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CME Evaluation

Oral Communication Session

Inherited Bleeding Disorders and Inhibitors

Session: VWD

OC 63.1 - Type 2M/2A von Willebrand disease: A shared phenotype between type 2M and 2A

Tuesday, June 25, 2024
14:45 – 15:00 ICT
Room: Ballroom B3

    Presenting Author(s)

  • Omid Seidizadeh, MSc, PhD

    University of Milan, Department of Pathophysiology and Transplantation, Milan, Italy
    Milan, Lombardia, Italy

    • Co-Author(s)

  • LM

    Luca Mollica

    Associate professor
    Università degli Studi di Milano, Department of Medical Biotechnologies and Translational Medicine
    Milan, Lombardia, Italy

  • SZ

    Serena Zambarbieri

    Biologist
    Università degli Studi di Milano, Department of Medical Biotechnologies and Translational Medicine
    Milan, Lombardia, Italy

  • Luciano Baronciani

    Biologist
    Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
    Milan, Lombardia, Italy

  • Andrea Cairo

    Professional research collaborator
    Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
    Milan, Lombardia, Italy

  • PC

    Paola Colpani

    Biologist
    Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
    Milan, Lombardia, Italy

  • GC

    Giovanna Cozzi

    Biologist
    Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
    Milan, Lombardia, Italy

  • Maria Teresa Pagliari

    Biologist
    Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
    Milan, Lombardia, Italy

  • Alessandro Ciavarella

    Clinician
    Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
    Milan, Lombardia, Italy

  • SS

    Simona Maria Siboni

    Physician
    Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
    Milan, Lombardia, Italy

  • Flora Peyvandi, MD, PhD

    Full Professor
    Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Department of Pathophysiology and Transplantation
    Milan, Lombardia, Italy

Background: Four frequently reported VWF variants have been subjected to debate and received different von Willebrand disease(VWD) classifications: p.R1374H, p.R1374C, p.R1315L, and p.R1315C.

Aims: To deeply investigate and characterize p.R1374H/C and p.R1315L/C variants with a full panel of VWD tests, protein modeling predictions and structural biology.

Methods: Forty-three patients with p.R1315L/C and p.R1374H/C were included. In addition, 70 patients with type 2A(n= 35) or 2M(n= 35) were included to understand their similarities and differences. Patients were investigated for phenotypic assays and underlying disease-mechanisms. We further applied deep protein modeling predictions and structural biology using Molecular and Langevin dynamics and AlphaFold2 to elucidate the effects of these variants on the VWF A1-A2 domains.

Results: Variant p.R1315C clearly represented a type 2M phenotype. However, p.R1374H/C and p.R1315L patients showed a common phenotype between type 2M and 2A using VWF activity/VWF:Ag and VWF:CB/VWF:Ag ratios and VWF multimeric profile(Figure 1). VWF synthesis/secretion was reduced in 2M and in p.R1374H/C and p.R1315L cases, but not in 2A. Reduced VWF survival was observed in most 2A(77%), 2M(80%) and all 40 cases(100%) with p.R1374H/C and p.R1315L(Figure 1). Since the mutual spatial arrangement of the A1-A2 and the overall system dynamic is unknown, we newly developed it in this study(Figure 2A). These were the only variants that fall at the interface between the A1-A2. The mutants of residue R1315 induce more compactness and increased internal mobility but residue R1374 displays more extended A1-A2(Figure 2B). Our analysis revealed that the pathological common trait can be related to the accessibility of sensibly populated states, the exploration of which is induced by mutations(Figure 2C).

Conclusion(s): We propose a new classification for p.R1374H/C and p.R1315L as type 2M/2A because they share a common phenotype between 2A and 2M. Structural analysis indicates the unique location of these variants on the A1-A2 domain and their distinctive effect on VWF.