PB0476 - Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genetic Variants

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Juraj Sokol, PhD.

researcher
Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin
Martin, Zilina, Slovakia

Co-Author(s)

MS

Maria Skerenova

researcher
Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava
Martin, Zilina, Slovakia
FN

Frantisek Nehaj

researcher
Slovak Medical University in Bratislava
Bratislava, Bratislava, Slovakia
MM

Michal Mokan

researcher
Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava
Martin, Zilina, Slovakia
Jana Zolkova, DSc, PhD (she/her/hers)

laboratory researcher
National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Slovakia
Martin, Zilina, Slovakia
LL

Lenka Lisa

researcher
Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava
Martin, Zilina, Slovakia
LL

Ludmila Linekova

PhD student
Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava
Martin, Zilina, Slovakia
MP

Monika Pecova

PhD student
Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava
Martin, Zilina, Slovakia
Jan Stasko, MD, PhD (he/him/his)

university professor
National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
Martin, Zilina, Slovakia

Background: Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels.

Aims: The purpose of our study is to investigate the effects of CYP2J2, CYP3A5 and CYP3A4 gene polymorphisms on DOAC plasma levels.

Methods: The local Ethical Committee approved this study. For the selection of tag single nucleotide polymorphism (SNP), the data from the International HapMap Project and an adopted algorithm implemented in Haploview 4.2 were used. High-resolution melting (HRM) analysis on LightCycler 480 II (Roche Diagnostics, Mannheim, Germany) was used for SNP genotyping. We assessed ten SNPs within the CYP2J2 gene, twelve within the CYP3A5 gene and six within the CYP3A4 gene. The anti-Xa activity (ng/L) was assessed using rivaroxaban- and apixaban-calibrated anti-Xa chromogenic assays (BIOPHEN Heparin kit, BIOPHEN Rivaroxaban Plasma Calibrator, BIOPHEN Apixaban Plasma Calibrator; Aniara Diagnostica, West Chester, OH). Treatment with dabigatran was monitored by Hemoclot Thrombin Inhibitor assay (Hyphen BioMed, Paris, France), according to the manufacturer’s instructions.

Results: Overall, 75 patients were included, with 25 receiving dabigatran, 27 apixaban and 23 rivaroxaban. The results suggest that the selected coding SNPs investigated in the present study are likely to contribute to the inter-individual variability in rivaroxaban, apixaban and dabigatran plasma concentrations. In addition, we also performed 16 subanalyses in order to identify the differences in the outcome of different comorbidities, age, dosage, liver and kidney function tests, and concomitant treatment. Results of the subgroup analyses were consistent with the findings of the main analysis; there was no apparent heterogeneity across the subgroups.

Conclusion(s): The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk. This work was supported by grant KEGA 056UK-4/2022 and VEGA 1/0250/22.