For decades
coumarins have been the most commonly prescribed drugs for
therapy and prophylaxis of thromboembolic conditions. Despite the limitation of their narrow therapeutic dosage window, the broad variation of intra- and inter-individual
drug requirement, and the relatively high incidence of
bleeding complications, prescriptions for
coumarins are increasing due to the aging populations in industrialised countries. The identification of the molecular target of
coumarins, VKORC1, has greatly improved the understanding of
coumarin treatment and illuminated new perspectives for a safer and more individualized oral anticoagulation
therapy. Mutations and SNPs within the translated and non-translated regions of the VKORC1 gene have been shown to cause
coumarin resistance and sensitivity, respectively. Besides the known
CYP2C9 variants that affect
coumarin metabolism, the haplotype VKORC1*2 representing a frequent SNP within the VKORC1 promoter has been identified as a major determinant of coumarin sensitivity, reducing VKORC1
enzyme activity to 50% of wild type. Homozygous carriers of the VKORC1*2 allele are strongly predisposed to coumarin sensitivity. Using individualized dose adaptation, a significant reduction of
bleeding complications can be expected, especially in the initial
drug saturation phase. Furthermore, concomitant application of low dose
vitamin K may significantly reduce intra-individual
coumarin dose variation and, thus, may stabilize oral anticoagulation
therapy. The use of new pharmacogenetics-based dosing schemes and the concomitant application of low-dose
vitamin K with
coumarins will decidedly influence the current practice of oral anticoagulation and greatly improve
coumarin drug safety.