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Pharmacogenetics of Oral Anticoagulants

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Omics for Personalized Medicine

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Abstract

Coumarin derivates have been considered an ideal target of personalized medicine because of their pharmacological characteristics as vitamin K antagonists. Thus, many pharmacogenetic investigators have focused in this field, developing numerous warfarin algorithms based on CYP2C9 and VKORC1 genotypes. These pharmacogenetic algorithms include both genetic and nongenetic factors.

Coumarin derivates (warfarin in the UK and USA, acenocoumarol and phenprocoumon in European countries) are the most prescribed oral anticoagulants in the prevention and treatment of thromboembolic events associated with atrial fibrillation, prosthetic valves, venous thromboembolism, and orthopedic surgery.

Vitamin K antagonists have demonstrated efficacy in anticoagulation although they have a narrow therapeutic window. Patients need frequent monitoring by measuring the prothrombin time. The main challenge for physicians is to introduce patients as soon as possible within the therapeutic range (INR 2–3) in the beginning of therapy as the risk of undercoagulation, INR <2 (risk of thrombus), or overanticoagulation, INR> 4 (risk of bleeding), is higher in this period.

The adjustment of the dose to achieve effective and stable anticoagulation depends on several environmental factors including age, gender, weight, concomitant medications and interactions with foods containing vitamin K, smoking status and alcohol intake, and genetic factors.

Allelic variants in CYP2C9*2 (Arg144Cys, rs1799853), CYP2C9*3 Ile359Leu (rs1057910), and VKORC1 (rs9923231, rs9934438) gene polymorphisms have demonstrated an influence of about 40 % on coumarin-required dose.

Despite of knowledge that pharmacogenetic models can improve dosing recommendations according to CYP2C9 and VKORC1 polymorphisms and thus would decrease the risk of thrombus and bleeding events during initial phases of anticoagulation, the translation of pharmacogenetic algorithms into clinical practice is a challenge to pursue in the advancement of personalized medicine.

On the other hand, a new wave of oral anticoagulants has been developed to improve the efficiency and safety of anticoagulant therapy and avoid the several drawbacks of vitamin K antagonists. This new generation of anticoagulants is expected to be the alternative in prevention of stroke and systemic embolism in non-valvular atrial fibrillation patients.

In this chapter, we will review the most relevant pharmacogenetic studies performed with coumarin derivates, the application of pharmacogenetics in predicting the optimal coumarin derivates’ initial dose based on genetic and environmental factors, genetic tests available for determination of main gene polymorphisms associated to warfarin sensitivity, the development of new oral anticoagulants (dabigatran, rivaroxaban, apixaban), and comparison of different pharmacological therapies available to use in patients with non-valvular atrial fibrillation requiring long-term anticoagulation.

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  1. Pharmacogenetics Unit, Pharmacy Service, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Enrique Jiménez-Varo, Marisa Cañadas-Garre, Margarita Aguilera, Desiree Gonzalez Callejas, Cristina Perez Ramirez & Miguel A. Calleja Hernández

  2. Instituto de Nutrición y Tecnología de los Alimentos “José Mataix Verdú” de la Universidad de Granada (INYTA); Centro de Investigación Biomédica (CIBM), Granada, Spain

    Margarita Aguilera

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  1. Enrique Jiménez-Varo
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  1. Centre for Genomics & Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur, West Bengal, India

    Debmalya Barh

  2. Institute of Life Sciences, B.V. Patel Pharmaceutical Education and Research Development Centre, Ahmedabad University, Ahmedabad, Gujarat, India

    Dipali Dhawan

  3. Policy Centre for Biomedical Research, Translational Health Science and Technology Institute (Department of Biotechnology Institute, Government of India), Office @ National Institute of Immunology, New Delhi, India

    Nirmal Kumar Ganguly

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Jiménez-Varo, E., Cañadas-Garre, M., Aguilera, M., Callejas, D.G., Ramirez, C.P., Hernández, M.A.C. (2013). Pharmacogenetics of Oral Anticoagulants. In: Barh, D., Dhawan, D., Ganguly, N. (eds) Omics for Personalized Medicine. Springer, New Delhi. https://doi.org/10.1007/978-81-322-1184-6_21

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