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Poster Networking

Platelet Disorders

PB1292 - Characterization of three patients with moderate bleeding diathesis and platelet dysfunction associated with novel genetic variants in GP6 and P2RY12

Tuesday, June 25, 2024
13:45 – 14:45 ICT
Room: Exhibition Hall

    Co-Author(s)

  • Ana Zamora-Cánovas

    PhD studeny
    Servicio de Hematología y Oncología Médica-HU Morales Meseguer-Centro Regional de Hemodonación-CIBERER-ISCIII-CB15/00055, IMIB-Pascual Parrilla, Universidad de Murcia, Murcia, Spain
    Murcia, Murcia, Spain

  • LD

    Lorena Díaz-Asenjo

    PhD studeny
    Departamento de Hematología, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cáncer, IBMCC-CSIC, Universidad de Salamanca (USAL), Salamanca, Spain
    Salamanca, Castilla y Leon, Spain

    • Presenting Author(s)

  • Ana Marín-Quilez, PhD

    PostDoc
    Servicio de Hematología y Oncología Médica-HU Morales Meseguer-Centro Regional de Hemodonación-CIBERER-ISCIII-CB15/00055, IMIB-Pascual Parrilla, Universidad de Murcia, Murcia, Spain
    Murcia, Murcia, Spain

    • Co-Author(s)

  • Pg

    Pedro Luis gómez-González

    Technician
    Servicio de Hematología y Oncología Médica-HU Morales Meseguer-Centro Regional de Hemodonación-CIBERER-ISCIII-CB15/00055, IMIB-Pascual Parrilla, Universidad de Murcia, Murcia, Spain
    Murcia, Murcia, Spain

  • Nuria Fernández-Mosteirin

    Hematologist
    Servicio de Hematología, Hospital Universitario Miguel Servet, Zaragoza, Spain
    ZARAGOZA, Aragon, Spain

  • jG

    josé Ramón González-Porras

    Hematologist
    Departamento de Hematología, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cáncer, IBMCC-CSIC, Universidad de Salamanca (USAL), Salamanca, Spain
    Salamanca, Castilla y Leon, Spain

  • RB

    Rocio Benito

    Facultative
    IBSAL, CIC, IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain.
    Salamanca, Castilla y Leon, Spain

  • AS

    Ana Sánchez-Fuentes

    Hematologist
    Servicio de Hematología y Oncología Médica-HU Morales Meseguer-Centro Regional de Hemodonación-CIBERER-ISCIII-CB15/00055, IMIB-Pascual Parrilla, Universidad de Murcia, Murcia, Spain
    Murcia, Murcia, Spain

  • ML

    María Luisa Lozano

    Hematologist
    Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
    Murcia, Murcia, Spain

  • José M Bastida

    Hematologist
    Departamento de Hematología, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cáncer, IBMCC-CSIC, Universidad de Salamanca (USAL), Salamanca, Spain. #Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC).
    Salamanca, Castilla y Leon, Spain

  • José Rivera, PhD

    Facultative-Senior investigator
    Servicio de Hematología y Oncología Médica-HU Morales Meseguer-Centro Regional de Hemodonación-CIBERER-ISCIII-CB15/00055, IMIB-Pascual Parrilla, Universidad de Murcia, Murcia, Spain.#Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC) de la SETH
    MURCIA, Murcia, Spain

Background: Inherited platelet function disorders (IPFD) are rare diseases due to defects in platelet surface receptors, enzymes, granules, or signaling proteins. Few patients ( < 20) have been reported with IPFD due to genetic variants affecting the ADP and collagen receptors P2Y12 and Glycoprotein-VI (GPVI), respectively.

Aims: To characterize three unrelated patients with normal platelet count and a lifelong mild bleeding tendency.

Methods: Three female patients (P1, P2, P3) with a lifelong mucocutaneos bleeding were recruited by the Spanish Group of Inherited Platelet Disorder (GEAPC). Platelet phenotyping included: blood cell count, platelet aggregation (LTA), glycoproteins (GPs) expression and platelet activation/secretion by flow cytometry (FC), immunoblotting of P2Y12 (P1&P2), and GPVI, FcRchain and CRP-induced phosphorylation (P) of PLCy2 and LAT (P3). Patient´s DNA was analyzed by HTS-gene panel. Mutant P2RY12 and GPVI proteins were expressed in 293T HEK cells and quantified by FC.

Results: Table 1 summarizes the main clinical and platelet data. Patients displayed normal platelet size and count. P1 and P2 showed impaired platelet aggregation, activation and granule secretion, mainly in response to ADP. In P3, the platelet dysfunction was in response to collagen/CRP. GPs levels were normal in P1 and P2, while P3 showed a half-reduced GPVI expression. DNA analysis revealed P2RY12 heterozygous variants c.44delG[p.Ser15Ilefs*33] and c.835 G>A[p.Val279Met] in P1 and P2, respectively. P3 carried the GP6 heterozygous variant c.708_711delCGAA[p.Asn236Lysfs*42]. Immunobloting showed normal P2Y12 levels P1 and P2. In P3, we found reduced GPVI and FcRchain levels and impaired CRP-induced GPVI signaling (P-PLCy2 and P-LAT). 293T HEK cells transfected with P1 and P3 variants displayed sharply reduced ( < 10%) P2Y12 and GPVI levels.

Conclusion(s): We report two novel variants in P2RY12 and one in GP6 selectively affecting the platelet reactivity to ADP and collagen/CRP, predisposing to bleeding. These variants expand the genetic landscape of P2Y12 and GPVI inherited deficiency.