Anticoagulation with vitamin K antagonists (VKAs) is problematic because of difficulties in safely managing dosing. Polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase genes (VKORC1) have been shown to affect VKA dosing in adults. The association of these polymorphisms on VKA dosing in children has not been investigated. The objective of the study was to assess associations of CYP2C9 and VKORC1 polymorphisms and clinical variables on VKA dosing in children. A nonselected cohort of pediatric patients receiving VKA were tested for CYP2C9 and VKORC1 polymorphisms, and clinical data were collected. Multiple linear regression modeling was used to assess relationships of VKA dose with genetic and clinical variables. Fifty-nine patients were recruited; 55.9% were receiving warfarin, and 44.1% were on phenprocoumon. There was a negative association of age with VKA dose (P < .001). Comparing VKORC1 genotypes, the AA group required significantly lower daily doses than GG group (P ‫؍‬ .011). In the full model including age, VKORC1 and CYP2C9 genotypes accounted for 38% of dose variation. Age explained 28.3% of VKA dose variations; VKORC1 and CYP2C9 explained only 3.7% and 0.4%, respectively. In children, the most critical factor in determining VKA dose is age. VKORC1/CYP2C9 genotypes only marginally explain dose variations. (Blood. 2010;116(26):6101-6105) IntroductionAlthough vitamin K antagonists (VKAs) have been in use for more than 5 decades, safe management of these drugs remains a major challenge. Bleeding complications are associated with the variation in drug response and account for a significant number of emergency admissions on a yearly basis. 1 Clinical factors such as age, sex, drug interactions, diet, and underlying disorders affect response to VKA. 2 In addition, polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase gene (VKORC1) have a well-described effect on VKA dosing in adults. The CYP2C9 enzyme is responsible for clearance of the Senantiomer of warfarin and patients with the CYP2C9*2 or *3 require lower dosages. [3][4][5][6][7][8][9] The VKORC1 gene encodes vitamin K epoxide reductase complex, which recycles reduced vitamin K, an essential component for post translational gamma carboxylation of the vitamin K dependent factors. Therefore, the pharmacodynamics of VKA are affected by VKORC1, and it is well described that patients with polymorphisms require lower dosages of VKA. [5][6][7][10][11][12] The impact of these 2 genetic markers has resulted in the Food and Drug Administration implementing a label change on warfarin suggesting lower dosages in patients with these polymorphisms. 13 In adults, the variation in dose of VKA is accounted for between 30% and 40% on the genetic factors and between 15%-22% on clinical characteristics. 10,12,14,15 In children, as in the adult, there are multiple characteristics affecting dose such as age, underlying medical condition, medication and diet. 16,17 However, age is overwhelming the single most important varia...

Dermal fibroblast strains cultured from affected members of a cancer-prone family with Li-Fraumeni syndrome (LFS) harbor a point mutation in one allele of the p53 tumor suppressor gene, resulting in loss of normal p53 function. In this study we have examined the ability of these p53-deficient strains to carry out the long-patch mode of excision repair, mediated by DNA polymerases delta and epsilon, after exposure to 60Co gamma radiation or far ultraviolet (UV) (chiefly 254 nm) light. Repair was monitored by incubation of the irradiated cultures in the presence of aphidicolin (apc) or 1-beta-D-arabinofuranosylcytosine (araC), each a specific inhibitor of long-patch repair, followed by measurement of drug-induced DNA strand breaks (reflecting non-ligated strand incision events) by alkaline sucrose velocity sedimentation. The LFS strains displayed deficient repair capacity in response to both gamma rays and UV light. The repair anomaly in UV-irradiated LFS cultures was manifested not only in the overall genome, but also in the transcriptionally active, preferentially repaired c-myc gene. Using autoradiography we also assessed unscheduled DNA synthesis (UDS) after UV irradiation and found this conventional measure of repair replication to be deficient in LFS strains. Moreover, both apc and araC decreased the level of UV-induced UDS by approximately 75% in normal cells, but each had only a marginal effect on LFS cells. We further demonstrated that the LFS strains are impaired in the recovery of both RNA and replicative DNA syntheses after UV treatment, two molecular anomalies of the DNA repair deficiency disorders xeroderma pigmentosum and Cockayne's syndrome. Together these results imply a critical role for wild-type p53 protein in DNA polymerase delta/epsilon-mediated excision repair, both the mechanism operating on the entire genome and that acting on expressed genes.

The dTT is the most suitable assay for measuring dabigatran concentrations in children. Fibrin clot generation and lysis assay responses to dabigatran in children over all ages were consistent and comparable to those of adults.

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