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Warfarin is an anticoagulant that requires INR-based dosage adjustment. Ascorbic acid may impair warfarin effectiveness according to limited literature. We report a rare case of a 63-year-old woman with an aortic valve replacement history who developed warfarin resistance after taking ascorbic acid for anemia following breast cancer surgery. Despite increasing the warfarin dose from 6 mg to 10 mg daily, her INR remained below the therapeutic range. After ruling out other causes of warfarin resistance, we discontinued ascorbic acid and observed a rapid increase in INR to target values. The temporal relationship and the absence of other confounding factors confirmed the causality of ascorbic acid in this case. We recommend that patients concomitantly taking vitamin C and warfarin should monitor their INR values closely and discontinue ascorbic acid as soon as possible if they exhibit signs of warfarin resistance.

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One 59-year-old female patient with deep venous thrombosis (DVT) and pulmonary embolism (PE) was treated with 6 mg warfarin once daily as an anticoagulant. Before taking warfarin, her international normalized ratio (INR) was 0.98. Two days after warfarin treatment, her INR did not change from baseline. Due to the high severity of the PE, the patient needed to reach her target range (INR goal = 2.5, range = 2~3) rapidly, so the dose of warfarin was increased from 6 mg daily to 27 mg daily. However, the patient's INR did not improve with the dose escalation, still maintaining an INR of 0.97-0.98. We drew a blood sample half an hour before administering 27 mg warfarin and detected single nucleotide polymorphism for the following genes, which were identified to be relevant with warfarin resistance: CYP2C9 rs1799853, rs1057910, VKORC1 rs9923231, rs61742245, rs7200749, rs55894764, CYP4F2 rs2108622, and GGCX rs2592551. The trough plasma concentration of warfarin was 196.2 ng/mL after 2 days of warfarin administration with 27 mg QD, which was much lower than the therapeutic drug concentration ranges of warfarin (500-3,000 ng/mL). The genotype results demonstrate that the CYP4F2gene has rs2108622 mutation which can explain some aspect of warfarin resistance. Further investigations are necessary to fully characterize other pharmacogenomics or pharmacodynamics determinants of warfarin dose-response in Chinese.

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Effective prevention of thromboembolism is essential for patients with mechanical prosthetic heart valves. For this group of patients, vitamin K antagonists (VKAs) remain the drug group of choice despite the widespread use of new anticoagulants in other diseases. As a consequence, warfarin resistance remains a serious challenge for physicians. The current report describes a 65-year-old male patient that had a mechanical prosthetic aortic valve implanted due to severe aortic insufficiency after infective endocarditis. Despite consistent increases in his warfarin dose, the level of international normalized ratio (INR) remained very low. The patient was considered to have warfarin resistance. Warfarin was successfully replaced by another VKA, acenocoumarol, which resulted in a stable INR observed over 1 year of follow-up. Achieving the target INR in patients with mechanical prosthetic heart valves using VKAs is the main goal of thromboprophylaxis. Although the genetic changes that cause warfarin resistance are understood, the options to overcome these pharmacogenetic issues remain limited. Based on the success with this current patient, physicians with similar patients with warfarin resistance might wish to consider replacing warfarin with acenocoumarol.

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BACKGROUND: We conducted a vitamin K epoxide reductase subcomponent 1 (Vkorc1)-based nonsynonymous Single Nucleotide Polymorphism (nsSNP) screen with focus on the house mouse (Mus musculus domesticus), but that also considered the Norway rat (Rattus norvegicus) and roof rat (R. rattus) in the USA. RESULTS: We detected six Vkorc1 nsSNPs underlying the amino-acid polymorphisms Ala21Thr, Trp59Leu, Ile104Val, Val118Leu, Leu128Ser and Tyr139Cys in house mice (average coverage/SNP; n = 182 individuals), two nsSNPs underlying Arg35Pro and Gly46Ser in the Norway rat (n = 93), with the notable absence of Tyr139Cys (n = 179), and one nsSNP underlying Tyr25Phe in the roof rat (n = 27). Inferred resistance frequency is 29.1% for mice (variability of states 0-98.8%), 6.5% (0-33.3%) for the Norway rat, and 39.3% (0-52.6%) for the roof rat based on Tyr25Phe frequencies. CONCLUSIONS: Resistance detected in the USA in the 1980s likely was the consequence of Vkorc1 mutations in mice (Leu128Ser and Tyr139Cys), Norway rats (Arg35Pro) and roof rats (Tyr25Phe). Patterns of variant sharing between the USA and Europe indicate the importance of convergent evolution and gene flow in spreading resistance. The spread of nsSNPs in mice between continents appears to have been more effective than in Norway rats. We hypothesize that Arg35Pro may have originated in Norway rats in the USA, whereas Tyr139Cys variants originated in Europe. Tyr25Phe is the likely cause for resistance in roof rats. Further genetic testing in the USA is required to close sampling gaps, and population genomic data are needed to study the origin and spread of this adaptive trait.

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Warfarin is a readily available anticoagulant used worldwide in a variety of clinical scenarios. Patients who need more than 15 mg/day are considered to be warfarin resistant. Numerous genes have been implicated in warfarin pharmacogenetics, with genes encoding CYP2C9 and VKORC1 shown to be the most important determinants of drug dosage requirements. A 27-year-old woman was admitted as she had a sub-therapeutic international normalized ratio (INR) after prosthetic mitral valve replacement. Even after a warfarin dose of 50 mg/day, her INR was not in the therapeutic range, so the heart team decided to replace her metallic valve with a bioprosthetic valve, thus alleviating the need for anticoagulation. LEARNING POINTS: Genetic warfarin resistance is rare and mainly associated with two genes encoding CYP2C9 and VKORC1.In addition to dietary counselling and drug compliance, options in warfarin-resistant patients include increasing the warfarin dose, which carries a risk of bleeding complications, or switching to novel oral anticoagulants, which increases the risk of prosthetic valve thrombosis.We replaced a metallic valve with a bioprosthetic valve, which is the first time this has been documented in a patient with warfarin resistance.

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@#Objective    To evaluate the quality of warfarin anticoagulant therapy in patients with stable stage after mechanical valve replacement surgery, to observe the effect of compound salvia miltiorrhiza tablet on the anticoagulant effect of warfarin in patients after mechanical valve replacement, and to understand the impact of genetic polymorphisms of VKORC1, CYP2C9 and CYP4F2 on warfarin resistance in patients with mechanical valve replacement in the stable period. Methods    From July 2011 to February 2014, 1 831 patients who had ≥ 6 months after mechanical valve  replacement surgery were enrolled at the outpatient follow-up. The basic clinical data were recorded. Anticoagulant therapy uses a target international normalized ratio（INR, 1.60–2.20) and a weekly warfarin dose adjustment strategy. Forty-six patients who needed compound salvia miltiorrhiza tablet were screened and the INR values. Before and after taking tablets were recorded and compared. The patients were divided into three groups according to the percentile of warfarin dosage including a warfarin sensitive patients group, a control patients group, and a warfarin resistance patients group. And 101 of them were selected. TIANGEN blood DNA Kit blood genomic DNA extraction kit was used to extract samples and polymerase chain restriction fragment length polymorphism (PCR-RELP) was used to determine the genotypes of patients. The detected gene loci included CYP4F2: rs2108622C>T locus; VKORC1:1639G>A locus; VKORC1:1173C>T locus; CYP2C9*2: rs1799853C>T locus; CYP2C9*3:1061A>C locus. Results    The time in therapeutic range (TTR) and fraction of time in therapeutic range (FTTR) in the target INR range of the patients included in the study period was 27.2% and 49.4%, respectively, and the TTR and FTTR in the acceptable INR range was 34.25% and 63.36%, respectively. Before and after the addition of compound salvia miltiorrhiza tablets, the INR value was 1.55±0.03 and 1.69±0.30, respectively, and the difference was statistically different (P<0.05). A total of 101 patients with genetic testing, in which the C/T composition of the VKORC1: 1173C>T locus increased in the warfarin sensitivity, contrast and warfarin resistance patients, while the ratio of allelic loci of C/T in CYP2C9*3: 1061A>C loci decreased in turn. There was no difference in the CYP4F2 gene, VKORC1639 gene, and CYP2C9*2 locus. The IWPC model predicts that warfarin dose is only consistent with the actual warfarin dose in warfarin sensitive patients. Conclusion    Relatively low TTR and FTTR are acceptable in patients with stable stage after mechanical valve replacement. It is beneficial to the patients with compound salvia miltiorrhiza tablets in terms of some appropriate patients. VKORC1: 1173C>T site and CYP2C9*3: 1061A>C site mutation is the main pharmacological gene factor of warfarin dose sensitivity and warfarin resistance in stable period after mechanical valve replacement. The IWPC dose prediction model is only consistent with the actual dose of warfarin sensitive patients.

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Anticoagulant pharmacists performed the pharmaceutical care for one child with warfarin resistance by detecting the relevant genes and retrieving the literatures. The reasons for warfarin resistance were analyzed, and the anticoagulation characteristics during menstrual period were explored in order to provide a reasonable anticoagulant recommendation for the child. Anticoagulant pharmacists defined the cause of warfarin resistance was gene polymorphism, and then implemented an individualized anticoagulant treatment according to the situation of the child. After the discharge of the patient, pharmacists carried out long -term follow -up to make the INR within the target range. Anticoagulant pharmacists should perform the whole course anticoagulation management during hospitalization and after discharge, and provide specific pharmaceutical services respectively for doctors and patients in order to guarantee the effectiveness and safety of anticoagulation and reflect the career value of pharmacists.

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Objective: To discuss the therapeutic regimen for warfarin resistant patients with the help of clinical pharmacists. Methods:The pharmacist analyzed the cause of warfarin resistance and provided the dose adjustment for a pulmonary embolism pa-tient. Results:The genotype of the patient was identified as VKORC1-1639AG by gene test. The patient was diagnosed as hereditary warfarin resistance excluding other causes. With the assistance of pharmacist, the problem of warfarin resistant was solved. Conclu-sion:For warfarin resistant patients, clinical pharmacists must definite the reason of warfarin resistant firstly and then carry out the therapeutic strategy. Gene detection may be used as an important guide for warfarin resistance.

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In contrast to other fat-soluble vitamins, dietary vitamin K is rapidly lost to the body resulting in comparatively low tissue stores. Deficiency is kept at bay by the ubiquity of vitamin K in the diet, synthesis by gut microflora in some species, and relatively low vitamin K cofactor requirements for γ-glutamyl carboxylation. However, as shown by fatal neonatal bleeding in mice that lack vitamin K epoxide reductase (VKOR), the low requirements are dependent on the ability of animals to regenerate vitamin K from its epoxide metabolite via the vitamin K cycle. The identification of the genes encoding VKOR and its paralog VKOR-like 1 (VKORL1) has accelerated understanding of the enzymology of this salvage pathway. In parallel, a novel human enzyme that participates in the cellular conversion of phylloquinone to menaquinone (MK)-4 was identified as UbiA prenyltransferase-containing domain 1 (UBIAD1). Recent studies suggest that side-chain cleavage of oral phylloquinone occurs in the intestine, and that menadione is a circulating precursor of tissue MK-4. The mechanisms and functions of vitamin K recycling and MK-4 synthesis have dominated advances made in vitamin K biochemistry over the last five years and, after a brief overview of general metabolism, are the main focuses of this review.

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Warfarin and other 4-hydroxycoumarin-based oral anticoagulants targeting vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) are administered to humans, mice and rats with different purposes in mind - to act as pesticides in high-dosage baits for killing rodents, but also to save lives when administered in low dosages as antithrombotic drugs in humans. However, high-dosage warfarin used to control rodent populations has resulted in numerous mutations causing warfarin resistance. Currently, six single missense mutations in mice, 12 distinct missense mutations in rats, as well as compound heterozygous or homozygous mutations with up to six distinct missense mutations per Vkorc1 allele have been described. Warfarin resistance missense mutations for human VKORC1 have also been found world-wide, but differ characteristically from those in rodents. In humans, 26 distinct mutations have been characterized, but occur only rarely either in heterozygous or, even rarer, in homozygous form. In this review, we summarize the known VKORC1 missense mutations causing warfarin and other 4-hydroxycoumarin drug resistance, identify genomics databases as new sources of data, explore possible underlying genetic mechanisms, and summarize similarities and differences between warfarin resistant VKORC1 variants in humans and rodents.

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BACKGROUND: Some patients show warfarin resistance needing more than 70 mg of warfarin per week. In this study, we examined if C3435T polymorphism of MDR1 gene could be a factor of warfarin resistance. METHODS: We examined 196 blood specimens from the patients who took warfarin more than 42 mg/week for at least 1 year. The subjects consisted of 74 European Americans, 59 African Americans, 42 Hispanic Americans and 21 Asian Americans. Genotype of C3435T polymorphism was determined by using real-time polymerase chain reaction (PCR). RESULTS: Ninety (45.9%) of the 196 patients had C3435T genotype and the remaining patients had C3435C genotype (35.7%) and T3435T genotype (18.4%). Mean dose of warfarin of patients with C3435C, C3435T and T3435T genotypes were 59.5mg/week, 56.9 mg/week and 55.6 mg/week, respectively. There was no statistical difference in the dose of warfarin between the 3 genotypes within each race. CONCLUSION: Our results suggest that C3435T polymorphism of MDR1 gene is not associated with warfarin resistance.

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