New Pharmacogenetic Markers to Predict the Risk of Bleeding During Taking of Direct Oral Anticoagulants

Abstract

Aim. To search for new pharmacogenetic biomarkers of bleeding risk in patients taking rivaroxaban and dabigatran for different indications: atrial fibrillation, endoprosthesis of large joints of lower limbs.Material and methods. The study enrolled 29 patients (17 patients received dabigatran and 12 –rivaroxaban), who had hemorrhagic complications during taking direct oral anticoagulants. To find new pharmacogenetic biomarkers of bleeding risk, a next generation sequencing (NGS) was performed for selected candidate genes.Results. Among the patients with bleeding who received dabigatran, 13 variants of the nucleotide sequence showed statistically significant deviation from the population values: 11 in the CES1 gene and 2 in the ABCB1 gene. Among the patients with bleeding who received rivaroxaban, 7 variants of nucleotide sequence showed significant deviation: 4 in the ABCG2 gene, 2 in the CYP3A4 gene, and 1 in the ABCB1 gene.Conclusion. The identified in this study polymorphisms of candidate genes ABCB1, ABCG2, CES1, CYP3A4 were associated with the risk of bleeding in patients taking rivaroxaban and dabigatran. It makes an important contribution to the pharmacogenetics of direct oral anticoagulants and require additional assessment of clinical significance in further studies.

Gene polymorphism as a cause of hemorrhagic complications in patients with non-valvular atrial fibrillation treated with oral vitamin K-independent anticoagulants

“… 16 – 18 The human carboxyesterase 1 ( CES1 ) gene encodes a hepatic esterase responsible for the hydrolysis of drugs containing multiple ester and amide bonds. 8 , 19 CES1 plays a greater role in the conversion of dabigatran etexilate to dabigatran than CES2 . 17 After 0.5–2 h, dabigatran reaches its maximum plasma concentration (Cmax).…”

“…To prevent cardioembolic stroke, patients with non-valvular atrial fibrillation (NVAF) are traditionally prescribed long-term or lifelong oral anticoagulants. 5 – 8 In recent years, direct oral anticoagulants (DOACs) have quickly gained their place among the mainstay of drugs in the treatment of NVAF, and their use has significantly increased worldwide. 4 , 9 DOACs include dabigatran (an inhibitor of clotting factor IIa), apixaban, rivaroxaban, and edoxaban (inhibitors of clotting factor Xa).…”

Prospects for the development of pharmacogenetics in Russia for the personalization of pharmacotherapy

“…Альтернативным методом для выявления кандидатных полиморфизмов генов выступают полногеномные ассоциативные исследования с дальнейшей проверкой валидности обнаруженных маркеров в проспективных клинических исследованиях. Примером может служить исследование, где изучались маркеры, ассоциированные с кровотечениями при применении прямых оральных антикоагулянтов дабигатрана и ривароксабана, методом секвенирования нового поколения и были найдены новые полиморфизмы генов транспортных систем, прогнозирующие данную нежелательную реакцию [9]. В тех случаях, когда не изучены пути метаболизма лекарственного препарата для уточнения основных ферментов биотрансформации и дальнейшего прогнозирования нежелательных реакций, применяются методы ком-…”