Association of CYP2C9 gene polymorphism with bleeding as a complication of warfarin therapy

The aim of this study was to determine the association of bleeding as a complication of warfarin therapy with polymorphism of CYP2C9 gene (alleles 1, 2 and 3). The CYP2C9 is the main enzyme for warfarin metabolism. Study included 181 patients receiving warfarin for at least one month. Allele 1 of CYP2C9 gene (in 94.5%) and genotype *1/*1 (57.5%) prevailed. Allele 3 was found in 12.7% patients. Bleeding side-effects occurred in 18 patients (10%). Patients with allele *1 needed significantly higher maintenance warfarin dose (p=0.011). Those with allele *3 had significantly lower maintenance warfarin dose (p=0.005) and higher prothrombin time (PT) at induction (p=0.034). Bleeding occurred significantly more often in those with lower maintenance warfarin dose (p=0.017). Patients with allele *3 had increased risk of bleeding, with marginal significance (p=0.05). Polymorphism of CYP2C9 could determine dose of warfarin therapy and thus it could be related to the risk of bleeding complications. Allele *3 carriers need lower warfarin dose. Therefore, initially reduced warfarin induction dose in allele *3 carriers could avoid more prolonged PT and decrease the risk of bleeding complication.     

Optimal loading dose for the initiation of warfarin: a systematic review

Background

Selection of the right warfarin dose at the outset of treatment is not straightforward, and current evidence is lacking to determine the optimal strategy for initiation of therapy.

Methods

We included randomized controlled trials in patients commencing anticoagulation with warfarin, comparing different loading dose or different regimens. We searched Medline, EMBASE, the Cochrane Library and the NHS Health Economics Database up to June 2009. Primary outcomes were time to stable INR and adverse events. We summarised results as proportion of INRs in range from date of initiation and compared dichotomous outcomes using relative risks (RR) and calculated 95% confidence intervals (CIs).

Results

We included 11 studies of 1,340 patients newly initiated on warfarin. In two studies that used single INR measures, a loading dose of 10 mg compared to 5 mg led to more patients in range on day five. However, in two studies which measured two consecutive INRs, a loading dose of 10 mg compared to 5 mg did not lead to more patients in range on day five (RR = 0.86, 95% CI, 0.62 to 1.19, p = 0.37). Patients receiving a 2.5 mg initiation does took longer to achieve the therapeutic range, whilst those receiving a calculated initiation dose achieved target range 0.8 days quicker (4.2 days vs. 5 days, p = 0.007). More elderly patients receiving an age adjusted dose achieved a stable INR compared to the Fennerty protocol (48% vs. 22% p = 0.02) and significantly fewer patients on the age adjusted regimens had high out-of-range INRs. Two studies report no significant differences between genotype guided and 5 mg or 10 mg initiation doses and in the one significant genotype study the control group INRs were significantly lower than expected.

Conclusion

Our review findings suggest there is still considerable uncertainty between a 10 mg and a 5 mg loading dose for initiation of warfarin. In the elderly, lower initiation doses or age adjusted doses are more appropriate, leading to less higher INRs. Currently there is insufficient evidence to warrant genotype guided initiation, and adequately powered trials to detect effects on adverse events are currently warranted.     

Lack of effect of influenza vaccine on warfarin anticoagulation in the elderly.

Influenza vaccine may inhibit hepatic metabolism of drugs and has been reported to prolong the prothrombin time in patients receiving warfarin by affecting the coagulation pathway. In a group of seven elderly residents of a long-term care facility who were receiving warfarin, prolongation of the prothrombin and partial thromboplastin times could not be shown up to 5 weeks after vaccination against influenza. The results were similar in nine elderly subjects who were not receiving warfarin.     

Interaction between warfarin and nonsteroidal anti-inflammatory drugs (NSAIDs) in rats

In fed rats, the following NSAIDs were administered orally 24 hr before or 18 hr after the intraperitoneal administration of 1.34 mg/kg warfarin: phenylbutazone, 150 mg/kg; diflunisal, 75 mg/kg; ibuprofen, 150 mg/kg; acetylsalicylic acid, 300 mg/kg; indomethacin, 8 mg/kg; tolmetin sodium, 50 mg/kg; ketoprofen, 8 mg/kg; and amfenac sodium, 8 mg/kg. The elevation of the 24-hr prothrombin time was indicative of the effect of the warfarin. Warfarin-treated fasted rats showed a significantly higher prothrombin time than warfarin-treated fed rats. Interaction with phenylbutazone and warfarin occurred in fed and not in fasted rats when administered 18 hr after administration of the warfarin. At the 24-hr pretreatment time, only phenylbutazone significantly reduced the elevated prothrombin time. With the exception of amfenac sodium, all the NSAIDs significantly enhanced the elevated prothrombin time when administered 18 hr after warfarin. Their decreasing order of activity in enhancing the elevated prothrombin time was phenylbutazone, diflunisal, acetylsalicylic acid, ibuprofen, indomethacin, tolmetin sodium, and ketoprofen. The results indicate that the rat is more sensitive than the human to the interaction between warfarin and NSAIDs.     

A Comparison of Warfarin Sodium and Bishydroxycoumarin in Long-Term Anticoagulant Therapy

Warfarin sodium was compared with bishydroxycoumarin (Dicumarol) in 16 patients on long-term anticoagulant therapy. When the patients were changed from bishydroxycoumarin to warfarin sodium there was no improvement in control of their prothrombin times. It was found that 5 mg. of warfarin had slightly less effect than 50 mg. of bishydroxycoumarin. It was concluded that the drugs were equally effective in long-term anticoagulant therapy. The metabolism of the ingested drug was more important than absorption in determining the control of the patients'' prothrombin times.     

Human gastric mucosal bleeding induced by low dose aspirin,but not warfarin.

OBJECTIVE--To investigate the suitability of treatment with low dose aspirin or warfarin, or both, as possible prophylaxis against cardiovascular disease by determining the effect on gastric mucosal bleeding. DESIGN--Randomised crossover trial. SETTING--Academic department of therapeutics. SUBJECTS--Twenty healthy male volunteers aged 19-22. INTERVENTIONS--On separate occasions and in randomised order all subjects received aspirin 75 mg, warfarin, or aspirin 75 mg combined with warfarin. Each treatment was given for 12 days or (when warfarin was used) for longer if necessary until the international normalised ratio of the prothrombin time was stable at 1.4-1.6. END POINT--Loss of blood over 10 minutes into gastric washings. MEASUREMENTS AND MAIN RESULTS--Bleeding over 10 minutes into gastric washings under baseline conditions and after five days, and at end of each regimen of treatment. Aspirin 75 mg increased bleeding from 0.60 (95% confidence interval 0.36 to 0.99) microliters/10 minutes to 1.26 (0.71 to 2.25) microliters/10 minutes at five days, with no evidence of either progressive change or adaptation thereafter. Warfarin had no effect on bleeding either alone or when combined with aspirin. CONCLUSIONS--Aspirin 75 mg causes gastric mucosal bleeding. Low dose warfarin neither induces gastric mucosal bleeding nor enhances that caused by aspirin.     

Biological Rhythms in the Physiology and Pharmacology of Blood Coagulation

This article reviews the current knowledge on time-dependent variations in the physiology of blood coagulation and in the anticoagulant effect of heparin and warfarin. Animal data indicated that the shortest blood clotting time and the highest levels of coagulation factors 11, VII, and IX were recorded during the resting period of the animal. These circadian rhythms were not altered by modifications of the lighting regimens. In healthy volunteers, the prothrombin time was longer at the end of the afternoon than early in the morning; the acrophases of activated partial thromboplastin time and thrombin time occurred in the evening or during the night. The acrophases of fibrinogen, factors 11, VII, VIII, and α-1-antitrypsin were obtained in the morning. There is no agreement on the chronobiology of platelet aggregation, and differences can be found in the time of maximal aggregability. The chronopharmacological studies of heparin infused at a constant rate to patients with thromboembolic diseases suggested that maximal effectiveness occurred at 04:00, while it was minimal at 08:00. Animal data indicated that oral administration of warfarin at the end of the activity period of rats produced maximal inhibition of vitamin K-dependent factors. This was the time of day when warfarin interference with the vitamin K cycle of the liver was highest. Further studies are needed to determine the clinical significance of biological rhythms in the physiology and pharmacology of blood coagulation.     

Biological Rhythms in the Physiology and Pharmacology of Blood Coagulation

This article reviews the current knowledge on time-dependent variations in the physiology of blood coagulation and in the anticoagulant effect of heparin and warfarin. Animal data indicated that the shortest blood clotting time and the highest levels of coagulation factors II, VII, and IX were recorded during the resting period of the animal. These circadian rhythms were not altered by modifications of the lighting regimens. In healthy volunteers, the prothrombin time was longer at the end of the afternoon than early in the morning; the acro-phases of activated partial thromboplastin time and thrombin time occurred in the evening or during the night. The acrophases of fibrinogen, factors II, VII, VIII, and a-1-antitrypsin were obtained in the morning. There is no agreement on the chronobiology of platelet aggregation, and differences can be found in the time of maximal aggregability. The chronopharmacological studies of heparin infused at a constant rate to patients with thromboembolic diseases suggested that maximal effectiveness occurred at 04:00, while it was minimal at 08:00. Animal data indicated that oral administration of warfarin at the end of the activity period of rats produced maximal inhibition of vitamin K-dependent factors. This was the time of day when warfarin interference with the vitamin K cycle of the liver was highest. Further studies are needed to determine the clinical significance of biological rhythms in the physiology and pharmacology of blood coagulation.     

Comparison of warfarin therapy clinical outcomes following implementation of an automated mobile phone-based critical laboratory value text alert system

Background

Computerized alert and reminder systems have been widely accepted and applied to various patient care settings, with increasing numbers of clinical laboratories communicating critical laboratory test values to professionals via either manual notification or automated alerting systems/computerized reminders. Warfarin, an oral anticoagulant, exhibits narrow therapeutic range between treatment response and adverse events. It requires close monitoring of prothrombin time (PT)/international normalized ratio (INR) to ensure patient safety. This study was aimed to evaluate clinical outcomes of patients on warfarin therapy following implementation of a Personal Handy-phone System-based (PHS) alert system capable of generating and delivering text messages to communicate critical PT/INR laboratory results to practitioners' mobile phones in a large tertiary teaching hospital.

Methods

A retrospective analysis was performed comparing patient clinical outcomes and physician prescribing behavior following conversion from a manual laboratory result alert system to an automated system. Clinical outcomes and practitioner responses to both alert systems were compared. Complications to warfarin therapy, warfarin utilization, and PT/INR results were evaluated for both systems, as well as clinician time to read alert messages, time to warfarin therapy modification, and monitoring frequency.

Results

No significant differences were detected in major hemorrhage and thromboembolism, warfarin prescribing patterns, PT/INR results, warfarin therapy modification, or monitoring frequency following implementation of the PHS text alert system. In both study periods, approximately 80% of critical results led to warfarin discontinuation or dose reduction. Senior physicians' follow-up response time to critical results was significantly decreased in the PHS alert study period (46.3% responded within 1 day) compared to the manual notification study period (24.7%; P = 0.015). No difference in follow-up response time was detected for junior physicians.

Conclusions

Implementation of an automated PHS-based text alert system did not adversely impact clinical or safety outcomes of patients on warfarin therapy. Approximately 80% immediate recognition of text alerts was achieved. The potential benefits of an automated PHS alert for senior physicians were demonstrated.

     

Verification of Pharmacogenetics-Based Warfarin Dosing Algorithms in Han-Chinese Patients Undertaking Mechanic Heart Valve Replacement

Objective

To study the performance of pharmacogenetics-based warfarin dosing algorithms in the initial and the stable warfarin treatment phases in a cohort of Han-Chinese patients undertaking mechanic heart valve replacement.

Methods

We searched PubMed, Chinese National Knowledge Infrastructure and Wanfang databases for selecting pharmacogenetics-based warfarin dosing models. Patients with mechanic heart valve replacement were consecutively recruited between March 2012 and July 2012. The predicted warfarin dose of each patient was calculated and compared with the observed initial and stable warfarin doses. The percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) were utilized to evaluate the predictive accuracy of all the selected algorithms.

Results

A total of 8 algorithms including Du, Huang, Miao, Wei, Zhang, Lou, Gage, and International Warfarin Pharmacogenetics Consortium (IWPC) model, were tested in 181 patients. The MAE of the Gage, IWPC and 6 Han-Chinese pharmacogenetics-based warfarin dosing algorithms was less than 0.6 mg/day in accuracy and the percentage within 20% exceeded 45% in all of the selected models in both the initial and the stable treatment stages. When patients were stratified according to the warfarin dose range, all of the equations demonstrated better performance in the ideal-dose range (1.88–4.38 mg/day) than the low-dose range (<1.88 mg/day). Among the 8 algorithms compared, the algorithms of Wei, Huang, and Miao showed a lower MAE and higher percentage within 20% in both the initial and the stable warfarin dose prediction and in the low-dose and the ideal-dose ranges.

Conclusions

All of the selected pharmacogenetics-based warfarin dosing regimens performed similarly in our cohort. However, the algorithms of Wei, Huang, and Miao showed a better potential for warfarin prediction in the initial and the stable treatment phases in Han-Chinese patients undertaking mechanic heart valve replacement.     

Anticoagulothérapie orale: analyse de l'efficacité d'un guide de posologie.

An empirical protocol for dosage adjustment in warfarin therapy was evaluated by means of retrospective analysis of the medical records of 106 outpatients at an anticoagulation clinic followed from January 1981 to August 1984. There were 203 cases in which the prothrombin time was abnormal (below the therapeutic range in 123 cases and above the range in 80). The protocol was successful in about 60% of cases in which the prothrombin time before dosage adjustment was below the therapeutic range and in 80% of cases in which it was above the range. Statistical analysis showed that the success rate could be improved by more precise definition of the percentage of dosage change in certain situations. However, individual variation in response of the prothrombin time to a standard dosage change limits the success that can be expected after the initial adjustment. We propose an improved protocol for adjustment of warfarin dosage.     

Bleeding time in patients with hepatic cirrhosis.

OBJECTIVE--To determine the frequency of an abnormal bleeding time in patients with cirrhosis and to relate this to known factors that affect primary haemostasis and to the severity of liver disease. DESIGN--Prospective clinical and laboratory study in patients admitted for complications or investigations of liver disease. SETTING--Royal Free Hospital hepatobiliary and liver transplantation unit. SUBJECTS--100 Consecutive inpatients aged 17-74 with various forms of cirrhosis, including alcoholic, biliary, autoimmune, viral, and cryptogenic. At least 10 days had elapsed since any episodes of bleeding, resolution of sepsis, or alcohol intake. No patient was taking any drug known to affect primary haemostasis. MAIN OUTCOME MEASURES--Bleeding time as measured with the Simplate double blade template device. A bleeding time longer than 10 minutes was considered abnormal. Other measures were platelet count, prothrombin time, partial thromboplastin time, packed cell volume, and blood urea, serum bilirubin, and serum albumin concentrations, all measured on each subject at the same time by standard laboratory methods. RESULTS--A weak but significant correlation existed between the bleeding time and the platelet count (rs = 0.483; p less than 0.001). There were significantly lower platelet counts, longer prothrombin times, and higher blood urea and serum bilirubin concentrations in the 42 patients with bleeding times of 10 minutes or more compared with the 58 patients with bleeding times less than 10 minutes. Multiple linear regression analysis showed that the bilirubin concentration as well as the platelet count was independently correlated with the bleeding time. The combination of a platelet count greater than 80 x 10(9)/l and a prothrombin time less than 17 seconds (usually taken as safe limits for performing routine liver biopsy) did not predict a normal bleeding time. Ten of 39 patients fulfilling these criteria had a prolonged bleeding time. CONCLUSIONS--Prolonged bleeding time is common in patients with cirrhosis, even in those with prothrombin times and platelet counts within "safe limits" for invasive procedures. The severity of liver disease as assessed by the bilirubin concentration plays an important part in determining the bleeding time in cirrhosis. The bleeding time should be measured when assessing patients for invasive procedures who have a raised bilirubin concentration or poor hepatic function, even if the platelet count and prothrombin time are considered adequate.     

High-dimensional pharmacogenetic prediction of a continuous trait using machine learning techniques with application to warfarin dose prediction in African Americans

MOTIVATION: With complex traits and diseases having potential genetic contributions of thousands of genetic factors, and with current genotyping arrays consisting of millions of single nucleotide polymorphisms (SNPs), powerful high-dimensional statistical techniques are needed to comprehensively model the genetic variance. Machine learning techniques have many advantages including lack of parametric assumptions, and high power and flexibility. RESULTS: We have applied three machine learning approaches: Random Forest Regression (RFR), Boosted Regression Tree (BRT) and Support Vector Regression (SVR) to the prediction of warfarin maintenance dose in a cohort of African Americans. We have developed a multi-step approach that selects SNPs, builds prediction models with different subsets of selected SNPs along with known associated genetic and environmental variables and tests the discovered models in a cross-validation framework. Preliminary results indicate that our modeling approach gives much higher accuracy than previous models for warfarin dose prediction. A model size of 200 SNPs (in addition to the known genetic and environmental variables) gives the best accuracy. The R(2) between the predicted and actual square root of warfarin dose in this model was on average 66.4% for RFR, 57.8% for SVR and 56.9% for BRT. Thus RFR had the best accuracy, but all three techniques achieved better performance than the current published R(2) of 43% in a sample of mixed ethnicity, and 27% in an African American sample. In summary, machine learning approaches for high-dimensional pharmacogenetic prediction, and for prediction of clinical continuous traits of interest, hold great promise and warrant further research.     

Association between polymorphisms of VKORC1 and CYP2C9 genes with warfarin maintenance dose in a group of warfarin users in Birjand city,Iran

Warfarin is the cardinal anticoagulant drug prescribed around the world. Due to stochastic bleeding in patients, it is essential to adjust the dose for every individual. The aim of the present study was to evaluate the frequency of CYP2C9 and VKORC1 gene polymorphisms and their association with warfarin maintenance dose in a sample of cardiovascular patients in Birjand, South-Khorasan province of Iran. Patients with a history of cardiovascular disorders who take warfarin daily were selected. CYP2C9 and VKORC1 gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in all participants. A total of 114 patients (mean age: 52.7 ± 14.9 years, M/F ratio: 0.76) participated in this study. Regarding CYP2C9 gene polymorphisms, the most frequent genotype was 1*/1* (80.4% in females and 62.5% in males). The frequency of 1*/2* and 2*/2* variants was 13% and 6.5% in females and 25% and 12.5% in males, respectively. The frequency of VKORC1 gene (1639 G > A), was 31.5%, 39.5%, and 29% for GG, GA, and AA in males, respectively. Besides, the mentioned genotype frequencies for females were 50%, 40.5%, and 9.5%, respectively. Moreover, there was a statistically significant correlation between VKORC1 gene −1639 G > A variant and warfarin maintenance dose (P < 0.001) but not for CYP2C9 variants. The results of the current study confirmed that the mutant variants of CYP2C9 are not frequent and do not have any impact on warfarin dose. In the case of VKORC1, the mutant allele (A) showed a positive correlation with warfarin dose adjustment.     

Inhibition by warfarin of prothrombin synthesis and of lipid-saccharide synthesis in rat liver

In vivo and in vitro studies using [³H]glucosamine incorporation into prothrombin and into glycolipids were conducted in rat liver to determine the role of lipid-saccharides in the biosynthesis of prothrombin.In vivo studies demonstrated that 10 mg warfarin/kg inhibited the incorporation of radiolabeled glucosamine into liver prothrombin and glycolipids. This inhibition was similar to the kinetics of inhibition of prothrombin synthesis in the liver.In vitro studies demonstrated a time-dependent increase in the incorporation of radiolabeled glucosamine into lipid-saccharides and prothrombin. This incorporation was inhibited 50% by 5 · 10^?4 M warfarin. Warfarin also inhibited the incorporation of radiolabeled glucosamine into glycolipids in a dose-related manner.In all studies, vitamin K-1 reversed the inhibition of glucosamine incorporation into glycolipids and into prothrombin.     

Circannual changes in blood coagulation factors and the effect of warfarin on the hedgehog Erinaceus europaeus

Levels of blood coagulation factors were measured monthly in hedgehogs kept at 20 degrees C under a natural-light schedule for 1 yr using prothrombin time and the P & P method. Hedgehogs display a circannual cycle of blood coagulation factors in the absence of temperature cues, with high levels corresponding to the active period and low levels corresponding to the hibernation period. Ten hedgehogs and ten guinea pigs were treated with clinical doses of warfarin and blood coagulation factors measured. Warfarin caused a similar decrease in vitamin K-dependent blood coagulation factors in both species.     

The effect of warfarin and vitamin K-1 on the carboxylation and glycosylation of prothrombin in vivo

The effect of warfarin and vitamin K-1 on the carboxylation and glycosylation of prothrombin in the rat in vivo was investigated. Neither warfarin nor vitamin K-1 has an effect on carboxylation. However, warfarin inhibited glycosylation 80–90% and this inhibition was readily reversed by the administration of vitamin K-1.     

Warfarin Dosage Response Related Pharmacogenetics in Chinese Population

Objectives

As the most frequently prescribed anticoagulant, warfarin has large inter-individual variability in dosage. Genetic polymorphisms could largely explain the differences in dosage requirement. rs9923231 (VKORC1), rs7294 (VKORC1), rs1057910 (CYP2C9), rs2108622 (CYP4F2), and rs699664 (GGCX) involved in the warfarin action mechanism and the circulatory vitamin K were selected to investigate their polymorphism characteristics and their effects on the pharmacodynamics and pharmacokinetics of warfarin in Chinese population.

Methods

220 patients with cardiac valve replacement were recruited. International normalized ratio and plasma warfarin concentrations were determined. The five genetic polymorphisms were genotyping by pyro-sequencing. The relationships of maintenance dose, plasma warfarin concentration and INR were assessed among groups categorized by genotypes.

Results

rs9923231 and rs7294 in VKORC1 had the analogous genotype frequencies (D’: 0.969). 158 of 220 recruited individuals had the target INR (1.5–2.5). Patients with AA of rs9923231 and CC of rs7294 required a significantly lower maintenance dose and plasma concentration than those with AG and TC, respectively. The mean weekly maintenance dose was also significantly lower in CYP2C9 rs1057910 mutated heterozygote than in patients with the wild homozygote. Eliminating the influence from environment factors (age, body weight and gender), rs9923231 and rs1057910 could explain about 32.0% of the variability in warfarin maintenance dose; rs7294 could explain 26.7% of the variability in plasma concentration. For patients with allele G of rs9923231 and allele T of rs7294, higher plasma concentration was needed to achieve the similar goal INR.

Conclusions

A better understanding of the genetic variants in individuals can be the foundation of warfarin dosing algorithm and facilitate the reasonable and effective use of warfarin in Chinese.     

Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery.

A prospective study was carried out to see whether a small fixed dose of warfarin (1 mg daily) given before operation (mean 20 days) would prevent deep vein thrombosis in patients having major gynaecological surgery. One hundred and four patients were randomised into three groups: fixed minidose warfarin; full dose oral anticoagulation; and no treatment (controls). There was a significantly lower incidence of deep vein thrombosis in the minidose warfarin and full dose anticoagulant treatment groups (9% (3/32) and 3% (1/35) respectively) than in the controls (30%; 11/37) but no significant difference between the two anticoagulant treatment groups. Prothrombin time and the activated partial thromboplastin time were normal on the day of surgery in the warfarin treatment group, whereas times were prolonged in the group given full dose anticoagulation. Mean haemoglobin concentrations fell in all three groups after operation but the fall was significantly less in the minidose warfarin treatment group than after full dose anticoagulation. The benefit from full dose oral anticoagulant prophylaxis, based on a preoperative international normalised ratio of 1.5-2.5 with rabbit brain Manchester reagent, was similar to the protection achieved in an oral anticoagulant treatment group controlled with human brain Manchester comparative reagent at a similar level of anticoagulation. The lack of disturbance of normal haemostasis at the time of operation together with a significant reduction in deep vein thrombosis may encourage surgeons to introduce minidose prophylaxis with warfarin.     

A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001). Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients.