PB0203 - Altered Bleeding Phenotype in Patients with Co-inheritance of Genetic Variants in Thrombosis and Hemostases Genes in Rare Bleeding Disorders

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Sterre Willems, Msc

PhD Candidate, resident internal medicine
Radboud university medical center, Hemophilia Treatment Center, Nijmegen – Eindhoven – Maastricht
Nijmegen, Gelderland, Netherlands

Co-Author(s)

AS

Annet Simons

Clinical Laboratory Geneticist
Department of Human Genetics, Radboud university medical center
Nijmegen, Gelderland, Netherlands
JS

Joline L. Saes

Resident internal medicine - hematology
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands
Nijmegen, Gelderland, Netherlands
MC

Marjon H. Cnossen

Associate professor, pediatric hematologist, MD, PhD
Department of Pediatric Hematology, Erasmus MC – Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
Rotterdam, Zuid-Holland, Netherlands
Pd

Paul L. den Exter

Internist - vascular medicine specialist
Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
IK

Ilmar C. Kruis

Representative
Netherlands Hemophilia Society, Nijkerk, The Netherlands
Nijkerk, Gelderland, Netherlands
Karina Meijer, MD, PhD (she/her/hers)

MD, PhD, Internist-haematologist, Professor
Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Groningen, Groningen, Netherlands
LN

Laurens Nieuwenhuizen

Internist-hematologist
Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands. Department of Hematology, Maxima Medical Center, Eindhoven, The Netherlands.
Eindhoven, Noord-Brabant, Netherlands
MP

Marjolein Peters

Pediatric hematologist
Department of Pediatric Hematology, Amsterdam University Medical Centers, location Emma Children’s Hospital, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
Roger E.G Schutgens, MD, PhD, MSc (he/him/his)

Internist-hematologist, Professor
Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands
Utrecht, Utrecht, Netherlands
MW

Marjan Weiss

Clinical Laboratory Geneticist
Department of Human Genetics, Radboud university medical center
Nijmegen, Gelderland, Netherlands
NB

Nicole M.A. Blijlevens

Internist-hematologist, Professor
Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands
Nijmegen, Gelderland, Netherlands
Wv

Waander L. van Heerde

Biochemist, Coagulation Physiologist, Chief Scientific Officer Enzyre BV
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands. Enzyre BV, Novio Tech Campus, Nijmegen, The Netherlands.
Nijmegen, Gelderland, Netherlands
SS

Saskia E.M. Schols

Internist-hematologist
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands
Nijmegen, Gelderland, Netherlands

Background: Rare bleeding disorders (RBDs) are defined as rare congenital coagulation factor deficiencies and disorders of fibrinolysis. In general, RBDs are considered monogenic, but bleeding phenotype is heterogeneous. Co-inheritance of multiple genetic variants may affect bleeding phenotype in RBD patients.

Aims: Describe genetic variants in Dutch RBD patients and highlight unexpected (high and low) ISTH-BAT scores, possibly associated with additional genetic variants.

Methods: The Rare Bleeding Disorders in the Netherlands (RBiN) study was a cross-sectional, nationwide, multicenter study. RBDs were defined as: proven homozygous or (compound) heterozygous variant(s) in an RBD gene, or coagulation factor activity levels below the lower limit of normal. ISTH-BAT scores were assessed and gene panel analysis by whole exome sequencing was performed.

Results: Analysis in 156 patients showed 214 likely relevant variants in thrombosis and hemostasis genes. Single nucleotide variants were responsible for 90%. The remainder existed of small ( < 20bp) insertion/deletions (7%) and copy number variants (3%). In some patients with additional genetic defects, unexpected ISTH-BAT scores were reported. Patient A with only mild FVII deficiency (FVII:51%), based on a heterozygous pathogenic variant in F7, and high bleeding score (ISTH-BAT:10), carried a heterozygous likely pathogenic variant in FGG(fibrinogen:1210 mg/L). Secondly, patient B with mild FXIII deficiency (FXIII:63%) and a high ISTH-BAT of 16, had additional variants in F7: heterozygous likely pathogenic variant and a heterozygous variant of unknown significance (FVII:52%). In contrast, two patients with α2-antiplasmin (A2AP) deficiency had heterozygous variants of unknown significance in PROS1, a prothrombotic gene. These patients had similar A2AP levels (A2AP:65%-66%) but lower mean ISTH-BAT scores (2) compared to 9 other heterozygous A2AP patients (mean ISTH-BAT:8).

Conclusion(s): Our data suggests that co-inheritance of multiple genetic variants may contribute to a more disturbed hemostatic balance, affecting the clinical bleeding phenotype. Presence of additional genetic variants may either aggravate or ameliorate bleeding severity in RBD patients.