OC 17.3 - Prothrombotic polymorphisms FV Leiden and prothrombin G20210A in 699 unrelated patients with congenital antithrombin deficiency: more than a prognostic value

Sunday, June 25, 2023

11:15 – 11:30 ET

Room: 524

Session Available As: On-Demand

Presenting Author(s)

Carlos Bravo Perez, MD, PhD

MD, PhD
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER, Murcia, Spain
Murcia, Murcia, Spain

Co-Author(s)

Christelle Orlando, PhD

Clinical lab expert
Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of laboratory haematology, Laarbeeklaan 101, 1090 Brussels, Belgium.
Brussels, Brussels Hoofdstedelijk Gewest, Belgium
RG

Réka Gindele

assistant lecturer
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary
RC

Rosa Cifuentes

Predoctoral fellow
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER, Murcia, Spain
Murcia, Murcia, Spain
KS

Katrien Stouffs

Molecular Biologist
Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of medical genetics, Laarbeeklaan 101, 1090 Brussels, Belgium.
Brussels, Brussels Hoofdstedelijk Gewest, Belgium
PI

Péter Ilonczai

MD, PhD
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen. Hungary
Debrecen, Hajdu-Bihar, Hungary
Maria Eugenia de la Morena-Barrio, PhD

Reseacher
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Murcia, Spain
Murcia, Murcia, Spain
�S

Ágota Schlammadinger

Researcher
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen. Hungary
Debrecen, Hajdu-Bihar, Hungary
GP

György Pfliegler

Researcher
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen. Hungary
Debrecen, Hajdu-Bihar, Hungary
Javier Corral, PhD

PhD
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER, Murcia, Spain
Murcia, Murcia, Spain
KJ

Kristin Jochmans

Head of department
Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Department of laboratory haematology, Laarbeeklaan 101, 1090 Brussels, Belgium.
Brussels, Brussels Hoofdstedelijk Gewest, Belgium
Zsuzsanna Bereczky, MD, PhD (she/her/hers)

head of division
Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Debrecen, Hajdu-Bihar, Hungary

Background: Antithrombin deficiency (ATD) is considered the strongest congenital thrombophilia. Nevertheless, there is considerable clinical heterogeneity partially explained by the type of deficiency (type II with heparin binding site [HBS] defects are less severe). Small studies support increased risk and severity of thrombosis when ATD is combined with prothrombotic polymorphisms FV Leiden (FVL) or prothrombin G20210A (PT). Special interest has the combination of ATD and FVL as their coding genes are in close localization (4.3MB).

Aims: To investigate the combination of FVL and PT with ATD and its clinical impact.

Methods: 699 unrelated cases with congenital ATD recruited and characterized in three European reference centers during >25 years. Family studies were also done.

Results: 128 cases carried prothrombotic polymorphisms: 96/699 (13.7%) FVL, and 32/699 (4.6%) PT. Although AT activity was similar among both groups and non-carriers, prevalence and characteristics of thrombosis tended to be more severe in carriers, particularly for FVL (Table 1). Interestingly, the HBS variant AT Budapest 3 (ATBp3), the most prevalent variant in our cohorts (214/699, 30.6%) was present in 67/96 patients with ATD and FVL (69.8%). Overall, 31.3% of patients ATBp3 also carried FVL, while few carriers of other frequent HBS variants (AT Toyama or AT Basel) were positive for FVL (Table 2). Family studies confirmed the linkage between ATBp3 and FVL, and identified cases who suffered recombination breaking this linkage. No linkage of FVL with other SERPINC1 mutation was identified. Among heterozygous ATBp3, FVL was associated with a higher prevalence of thrombosis and with a more severe thrombotic phenotype (Table 2).

Conclusion(s): We demonstrated that ATBp3, a founder mutation causing the most recurrent ATD in Europe, and FVL are in linkage disequilibrium. This combination, present in 31.3% of carriers of ATBp3, increases the risk and severity of thrombosis, thus recommending the screening of FVL in patients with this ATD. PI21/00174(ISCIII&Feder)-PMP21/00052(ISCIII&NG-EU)-21866/PI/22(FundaciónSéneca)

Learning Objectives:

Assess the frequency of the prothrombotic polymorphisms FVL and PTG20210A in a large cohort of 699 patients with antithrombin deficiency.
Describe the biological and molecular characteristics of patients with antithrombin deficiency and concurrent FVL or PTG20210A, as well as the clinical impact of these prothrombotic polymorphisms in one of the most severe thrombophilic states.
Identify the association of FVL with antithrombin Budapest 3 variant, and its clinical impact, which expands the clinical-molecular spectrum of antithrombin deficiency.