PB0329 - Results of the Working Group Genetic characterization of protein C deficiencies from the Spanish Society of Thrombosis and Haemostasis: update of the last four years

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

JO

Julia Oto

Postdoctoral researcher
Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe
Valencia, Comunidad Valenciana, Spain
RH

Raquel Herranz

PhD candidate
Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe
Valencia, Comunidad Valenciana, Spain
FC

Fernando Cana

Laboratory technician
Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe
Valencia, Comunidad Valenciana, Spain
EW

Ewa Wypasek

MD
The John Paul II Hospital
Krakov, Malopolskie, Poland
AW

Anna Weronska

Postdoctoral researcher
Faculty of Medicine and Health Sciences,Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University
Krakow, Malopolskie, Poland
AU

Anetta Undas

Professor
Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College
Kraków, Malopolskie, Poland
AR

Agustín Rodríguez-Alen

Hematologist
Servicio de Hematología, Hospital Universitario de Toledo, Toledo, Spain
Toledo, Castilla-La Mancha, Spain
ML

María F. López-Fernández

PhD MD
Servicio de Hematología, Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
La Coruña, Galicia, Spain
SH

Sonia Herrero

Medical doctor
Hematology Service, University Hospital of Guadalajara
Guadalajara, Castilla-La Mancha, Spain
RL

Ramón Lecumberri

Medical doctor
Hematology Service, University of Navarra Clinic
Pamplona, Navarra, Spain
RO

Remedios Otero

Medical doctor
Medical-Surgical Unit of Respiratory Diseases, Virgen del Rocío University Hospital-IBIS-CIBERES
Sevilla, Andalucia, Spain
OG

Olga Gavín

Medical doctor
Hematology Service, Lozano Blesa Clinical University Hospital
Zaragoza, Aragon, Spain
EM

Edelmira Martí

Medical doctor
Hematology Service, Clinical University Hospital of Valencia
Valencia, Comunidad Valenciana, 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
MM

María Paz Martínez-Badas

Medical doctor
Department of Haematology, Hospital de Avila
Ávila, Castilla y Leon, Spain
SA

Susana Asenjo

PhD MD
Servicio de Hematología, Hospital Clínico San Carlos,
Madrid, Madrid, Spain
MP

Montserrat Pérez-Sánchez

Medical doctor
Hematology Service, Virgen de la Concha Hospital, Zamora
Zamora, Castilla y Leon, Spain
EP

Emma Plana

Postdoctoral Researcher
Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe
Valencia, Comunidad Valenciana, Spain
SB

Santiago Bonanad

Head of Thrombosis and Hemostasis Unit
Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe
Valencia, Comunidad Valenciana, Spain

Presenting Author(s)

Pilar Medina, PhD

Principal Investigator
Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Health Research Institute Hospital La Fe
Valencia, Comunidad Valenciana, Spain

Background: Protein C (PC) deficiency is an inherited thrombophilic disorder caused by mutations in the gene encoding for PC (PROC).

Aims: The working group "Genetic characterization of protein C deficiencies. Identification of carriers" of the Spanish Society of Thrombosis and Haemostasis aims to identify the causal mutation of PC deficiencies in Spanish families and to provide genetic counseling to their relatives.

Methods: From February 2020 to January 2024, we sequenced the 9 exons and flanking intronic regions of the PROC gene in 68 probands and 23 relatives, and analyzed the genotype-phenotype association.

Results: Of the 68 probands studied, 44 had at least one previous thrombotic episode. We ascertained the mutation responsible for PC deficiency in 44 families, identifying 29 different mutations (Table1), most missense. Eight mutations were novel: 7 missense and 1 affecting intron 5 splicing and potentially creating a stop codon downstream. Remarkably, we identified the complex mutation c.344_355delTCGGCAGCTTCAinsCGT p.Ile115_Ser119delinsThrCys in exon 5, producing a deletion of 5 amino acids (IleGlySerPheSer) and an insertion of 2 amino acids (ThrCys). Of the 29 identified mutations, 28 caused type I (96.6%) and 1 type II (3.4%) deficiencies. One proband carried the p.Val339Met in homozygosity presenting undetectable PC levels and a complex thrombotic phenotype. The main PROC hotspots are exon 5 (14%mutations), exon 7 (12%) and exon 9 (30%).

Conclusion(s): Since 2020, 11 Spanish and 1 Polish hospital have contributed to this SETH registry with 91 individuals. We identified 29 PROC mutations causing PC deficiency, mainly type I, in 44 probands, of which 8 were novel. Most are missense and privative. Our study provides: 1) diagnostic support to other hospitals, 2) clear diagnoses in suspicious patients or with PC levels in the lower limit, avoiding unnecessary treatments, 3) genetic counseling in relatives, to avoid future thrombosis in carriers. ISCIII-FEDER (PI20/00075-FI21/00171-PI23/00449) and SETH Grants for the Working Group.