using multiple linear regression analysis in 770 individuals with venous thrombosis from the Marseille Thrombosis Association (MARTHA) study. Proteins associated with at least 3 TGA parameters were selected for validation in an independent population of 536 healthy individuals (Etablissement Francais du Sang Alpes-Mediterranee [EFS-AM]). Proteins with strongest associations in both groups underwent additional genetic analyses and in vitro experiments. Results: Eighteen proteins were associated (P < 1.33 x 10(-4)) with at least 3 TGA parameters in MARTHA, among which 13 demonstrated a similar pattern of associations in EFS-AM. Complement proteins C5 and C9 had the strongest associations in both groups. Ex vivo supplementation of platelet-poor plasma with purified C9 protein had a significant dose-dependent effect on TGA parameters. No effect was observed with purified C5. Several single nucleotide polymorphisms associated with C5 and C9 plasma levels were identified, with the strongest association for the C5 missense variant rs17611, which was associated with a decrease in C5 levels, endogenous thrombin potential, and peak in MARTHA. No association of this variant with TGA parameters was observed in EFS-AM. Conclusion: This study identified complement proteins C5 and C9 as potential determinants of thrombin generation. Further studies are warranted to establish causality and elucidate the underlying mechanisms.
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2.
  • Iglesias, Maria Jesus, et al. (författare)
  • Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.
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