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    Poster Networking

    Hemophilia and Rare Bleeding Disorders

    Poster Networking Session

    PB0214 - Evaluation of innovative laboratory tests to predict a thrombotic phenotype in a family with dysfibrinogenemia and a novel FGG mutation

    Sunday, June 25, 2023
    18:30 – 19:30 ET
    Room: Exhibition

      Presenting Author(s)

    • Amaury LL Monard, MD (she/her/hers)

      Medical docter and researcher
      Department of internel Medicine and Central Diagnostic Laboratory MUMC+, Maastricht, The Netherlands
      Maastricht, Limburg, Netherlands

      • Co-Author(s)

    • FH

      Floor C.J.I. Heubel-Moenen

      Hematologist
      Department Hematology, MUMC+, Maastricht, the Netherlands
      Maastricht, Limburg, Netherlands

    • Elisabetta Castoldi, PhD

      Associate Professor
      Department of Biochemistry, CARIM, Maastricht University, Maastricht (The Netherlands)
      Maastricht, Limburg, Netherlands

    • Ilaria de simone, MA

      PhD
      Department of Biochemistry, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
      Maastricht, Limburg, Netherlands

    • Paola van der Meijden, PhD

      Assistant Professor
      Department of Biochemistry, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
      Maastricht, Limburg, Netherlands

    • KW

      Kanin Wichapong

      Post doc
      Department of Biochemistry, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
      Maastricht, Limburg, Netherlands

    • Wv

      William van Doorn

      Clinical Chemist in training
      Department of Central Diagnostic Laboratory, MUMC+, Maastricht, The Netherlands
      Maastricht, Limburg, Netherlands

    • SS

      Stefano Spada, MSc

      PhD
      Center for Thrombosis and Hemostasis (CTH), University Medical Centre Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • DH

      Dave Hellenbrand

      Senior Researcher
      Department of Central Diagnostic Laboratory, MUMC +, Maastricht, The Netherlands
      Maastricht, Limburg, Netherlands

    • AS

      Alexander Stork

      MD, PhD
      Internal Medicine, St Anna Ziekenhuis, Geldrop, The Netherlands
      Geldrop, Noord-Brabant, Netherlands

    • Hugo ten Cate, MD, PhD, FAHA (he/him/his)

      Professor, MD, PhD
      Thrombosis Expertise Center, Heart & Vascular Center, Maastricht University Medical Center, Maastricht, the Netherlands
      Maastricht, Limburg, Netherlands

    • EB

      Erik A.M. Beckers

      Head of Haematology
      Department of Hematology, Maastricht University Medical Center + and Maastricht University, Maastricht, The Netherlands
      Maastricht, Limburg, Netherlands

    • Yvonne Henskens, MSc PhD

      Professor in Clinical Chemistry, Clinical chemist
      Central Diagnostic Laboratory at Maastricht University Medical Centre+
      Maastricht, Limburg, Netherlands

    Background: Hypodysfibrinogenemia is a rare hereditary fibrinogen disorder characterized by quantitative and qualitative fibrinogen defects. These fibrinogen defects can cause thrombotic and hemorrhagic phenotypes. Unfortunately, predicting the phenotype in a specific patient is often not possible with routine coagulation tests.

    Aims: To characterize the phenotype and the genetic profile of a family with hypodysfibrinogenemia and to investigate the ability of innovative tests to predict bleeding and/or thrombotic phenotypes in asymptomatic family members.

    Methods: The proband, a 60-year-old woman with both bleeding and thrombotic complications who is currently on DOAC treatment, and two daughters were referred to our Hemophilia Treatment Center (HTC) for phenotypical and genotypical analysis of a congenital fibrinogen disorder (CFD). Extensive laboratory testing was done, as well as DNA-sequence analysis and molecular modelling. Thrombin generation and microfluidic testing were also performed to investigate their ability in phenotype prediction.

    Results: Fibrinogen activity and antigen levels led to the diagnosis of dysfibrinogenemia in the proband and hypodysfibrinogenemia in both daughters. In all three cases, the same heterozygous missense mutation in the FGG gene was uncovered. This likely pathogenic mutation leads to the p.(Tyr375Cys) amino acid change. Molecular modeling predicted possible conformational changes or covalent dimerization of the fibrinogen molecule. Thrombin generation was elevated in one daughter. Microfluidic testing showed enhanced fibrin formation in both daughters, regardless of the coagulation trigger (figure 1 and 2).

    Conclusion(s): We described a family with hypodysfibrinogenemia in whom a novel heterozygous missense mutation in the FGG gene was found, possibly leading to conformational changes or covalent dimerization of the fibrinogen molecule. Furthermore we showed that microfluidic testing and thrombin generation can indicate a thrombotic phenotype in these patients, not detected with routine coagulation tests.
    Informed consent and approval from the medical-ethical committee from Maastricht (METC azM/UM) were obtained.