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    Oral Communication

    Diagnostics and OMICs

    Discovering the Real Interactions in Complex Systems: RNAs, Proteins, and Sugars

    OC 68.3 - Plasma levels of Complement C5 are associated with thrombin generation

    Tuesday, June 27, 2023
    15:15 – 15:30 ET
    Room: 515
    Session Available As: On-Demand

      Presenting Author(s)

    • Rocio Vacik Diaz

      PhD student
      C2VN, Aix-Marseille University, INSERM, INRAE, Marseille, France
      Marseille, Provence-Alpes-Cote d'Azur, France

      • Co-Author(s)

    • Manal Ibrahim-Kosta, MD PHD

      MD, PhD
      Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, Hôpitaux de Marseille, Marseille, France
      Marseille, Provence-Alpes-Cote d'Azur, France

    • MI

      Maria Jesus Iglesias

      Senior Researcher
      Science for Life Laboratory, KTH-Royal Institute of Technology, SE-171 21 Stockholm, Sweden
      Stockholm, Stockholms Lan, Sweden

    • Alejandro Pallares Robles

      PhD student
      Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz (UMCM), Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • AB

      Anne Boland

      Researcher
      Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)
      Évry, Ile-de-France, France

    • MG

      Marine Germain

      INSERM Research Assistant
      University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR1219, Bordeaux, France.
      Bordeaux, Aquitaine, France

    • JD

      Jean-François Deleuze

      Director
      Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)
      Evry, Ile-de-France, France

    • JO

      Jacob Odeberg

      Principal Investigator
      Science for Life Laboratory, KTH-Royal Institute of Technology, SE-171 21 Stockholm, Sweden
      Stockholm, Stockholms Lan, Sweden

    • David-Alexandre TREGOUET, PhD (he/him/his)

      Senior Investigator
      Bordeaux Population Health research center - INSERM UMR1219
      Bordeaux, Aquitaine, France

    • LG

      Louisa Goumidi

      Research Scientist
      Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, CRB Assistance Publique – Hôpitaux de Marseille, HemoVasc (CRB AP-HM HemoVasc), Marseille, France.
      Marseille, Provence-Alpes-Cote d'Azur, France

    • PM

      Pierre-Emmanuel Morange, MD, PhD

      MD, PhD
      Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, Hôpitaux de Marseille, Marseille, France
      Marseille, Provence-Alpes-Cote d'Azur, France

    Background: The thrombin generation assay (TGA) is a global coagulation assay that measures the potential of a plasma to generate thrombin over time in vitro, providing a global picture of the plasma hemostatic balance of an individual.

    Aims: We aimed to identify novel biological determinants of thrombin generation by integrating plasma proteomics and thrombin generation data.

    Methods: Associations between TGA parameters and plasma levels of 377 antibodies targeting 236 unique proteins selected because of their potential role in the coagulation and fibrinolysis cascades or because they have been linked to cardiovascular traits, were tested using multiple linear regression analysis in 770 individuals with venous thrombosis from the MARTHA study. Proteins associated (p < 1.33x10-4) to at least three TGA parameters were selected for further validation in an independent population of 535 healthy individuals. Proteins showing similar pattern of association with thrombin generation in both studies, underwent a genome wide association (GWAS) study to identify common (MAF>5%) single nucleotide polymorphisms (SNPs) influencing plasma protein levels. The GWAS was performed in MARTHA patients and SNPs with statistical evidence (p < 5x10-8) for association with protein levels were further tested for its association with TGA parameters.

    Results: Eighteen proteins were associated with at least three TGA parameters in MARTHA subjects, among which 13 demonstrated similar associations in healthy individuals. Only one of these proteins, C5, was further shown to be under a strong genetic control with rs17611 (p.Val802Ile) being significantly (p=9.4x10-31) associated with C5 plasma levels. The rs17611 Ile variant that decreases C5 plasma levels was further observed to decrease both ETP (p=0.04) and peak height (p=0.03) in MARTHA patients.

    Conclusion(s): This study has identified candidate plasma proteins associated with thrombin generation parameters. We provided evidence that genetic factors influencing C5 plasma levels also associate with TGA parameters. Fine mapping of these findings deserves further epidemiological and experimental investigations.

    Learning Objectives:

    • Upon completion, participants will be able to understand the basic principles and components of the thrombin generation assay (TGA).
    • Upon completion, participants will be able to explore the determinants of thrombin generation and their significance.
    • Upon completion, participants will be able to learn new approaches to unravel new determinants of thrombin generation.