Warfarin resistance is a phenomenon that patients need to take much higher than normally prescribed dosage of warfarin to maintain the target therapeutic international normalized ratio (INR) range, or even fail to reach the target INR. Warfarin resistance can be categorized in etiologic terms as hereditary vs acquired, or in pharmacologic terms as pharmacokinetic vs pharmacodynamic. Once warfarin resistance is diagnosed, the type of resistance should be determined as soon as possible so that treatment could be oriented toward the causes. Poor compliance, genetic mutations, concurrent medications that could decrease the absorption or increase the clearance of warfarin, and consumption of diet rich in vitamin K are the major reasons for warfarin resistance. Educating patients, increasing warfarin dosage and switching to other anticoagulants would be effective for warfarin resistance.
Anticoagulants ; pharmacology ; Drug Monitoring ; methods ; Female ; Humans ; International Normalized Ratio ; Male ; Metabolism, Inborn Errors ; diagnosis ; etiology ; genetics ; Vitamin K ; administration & dosage ; Vitamin K Epoxide Reductases ; genetics

The study aimed to establish a population pharmacokinetic/pharmacodynamic (PPK/PD) model of warfarin. PCR-RFLP technique was used to genotype the CYP2C9 and VKORC1 polymorphisms of 73 patients. RP-HPLC-UV method was used to determine the 190 plasma concentrations of warfarin. Application of NONMEM, the clinical information and 263 international normalized ratio (INR) monitoring data were used to investigate the effect of genetic, physiological, pathological factors, other medication on clearance and anticoagulant response. The final model of warfarin PPK/PD was described as follows: CL = θCL · (WT/60)θWT · θCYP · eηCL (if CYP2C9*1/*1, θCYP = 1; if *1/*3, θCYP = 0.708); EC50 = θEC50 · θVKOR · eηEC50 (if VKORC1- 1639AA, θVKOR = 1; if GA, θVKOR = 2.01; V = θV; K(E0) = θK(E0); Emax = θEmax; E0 = θE0 · eηE0. Among them, the body weight (WT), CYP2C9 and VKORC1 genotype had conspicuous effect on warfarin PK/PD parameters. The goodness diagnosis, Bootstrap, NPDE verification showed that the final model was stable, effective and predictable. It may provide a reference for opitimizing the dose regimen of warfarin.
Anticoagulants ; pharmacology ; Body Weight ; Cytochrome P-450 CYP2C9 ; genetics ; Genotype ; Humans ; International Normalized Ratio ; Nonlinear Dynamics ; Polymorphism, Genetic ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; pharmacokinetics

OBJECTIVETo investigate the possible relationship between vitamin K epoxide reductase complex 1 (VKORC1) gene polymorphism and warfarin dose requirements in Chinese patients.

METHODGenotyping for the C1173T polymorphism in the VKORC1 gene was performed using a restriction enzyme digestion of PCR-amplified DNA in 102 Chinese patients treated with warfarin.

RESULTSTT genotype was found in 83 patients (81.4%), CT genotype in 16 patients (15.7%) and CC genotype in 3 patients (2.9%). To achieve similar target INR range (1.5 - 2.5), the warfarin dose requirement was significantly lower in patients with TT genotype than that in patients with CT/CC genotypes (P < 0.01).

CONCLUSIONC1173T polymorphism in the VKORC1 gene might be one important determinant for warfarin dose requirement in Chinese patients.

Adult ; Aged ; Asian Continental Ancestry Group ; genetics ; Dose-Response Relationship, Drug ; Female ; Genotype ; Humans ; International Normalized Ratio ; Male ; Middle Aged ; Mixed Function Oxygenases ; genetics ; Polymorphism, Single Nucleotide ; Vitamin K 1 ; Vitamin K Epoxide Reductases ; Warfarin ; administration & dosage

OBJECTIVE: To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population. METHODS: One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE). RESULTS: The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively. CONCLUSION The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.
Anticoagulants ; administration & dosage ; Aryl Hydrocarbon Hydroxylases ; Cytochrome P-450 CYP2C9 ; genetics ; Cytochrome P450 Family 4 ; genetics ; Dose-Response Relationship, Drug ; Genotype ; Humans ; Models, Theoretical ; Polymorphism, Genetic ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; administration & dosage

OBJECTIVETo assess the association of VKORC1 gene -1639G/A polymorphism with atrial fibrillation (AF) in ethnic Uygurs and Hans from Xinjiang.

METHODSThe above polymorphism was detected among 100 Uygur and 102 Han AF patients and 103 Uygur and 111 Han subjects that have no AF with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

RESULTSA statistically significant difference was detected between the patient and control groups of Uygur origin in terms of genotypic and allelic frequencies (P<0.05). Logistic regression analysis also indicated the -1639G/A polymorphism as an independent risk factor for AF in Uygur population (OR=2.085, 95% CI: 1.067-4.072, P=0.031). No similar statistical difference was found between the patient and control groups of Han origin (P>0.05).

CONCLUSIONThe -1639G/A polymorphism of VKORC1 gene is associated with AF in the Uygur population but not in Hans.

Adult ; Aged ; Asian Continental Ancestry Group ; ethnology ; genetics ; Atrial Fibrillation ; ethnology ; genetics ; Base Sequence ; China ; ethnology ; Female ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Polymorphism, Single Nucleotide ; Vitamin K Epoxide Reductases ; genetics

OBJECTIVE To assess the influence of genetic polymorphisms and non-genetic factors on warfarin maintenance dose variations in order to provide guidance for personalized use of warfarin. METHODS Two hundred patients from outpatient and inpatient with stable international normalized ratio(INR) were recruited. Clinical data and blood samples were collected. Genotypes of 4 genes involved in warfarin metabolic pathways were determined with Sanger sequencing. Based on statistical analysis of warfarin maintenance dosage, a mathematical model was established. RESULTS Among non-genetic factors, the age and height have significant influence in warfarin dosage. The dosage is negatively correlated with age but positively correlated with height. The difference in dosage for between the 20-year-old group and 60-year-old group has reached 1.81 mg/day, and that for between the 140 cm in height and 180 cm in height groups has reached 1.06 mg/day. VKORC1 -1639G/A, CYP2C9 430C/T, CYP2C9 1075A/C and CYP4F2 V433M polymorphisms have significant influence on stable warfarin dosage. The dosage for patients with wild type and mutant genotypes has varied from 0.35 mg/day to 0.84 mg/day. CONCLUSION Non-genetic factors and genetic polymorphisms play important roles in personalized variations of warfarin maintenance dose. The establishment of mathematical models considering multiple factors is helpful in evaluating the safety and effectiveness of warfarin dosage.
Adult ; Aged ; Anticoagulants ; administration & dosage ; Cytochrome P-450 CYP2C9 ; genetics ; Cytochrome P-450 Enzyme System ; genetics ; Cytochrome P450 Family 4 ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; administration & dosage

OBJECTIVETo assess the contribution of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotype, age, body size, height, and weight to warfarin dose requirement.

METHODSBlood samples were collected from 191 patients receiving warfarin therapy. Patients's age, gender, height, and weight were registered. PCR-RFLP method was used for the detection of VKORC1-1639G > A and CYP2C9 genotype.

RESULTSVKORC1-1639G > A genotyping showed that 159 patients were homozygous AA, 31 were heterozygous GA, and 1 was homozygous GG genotype. CYP2C9 genotyping showed that 176 patients were *1/*1, 15 patients were heterozygous *1/*3. Patients with VKORC1-1639 (G > A) GG + GA genotype required a significantly higher warfarin dose than those with AA genotype [(3.36 +/- 0.97) mg/d vs. (1.75 +/- 0.56) mg/d, P < 0.01], and patients with CYP2C9*1/*1 genotype also required a higher warfarin dose than those with CYP2C9*1/*3 genotype [(2.06 +/- 0.83) mg/d vs. (1.55 +/- 1.32) mg/d, P < 0.05]. The multiple linear regression model for warfarin dose indicated age, weight and VKORC1 genotype could explain the inter-individual variation in dose requirement of 9.3%, 7.4%, 51.9% patients, respectively; age, weight, CYP2C9 and VKORC1 genotype together could explain the inter-individual variation in dose requirement of 64.1% patients.

CONCLUSIONThis study showed that age, weight and VKORC1 and CYP2C9 polymorphism had significant influences on warfarin dose requirements and should be considered on dosing regimens modification to improve the safety of warfarin therapy.

Adult ; Aged ; Aged, 80 and over ; Anticoagulants ; therapeutic use ; Aryl Hydrocarbon Hydroxylases ; genetics ; Cytochrome P-450 CYP2C9 ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Mixed Function Oxygenases ; genetics ; Polymorphism, Genetic ; Treatment Outcome ; Vitamin K Epoxide Reductases ; Warfarin ; therapeutic use

BACKGROUNDPatients with the genotypes of both CYP2C9*3/*3 and VKORC1-1639 A/A are expected to require the lowest dose of warfarin, and to have a greatly increased risk of bleeding. The experience for the dosing of warfarin in such extremely rare cases has been seldom reported.

METHODSDemographic and clinical data from two cases with stable low dose of warfarin in China were studied by resequencing the corresponding gene segments in their whole blood DNA. The potential clinical value of the pharmacogenetic algorithm for them was evaluated by calculating the stable dose of warfarin in pharmacogenetic algorithm developed by International Warfarin Pharmacogenetics Consortium.

RESULTSBoth cases (68-year-old female and 50-year-old male) were diagnosed as chronic nonvalvular atrial fibrillation needing warfarin treatment, with target international normalized ratio (INR) 2 to 3. Case 1 had stable warfarin dose of 0.625 mg/d and case 2 1.25 mg/d. They needed more than 1 month to stabilize their anticoagulation. Exceeding INR values were recorded for them when the dose of warfarin was no more than 2 mg/d. Hemorrhagic complication appeared in case 1 when the dose was titrated from 2.5 to 1.25 mg/d. No concomitant medicine to increase or decrease the INR value was recorded for them. Genotyping CYP2C9 and VKORC1 showed both patients were the carriers of the homozygous alleles -CYP2C9*3/*3 and VKORC1-1639 A/A. Their stable doses of warfarin calculated by the pharmacogenetic dose algorithm (0.672 mg/d for case 1 and 1.16 mg/d for case 2) were comparable with their actual stable therapeutic doses.

CONCLUSIONSTwo Chinese with the rare genotypes of both CYP2C9*3/*3 and VKORC1-1639 A/A were found to require the extremely low dose of warfarin. The pharmacogenetic algorithm incorporating the variances of VKORC1 and CYP2C9 genotypes, as well as the non-genetic factors could predict their stable dose of warfarin with high accuracy.

Aged ; Anticoagulants ; adverse effects ; Aryl Hydrocarbon Hydroxylases ; genetics ; Cytochrome P-450 CYP2C9 ; Female ; Genotype ; Hemorrhage ; chemically induced ; Humans ; Male ; Middle Aged ; Mixed Function Oxygenases ; genetics ; Pharmacogenetics ; Vitamin K Epoxide Reductases ; Warfarin ; adverse effects

OBJECTIVETo compared the therapeutic effect of a Chinese patent medicine Naoxintong Capsule (, NXT) and aspirin with adjusted-dose warfarin in Chinese elderly patients (over 65 years) with nonvalvular atrial fibrillation (NVAF) and genetic variants of vitamin K epoxide reductase (VKORC1), who are at high-risk of thromboembolism.

METHODSA total of 151 patients, with NVAF and AA genotype of VKORC1-1639 (a sensitive genotype to warfarin) and a CHADS-VASc clinical risk score of 2 or above, were chosen for this study. Patients were randomized into two groups and orally treated with a combination of aspirin (100 mg/day) and NXT (1.6 g thrice a day) or adjusted-dose warfarin [international normalized ratio 2.0-3.0). The primary end points including ischemic stroke and death as well as the secondary end points including hemorrhage events were followed up for at least 1 year.

RESULTSBaseline clinical data and the rates of primary end points were similar between groups. However, the rate of serious bleeding (secondary event) in the combination therapy group was lower than that in the adjusted-dose warfarin group (0% vs. 7.9%, odds ratio: 0.921, 95% confidence interval: 0.862-0.984, P=0.028).

CONCLUSIONSAspirin combined with NXT and warfarin displayed comparable rates of primary end point including ischemic stroke and all-cause death during the 1-year follow-up. However, as compared with warfarin, the combination therapy reduced the rate of serious bleeding. Therefore, aspirin combined with NXT might provide an alternative pharmacotherapy in preventing ischemic stroke for elderly patients with NAVF who cannot tolerate warfarin. (No. ChiCTR-TRC-13003596).

Aged ; Aspirin ; therapeutic use ; Atrial Fibrillation ; drug therapy ; enzymology ; genetics ; Base Sequence ; Capsules ; Drugs, Chinese Herbal ; therapeutic use ; Endpoint Determination ; Female ; Genetic Variation ; Humans ; Male ; Risk Factors ; Treatment Outcome ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; therapeutic use

OBJECTIVETo investigate the effect of genetic polymorphisms in VKORC1, CYP2C9, GGCX, EPHX1, APOE genes on inter-individual variation in warfarin maintenance dose.

METHODSTwo hundred and forty-nine patients with stable warfarin dose were enrolled in this study, and the clinical data and blood samples of the patients were collected. Genotypes for the 5 genes were determined by using PCR and denaturing high performance liquid chromatography (DHPLC) assay. The warfarin maintenance doses were compared among patients with different genotypes of the 5 genes, and a warfarin stable dosing algorithm was derived based on genetic and non-genetic factors.

RESULTSOf the 5 genes, VKORC1, CYP2C9 and GGCX were associated with warfarin stable dose. The multiple linear regression analysis indicated that VKORC1, CYP2C9 and GGCX genes, age and weight, had significant influence on inter-individual variation in warfarin stable dose, which contributed 30.2%, 22.8%, 1.5%, 4.7% and 6.7% respectively. The warfarin stable dosing algorithm acquired from the optimal regression model could explain 57.8% variation in warfarin dose.

CONCLUSIONThis study suggested that genetic factors are the major determinants of the warfarin maintenance dose, and warfarin stable dosing algorithm may be useful for helping clinicians to prescribe warfarin with greater safety and efficiency.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alleles ; Anticoagulants ; administration & dosage ; Apolipoproteins E ; genetics ; Aryl Hydrocarbon Hydroxylases ; genetics ; Carbon-Carbon Ligases ; genetics ; Cytochrome P-450 CYP2C9 ; Epoxide Hydrolases ; genetics ; Female ; Gene Frequency ; Genotype ; Humans ; Male ; Middle Aged ; Mixed Function Oxygenases ; genetics ; Pharmacogenetics ; Polymorphism, Single Nucleotide ; Precision Medicine ; Vitamin K Epoxide Reductases ; Warfarin ; administration & dosage ; Young Adult