Warfarin has been used as anticoagulant for the long-term treatment of thromboembolic disease, however, the wide spread use is limited by a wide inter-individual variation in dose requirement. Recent studies have demo...Warfarin has been used as anticoagulant for the long-term treatment of thromboembolic disease, however, the wide spread use is limited by a wide inter-individual variation in dose requirement. Recent studies have demonstrated that amiodarone may interact with warfarin to potentiate the anticoagulant effects and lead to an elevated international normalized ratio（INR）. In addition, genetic variation in the vitamin K epoxide reductase complex subunit 1（VKORC1） and cytochrome P450 2C9（CYP2C9） may also affect the dose of warfarin in single or combination therapy. In our study, we aim to examine the effect of amiodarone on the warfarin in different CYP2C9 and VKORC1 status. From September 2008 to November 2009, 207 patients from Beijing, China were enrolled in our study, including 34 patients on combination therapy of amiodarone and warfarin and 173 patients on warfarin therapy. VKORCl and CYP2C9 genotypes were examined using ligation detection reaction（LDR） method. We compared the stable dosage of warfarin and INR between patients on warfarin therapy and patients on warfarin-amiodarone therapy when they are stratified with VKORC1 or CYP2C9 genotype. We did not observe significant difference in dosage or INR between these two groups. The difference in characteristics between these two groups, the blood collection time after amiodarone administration and the method for monitoring may all contribute to the negative finding. Large studies taking into account of these factors are needed to improve our understanding of the interaction between warfarin and amiodarone, as well as the effect of genotype in such interaction.展开更多
Oral anticoagulation therapy with warfarin is used to prevent and treat venous and arterial thrombosis and embolism. Its narrow therapeutic index should be monitored carefully in order to reach the desired outcomes. T...Oral anticoagulation therapy with warfarin is used to prevent and treat venous and arterial thrombosis and embolism. Its narrow therapeutic index should be monitored carefully in order to reach the desired outcomes. The complexity of the pharmacokinetic and pharmacodynamics profile of warfarin makes it a challenge to use during treatment. Its manufacturing characteristics play a key role in its dosage. The aim of this study is to examine and evaluate the effect of two different warfarin regimens in Chinese patients. A cross-sectional study design was adopted. Medical records of all patients （n = 368） who received warfarin therapy in cardio-thoracic surgery wards between Sep. 2008 and Dec. 2009 were reviewed. Details of antithrombotic results of international normalized ratio （INR） monitoring were obtained. Statistical analysis was performed to assess factors predictive of INR therapeutic range at patients＇ discharge time according to different warfarin regimens （2.5 mg in China and 3.0 mg in USA）. The patients＇ mean age was （48.23~12.96） years. The percentage of patients within the INR therapeutic range in the group treated with 2.5 mg warfarin （35.17%） was much lower than that in group treated with 3.0 mg warfarin （47.72%）. Therefore, a significance difference was observed （P = 0.032〈0.05）. In this study, statistical values have shown that most of the patients were related to medical case requesting INR target range of 1.8-2.2 and 2.0-2.5, respectively. There was a statistically significant difference between the two groups. The study showed that the 2.5 mg-warfarin regimen was less suitable than the 3.0 mg-warfarin regimen. Medication regimen should be simplified as much as possible, especially during different treatment period.展开更多
Objective： To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. Methods： Rats were exposed to wa...Objective： To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. Methods： Rats were exposed to warfarin by applying 10 μg of warfarin‐sodium to 10‐12 cm 2 skin （range 0.8‐1 μg per 1 cm 2 ） for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. Results： Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury （increased malondialdehyde, MDA, production, evident histo‐morphological changes in epidermis and dermis depicting cell injury and death）. Increased numbers of proliferating cell nuclear antigen （PCNA ＋ ） cells indicated reparative processes in injured skin. Infiltration of CD3 ＋ cells （T lymphocytes） along with the increased production of tumor necrosis factor‐α （TNF‐α） by epidermal cells from warfarin‐treated skin and their co‐stimulatory effect in an in vitro T‐cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. Conclusion： Presented data have documented tissue damage associated with immune/ inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.展开更多
The safety and efficacy of combined low dose aspirin and warfarin therapy in patients with atrial fibrillation after mechanical heart valve replacement were evaluated. A total of 1016 patients （620 females, mean age ...The safety and efficacy of combined low dose aspirin and warfarin therapy in patients with atrial fibrillation after mechanical heart valve replacement were evaluated. A total of 1016 patients （620 females, mean age of 36.8-4-7.7 years） admitted for cardiac valve replacement and complicated with atrial fibrillation after surgery were randomly divided into study （warfarin plus 75-100 mg aspirin） or control （warfarin only） groups. International normalized ratio （INR） and prothrombin time were main- tained at 1.8-2.5 and 1.5-2.0 times the normal values, respectively. Thromboembolic events and major bleedings were registered during the follow-up period. Patients were followed up for 24±9 months. The average dose of warfarin in the study and control groups was 2.91±0.83 mg and 2.88±0.76 mg, respec- tively （P〉0.05）. The incidence of overall thromboembolic events in study group was lower than that in control group （2.16% vs. 4.35%, P=0.049）. No statistically significant differences were found in hem- orrhage events （3.53% vs. 3.95%, P=-0.722） or mortality （0.20% vs. 0.40%, P=0.559） between the two groups. Combined low dose aspirin and warfarin therapy in the patients with atrial fibrillation following mechanical heart valve replacement significantly decreased thromboembolic events as compared with warfarin therapy alone. This combined treatment was not associated with an increase in the risk of major bleeding or mortality.展开更多
Deep venous thrombosis(DVT)poses a major challenge to public health worldwide.Endothelial cell injury evokes inflammatory and oxidative responses that contribute to thrombus formation.Tea polyphenol(TP)in the form of ...Deep venous thrombosis(DVT)poses a major challenge to public health worldwide.Endothelial cell injury evokes inflammatory and oxidative responses that contribute to thrombus formation.Tea polyphenol(TP)in the form of epigallocatechin-3-gallate(EGCG)has anti-inflammatory and oxidative effect that may ameliorate DVT.However,the precise mechanism remains incompletely understood.The current study was designed to investigate the anti-DVT mechanism of EGCG in combination with warfarin(an oral anticoagulant).Rabbits were randomly divided into five groups.A DVT model of rats was established through ligation of the inferior vena cava(IVC)and left common iliac vein,and the animals were orally administered with EGCG,warfarin,or vehicle for seven days.In vitro studies included pretreatment of human umbilical vein endothelial cells(HUVECs)with different concentrations of EGCG for 2 h before exposure to hydrogen peroxide.Thrombus weight and length were examined.Histopathological changes were observed by hematoxylin-eosin staining.Blood samples were collected for detecting coagulation function,including thrombin and prothrombin times,activated partial thromboplastin time,and fibrinogen levels.Protein expression in thrombosed IVCs and HUVECs was evaluated by Western blot,immunohistochemical analysis,and/or immunofluorescence staining.RT-qPCR was used to determine the levels of AGTR-1 and VEGF mRNA in IVCs and HUVECs.The viability of HUVECs was examined by CCK-8 assay.Flow cytometry was performed to detect cell apoptosis and ROS generation was assessed by 2′,7ʹ-dichlorofluorescein diacetate reagent.In vitro and in vivo studies showed that EGCG combined with warfarin significantly reduced thrombus weight and length,and apoptosis in HUVECs.Our findings indicated that the combination of EGCG and warfarin protects HUVECs from oxidative stress and prevents apoptosis.However,HIF-1αsilencing weakened these effects,which indicated that HIF-1αmay participate in DVT.Furthermore,HIF-1αsilencing significantly up-regulated cell apoptosis and ROS generation,and enhanced VEGF expression and the activation of the PI3K/AKT and ERK1/2 signaling pathways.In conclusion,our results indicate that EGCG combined with warfarin modifies HIF-1αand VEGF to prevent DVT in rabbits through anti-inflammation via the PI3K/AKT and ERK1/2 signaling pathways.展开更多
The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group...The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg-1 for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry(LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg-1 were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.展开更多
A novel sensor for the determination of warfarin based on a simple and sensitive method was developed on multiwalled-carbon-nanotube modified ZnCrFeO4 carbon paste electrodes（MWCNT/ZnCrFeO4/CPEs）. Cyclic voltammetry...A novel sensor for the determination of warfarin based on a simple and sensitive method was developed on multiwalled-carbon-nanotube modified ZnCrFeO4 carbon paste electrodes（MWCNT/ZnCrFeO4/CPEs）. Cyclic voltammetry, differential pulse voltammetry, chronoamperometry, and electrochemical impedance spectroscopy were used to investigate the electrochemical behavior of warfarin at the chemically modified electrode. According to the results, MWCNT/ZnCrFeO4/CPEs showed high electrocatalytic activity for warfarin oxidation, producing a sharp oxidation peak current at about ＋0.97 vs Ag/AgCl reference electrode at pH = 4.0. The peak current was linearly dependent on warfarin concentration over the range of 0.02–920.0 μmol/L with a detection limit of 0.003 μmol/L. In addition, chronoamperometry was also used to determine warfarin＇s catalytic rate constant and diffusion coefficient at MWCNT/ZnCrFeO4/CPEs.展开更多
BACKGROUND Most of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation(AF)originated from western countrie...BACKGROUND Most of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation(AF)originated from western countries.AIM To systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran,rivaroxaban,and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF.METHODS Medline,Cochrane,and ClinicalTrial.gov databases were reviewed.A randomeffect model meta-analysis was used and I-square was utilized to assess the heterogeneity.The primary outcome was ischemic stroke.The secondary outcomes were all-cause mortality,major bleeding,intracranial hemorrhage,and gastrointestinal bleeding.RESULTS Twelve studies from East Asia or Southeast Asia and 441450 patients were included.Dabigatran,rivaroxaban,and apixaban were associated with a significant reduction in the incidence of ischemic stroke[hazard ratio(HR)=0.78,95%confidence interval(CI):0.65-0.94;HR=0.79,95%CI:0.74-0.85,HR=0.70,95%CI:0.62-0.78;respectively],all-cause mortality(HR=0.68,95%CI:0.56-0.83;HR=0.66,95%CI:0.52-0.84;HR=0.66,95%CI:0.49-0.90;respectively),and major bleeding(HR=0.61,95%CI:0.54-0.69;HR=0.70,95%CI:0.54-0.90;HR=0.58,95%CI:0.43-0.78;respectively)compared to warfarin.CONCLUSION Dabigatran,rivaroxaban,and apixaban appear to be superior to warfarin in both efficacy and safety in Asians with non-valvular AF.展开更多
BACKGROUND Heparin is commonly recommended for warfarin-induced skin necrosis;however, there is currently no established therapy for this disease. We present a serious case of warfarin-induced skin necrosis that was s...BACKGROUND Heparin is commonly recommended for warfarin-induced skin necrosis;however, there is currently no established therapy for this disease. We present a serious case of warfarin-induced skin necrosis that was successfully treated with oral rivaroxaban, a factor Xa inhibitor.CASE SUMMARY A 48-year-old woman was admitted to the hospital for cellulitis of the right lower extremity. After antibiotic treatment, she developed pain and swelling of the left lower extremity, and deep vein thrombosis of both lower extremities was diagnosed. She was treated with a continuous heparin injection;subsequently,oral warfarin was concomitantly administered. Heparin was terminated after the therapeutic range was reached. On the following day, the patient had swelling and pain in the left lower extremity. In addition to decrease in protein S activity due to systemic lupus erythematosus, warfarin also reduced protein C activity,resulting in further hypercoagulation and skin necrosis. Warfarin was discontinued, and continuous heparin injection was resumed. Although the patient had to undergo amputation of the distal end of her left foot, continuous heparin injection was switched to oral rivaroxaban, and she was eventually discharged from the hospital in remission.CONCLUSION Administration of direct oral anticoagulants instead of warfarin is important in patients with decreased protein S and C activity.展开更多
This study aims to establish the occupational exposure limit （OEL） in the air for workplace of warfarin based on the available toxicological studies and field investigations by using questionnaire and air monitoring...This study aims to establish the occupational exposure limit （OEL） in the air for workplace of warfarin based on the available toxicological studies and field investigations by using questionnaire and air monitoring. The clinical therapeutic dose was used as lowest observed effect level （LOEL）, and no observed effect level （NOEL） was achieved by using a safety factor. The highest concentration of warfarin monitored in the worksite of centrifuge washing, drying and packing were 0.029 mg/m3, 0.052 mg/m3 respectively, which did not exceed the OEL 0.2 mg/m3 recommended by NIOSH and ACGIH. Considering its feasibility for enforcement and protection for workers, we recommend OEL 0.2 mg/m3 of warfarin in China.展开更多
Warfarin is a commonly used anticoagulant with a narrow therapeutic range and risk of hemorrhagic complications. After CYP2C9 and VKORC1, CYP4F2 was confirmed as the third principle genetic determinant of warfarin dos...Warfarin is a commonly used anticoagulant with a narrow therapeutic range and risk of hemorrhagic complications. After CYP2C9 and VKORC1, CYP4F2 was confirmed as the third principle genetic determinant of warfarin dose variability.展开更多
Background Asian population are at increased risk of bleeding during the warfarin treatment,so the recommended optimal international normalized ratio(INR)level may be lower in Asians than in Westerners.The aim of this...Background Asian population are at increased risk of bleeding during the warfarin treatment,so the recommended optimal international normalized ratio(INR)level may be lower in Asians than in Westerners.The aim of this prospective multicenter study was to determine the optimal INR level in Thai patients with non-valvular atrial fibrillation(NVAF).Methods Patients with NVAF who were on warfarin for stroke prevention were recruited from 27 hospitals in the nationwide COOL-AF registry in Thailand.We collected demographic data,medical history,risk factors for stroke and bleeding,concomitant disease,electrocardiogram and laboratory data including INR and antithrombotic medications.Outcome measurements included ischemic stroke/transient ischemic attack(TIA)and major bleeding.Optimal INR level was assessed by the calculation of incidence density for six INR ranges(<1.5,1.5–1.99,2–2.49,2.5–2.99,3–3.49,and≥3.5).Results A total of 2,232 patients were included.The mean age of patients was 68.5±10.6 years.The mean follow-up duration was 25.7±10.6 months.There were 63 ischemic stroke/TIA and 112 major bleeding events.The lowest prevalence of ischemic stroke/TIA and major bleeding events occurred within the INR range of 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.Conclusions The INR range associated with the lowest risk of ischemic stroke/TIA and bleeding in the Thai population was 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.The rates of major bleeding and ischemic stroke/TIA were both higher than the rates reported in Western population.展开更多
Background: Interaction between proton pump inhibitors (PPI) and warfarin is controversial. Previous clinical studies have only a short follow-up period. Methods and Results: All patients (n = 716) for whom warfarin w...Background: Interaction between proton pump inhibitors (PPI) and warfarin is controversial. Previous clinical studies have only a short follow-up period. Methods and Results: All patients (n = 716) for whom warfarin was prescribed from November 1, 2010 to October 30, 2011 were extracted from electronic health records. In retrospective analysis for 1 year, PPI were prescribed to 404 patients. Among them, 108 patients were taking warfarin for more than 6 weeks before and after PPI. The profile of these patients was analyzed: 63 patients took lansoprazole;15 patients took omeprazole;30 patients took rabeprazole. No statistical difference was observed among 3 groups in age, body weight, concomitant use of other drugs, and comorbidity. Warfarin dose and INR did not change after PPI. Multivariate stepwise logistic regression analysis revealed that upper quartile of increment of INR was associated with the presence of atrial fibrillation (OR 3.77, 95% CI 1.16 - 12.27). The patients who had warfarin for shorter periods before PPI, or those who had PPI first (n = 141) had similar dose of warfarin and INR. In all patients analyzed (n = 404), including patients whose follow-up periods were shorter than 6 weeks (n = 155), a patient had cerebral bleeding, and 2 patients had cerebral infarction. Conclusions: Unfavorable interaction between warfarin and PPI was negligible in clinical use. Relatively higher INR was achieved after PPI in the presence of atrial fibrillation.展开更多
BACKGROUND The quality of warfarin therapy can be determined by the time in the therapeutic range(TTR)of international normalized ratio(INR).The estimated minimum TTR needed to achieve a benefit from warfarin therapy...BACKGROUND The quality of warfarin therapy can be determined by the time in the therapeutic range(TTR)of international normalized ratio(INR).The estimated minimum TTR needed to achieve a benefit from warfarin therapy is≥60%.AIM To determine TTR and the predictors of poor TTR among atrial fibrillation patients who receive warfarin therapy.METHODS A retrospective observational study was conducted at a cardiology referral center in Selangor,Malaysia.A total of 420 patients with atrial fibrillation and under follow-up at the pharmacist led Warfarin Medication Therapeutic Adherence Clinic between January 2014 and December 2018 were included.Patients’clinical data,information related to warfarin therapy,and INR readings were traced through electronic Hospital Information system.A data collection form was used for data collection.The percentage of days when INR was within range was calculated using the Rosendaal method.The poor INR control category was defined as a TTR<60%.Predictors for poor TTR were further determined by using logistic regression.RESULTS A total of 420 patients[54.0%male;mean age 65.7(10.9)years]were included.The calculated mean and median TTR were 60.6%±20.6%and 64%(interquartile range 48%-75%),respectively.Of the included patients,57.6%(n=242)were in the good control category and 42.4%(n=178)were in the poor control category.The annual calculated mean TTR between the year 2014 and 2018 ranged from 59.7%and 67.3%.A high HAS-BLED score of≥3 was associated with poor TTR(adjusted odds ratio,2.525;95%confidence interval:1.6-3.9,P<0.001).CONCLUSION In our population,a high HAS-BLED score was associated with poor TTR.This could provide an important insight when initiating an oral anticoagulant for these patients.Patients with a high HAS-BLED score may obtain less benefit from warfarin therapy and should be considered for other available oral anticoagulants for maximum benefit.展开更多
VKORC1 and CYP2C9 have been shown to be strongly associated with Warfarin dosing. However, it is still unclear whether other common genetic variants also contribute to the variation in Warfarin dosing. In the present ...VKORC1 and CYP2C9 have been shown to be strongly associated with Warfarin dosing. However, it is still unclear whether other common genetic variants also contribute to the variation in Warfarin dosing. In the present study, we aim to investigate possible effects of single nucleotide polymorphisms （SNPs） in other candidate genes （CYP4F2, CACNAIC and STX4）, as well as several factors, on stable daily Warfarin dosage （DWMD） in Chinese cardiovascular disease patients. 207 cardiovascular disease patients treated with Warfarin were recruited from Beijing Hospital. DNA was extracted from the blood samples collected one day after Warfarin administration. Nine SNPs （i.e. rs9923231, rs9934438, rs7294, rs1799853, rs1057910, rs4086116, rs2108622, rs216013 and rs10871454 in five genes （i.e. VKORC1, CYP2Cg, CYP4F2, CACNA1C and STX4） were analyzed using ligase detection reactions （LDR）. Univariate analyses and multiple linear regression analyses were performed to analyze the associations between SNPs and other factors （i.e. body surface area （BSA）, Statin medication） and DWMD. Four SNPs （i.e. rs9923231, rs9934438, rs7294 in VKORC1 and rsi0871454 in STX4） had significant statistically effects on DWMD. The multiple linear regression model showed that rs10871454 in STX4, BSA, statin medication, and rs1057910 in CYP2C9 were the significant independent covariates of DWMD. SNP （rs10871454） in STX4 had the strongest effect on Warfarin dosing among the examined candidate genes, indicating that it might serve as a key genetic factor for prediciting the Warfarin maintenance dose in Chinese patients.展开更多
Management of warfarin-induced major bleeding in patients with mechanical heart valves is challenging. There is vast controversy and confusion in the type of treatment required to reverse anticoagulation and stop blee...Management of warfarin-induced major bleeding in patients with mechanical heart valves is challenging. There is vast controversy and confusion in the type of treatment required to reverse anticoagulation and stop bleeding as well as the ideal time to restart warfarin therapy safely without recurrence of bleeding and/or thromboembolism. Presently, the treatments available to reverse warfarin-induced bleeding are vitamin K, fresh frozen plasma, prothrombin complex concentrates and recombinant activated factor VIIa. Currently, vitamin K and fresh frozen plasma are the recommended treatments in patients with mechanical heart valves and warfarin-induced major bleeding. The safe use of prothrombin complex concentrates and recombinant activated factor VIIa in patients with mechanical heart valves is controversial and needs well-designed clinical studies. With regard to restarting anticoagulation in patients with warfarin-induced major bleeding and mechanical heart valves, the safe period varies from 7-14 d after the onset of bleeding for patients with intracranial bleed and 48-72 h for patients with extra-cranial bleed. In this review article, we present relevant literature about these controversies and suggest recommendations for management of patients with warfarin-induced bleeding and a mechanical heart valve. Furthermore, there is an urgent need for separate specific guidelines from major associations/ professional societies with regard to mechanical heart valves and warfarin-induced bleeding.展开更多
BACKGROUND The drug interaction between warfarin and rifampicin is widely known,but there are still some difficulties in managing the combination of the two drugs.CASE SUMMARY A patient with brucellosis received stric...BACKGROUND The drug interaction between warfarin and rifampicin is widely known,but there are still some difficulties in managing the combination of the two drugs.CASE SUMMARY A patient with brucellosis received strict monitoring from a Chinese pharmacist team during combination of warfarin and rifampicin.The dose of warfarin was increased to 350%in 3 mo before reaching the lower international normalized ratio treatment window.No obvious adverse reaction occurred during the drugadjustment period.This is the first case report of long-term combined use of rifampicin and warfarin in patients with brucellosis and valve replacement in China based on the Chinese lower warfarin dose and international normalized ratio range.CONCLUSION Anticoagulation for valve replacement in Chinese patients differs from that in other races.Establishment of a pharmacist clinic provides vital assistance in warfarin dose adjustment.展开更多
Background In recent years, it is found that the polymorphisms of genes which are involved in the pharmacokinetic and pharmacodynamic pathways play important roles in the clinical anticoagulation treatment with warfar...Background In recent years, it is found that the polymorphisms of genes which are involved in the pharmacokinetic and pharmacodynamic pathways play important roles in the clinical anticoagulation treatment with warfarin. The aim of the study was to investigate the impact of the genetic polymorphism of r-glutamic acid carboxylase （gamma-glutamyl carboxylase gene, GGCX） on the response of warfarin initial anticoagulant therapy. Methods Seven hundred and ninety-eight Chinese Han patients who received valve replacement surgery and orally taken warfarin in long term for anticoagulant therapy in Guangdong General Hospital from 2000 to 2008 were enrolled in the study, a polymorphic SNPs point （rs699664） of GGCX was selected, and SnaPshot was adopted to perform single nucleotide polymorphism （SNP） test, and by grouping according to genotype, GGCX average daily dose of warfarin, time for PT-INR to reach the target value and differences in the incidence of excessive coagulation between different genotypes were compared respectively. Hardy-Weinberg genetic equilibrium test was applied for population representative test. Results Within the 20 days of warfarin initial therapy, male average daily dose of warfarin （2.92 ± 1.18 mg/d） was apparently higher than that of female （2.64 ± 0.98 mg/d）, while there were no significant differences in the average time required for PT-INR to reach the target value （ 1.8） and the excessive coagulation ratio at the initial therapy stage between male and female. And there were no significant differences in the average daily dose of warfarin, time to reach the target value and excessive coagulation ratio among different GGCX genotypes. Conclusions GGCX genovariation had no significant impact on the warfarin daily dose within the 20-day initial therapy of Chinese Han Population, and for the conventional dosage program, the risk of bleeding in the GGCX mutation individuals did not increase obviously at the initial administration period.展开更多
基金The Research Special Fund for Public WelfareIndustry of Health(Grant No.200902008)
文摘Warfarin has been used as anticoagulant for the long-term treatment of thromboembolic disease, however, the wide spread use is limited by a wide inter-individual variation in dose requirement. Recent studies have demonstrated that amiodarone may interact with warfarin to potentiate the anticoagulant effects and lead to an elevated international normalized ratio（INR）. In addition, genetic variation in the vitamin K epoxide reductase complex subunit 1（VKORC1） and cytochrome P450 2C9（CYP2C9） may also affect the dose of warfarin in single or combination therapy. In our study, we aim to examine the effect of amiodarone on the warfarin in different CYP2C9 and VKORC1 status. From September 2008 to November 2009, 207 patients from Beijing, China were enrolled in our study, including 34 patients on combination therapy of amiodarone and warfarin and 173 patients on warfarin therapy. VKORCl and CYP2C9 genotypes were examined using ligation detection reaction（LDR） method. We compared the stable dosage of warfarin and INR between patients on warfarin therapy and patients on warfarin-amiodarone therapy when they are stratified with VKORC1 or CYP2C9 genotype. We did not observe significant difference in dosage or INR between these two groups. The difference in characteristics between these two groups, the blood collection time after amiodarone administration and the method for monitoring may all contribute to the negative finding. Large studies taking into account of these factors are needed to improve our understanding of the interaction between warfarin and amiodarone, as well as the effect of genotype in such interaction.
文摘Oral anticoagulation therapy with warfarin is used to prevent and treat venous and arterial thrombosis and embolism. Its narrow therapeutic index should be monitored carefully in order to reach the desired outcomes. The complexity of the pharmacokinetic and pharmacodynamics profile of warfarin makes it a challenge to use during treatment. Its manufacturing characteristics play a key role in its dosage. The aim of this study is to examine and evaluate the effect of two different warfarin regimens in Chinese patients. A cross-sectional study design was adopted. Medical records of all patients （n = 368） who received warfarin therapy in cardio-thoracic surgery wards between Sep. 2008 and Dec. 2009 were reviewed. Details of antithrombotic results of international normalized ratio （INR） monitoring were obtained. Statistical analysis was performed to assess factors predictive of INR therapeutic range at patients＇ discharge time according to different warfarin regimens （2.5 mg in China and 3.0 mg in USA）. The patients＇ mean age was （48.23~12.96） years. The percentage of patients within the INR therapeutic range in the group treated with 2.5 mg warfarin （35.17%） was much lower than that in group treated with 3.0 mg warfarin （47.72%）. Therefore, a significance difference was observed （P = 0.032〈0.05）. In this study, statistical values have shown that most of the patients were related to medical case requesting INR target range of 1.8-2.2 and 2.0-2.5, respectively. There was a statistically significant difference between the two groups. The study showed that the 2.5 mg-warfarin regimen was less suitable than the 3.0 mg-warfarin regimen. Medication regimen should be simplified as much as possible, especially during different treatment period.
基金supported by the Ministry of Science and Technological Development of the Republic of Serbia, Grant # 143038
文摘Objective： To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. Methods： Rats were exposed to warfarin by applying 10 μg of warfarin‐sodium to 10‐12 cm 2 skin （range 0.8‐1 μg per 1 cm 2 ） for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. Results： Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury （increased malondialdehyde, MDA, production, evident histo‐morphological changes in epidermis and dermis depicting cell injury and death）. Increased numbers of proliferating cell nuclear antigen （PCNA ＋ ） cells indicated reparative processes in injured skin. Infiltration of CD3 ＋ cells （T lymphocytes） along with the increased production of tumor necrosis factor‐α （TNF‐α） by epidermal cells from warfarin‐treated skin and their co‐stimulatory effect in an in vitro T‐cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. Conclusion： Presented data have documented tissue damage associated with immune/ inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.
文摘The safety and efficacy of combined low dose aspirin and warfarin therapy in patients with atrial fibrillation after mechanical heart valve replacement were evaluated. A total of 1016 patients （620 females, mean age of 36.8-4-7.7 years） admitted for cardiac valve replacement and complicated with atrial fibrillation after surgery were randomly divided into study （warfarin plus 75-100 mg aspirin） or control （warfarin only） groups. International normalized ratio （INR） and prothrombin time were main- tained at 1.8-2.5 and 1.5-2.0 times the normal values, respectively. Thromboembolic events and major bleedings were registered during the follow-up period. Patients were followed up for 24±9 months. The average dose of warfarin in the study and control groups was 2.91±0.83 mg and 2.88±0.76 mg, respec- tively （P〉0.05）. The incidence of overall thromboembolic events in study group was lower than that in control group （2.16% vs. 4.35%, P=0.049）. No statistically significant differences were found in hem- orrhage events （3.53% vs. 3.95%, P=-0.722） or mortality （0.20% vs. 0.40%, P=0.559） between the two groups. Combined low dose aspirin and warfarin therapy in the patients with atrial fibrillation following mechanical heart valve replacement significantly decreased thromboembolic events as compared with warfarin therapy alone. This combined treatment was not associated with an increase in the risk of major bleeding or mortality.
基金supported by the National Nature Science Foundation of China(No.81871463)Nanjing Health Science and Technology Development Special Fund Project(No.YKK19086).
文摘Deep venous thrombosis(DVT)poses a major challenge to public health worldwide.Endothelial cell injury evokes inflammatory and oxidative responses that contribute to thrombus formation.Tea polyphenol(TP)in the form of epigallocatechin-3-gallate(EGCG)has anti-inflammatory and oxidative effect that may ameliorate DVT.However,the precise mechanism remains incompletely understood.The current study was designed to investigate the anti-DVT mechanism of EGCG in combination with warfarin(an oral anticoagulant).Rabbits were randomly divided into five groups.A DVT model of rats was established through ligation of the inferior vena cava(IVC)and left common iliac vein,and the animals were orally administered with EGCG,warfarin,or vehicle for seven days.In vitro studies included pretreatment of human umbilical vein endothelial cells(HUVECs)with different concentrations of EGCG for 2 h before exposure to hydrogen peroxide.Thrombus weight and length were examined.Histopathological changes were observed by hematoxylin-eosin staining.Blood samples were collected for detecting coagulation function,including thrombin and prothrombin times,activated partial thromboplastin time,and fibrinogen levels.Protein expression in thrombosed IVCs and HUVECs was evaluated by Western blot,immunohistochemical analysis,and/or immunofluorescence staining.RT-qPCR was used to determine the levels of AGTR-1 and VEGF mRNA in IVCs and HUVECs.The viability of HUVECs was examined by CCK-8 assay.Flow cytometry was performed to detect cell apoptosis and ROS generation was assessed by 2′,7ʹ-dichlorofluorescein diacetate reagent.In vitro and in vivo studies showed that EGCG combined with warfarin significantly reduced thrombus weight and length,and apoptosis in HUVECs.Our findings indicated that the combination of EGCG and warfarin protects HUVECs from oxidative stress and prevents apoptosis.However,HIF-1αsilencing weakened these effects,which indicated that HIF-1αmay participate in DVT.Furthermore,HIF-1αsilencing significantly up-regulated cell apoptosis and ROS generation,and enhanced VEGF expression and the activation of the PI3K/AKT and ERK1/2 signaling pathways.In conclusion,our results indicate that EGCG combined with warfarin modifies HIF-1αand VEGF to prevent DVT in rabbits through anti-inflammation via the PI3K/AKT and ERK1/2 signaling pathways.
基金supported by the Natural Science Foundation of China(No.31101241)the Independent Innovation Foundation of Shandong University(IIFSDU,No.2012TS163)
文摘The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg-1 for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry(LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg-1 were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.
文摘A novel sensor for the determination of warfarin based on a simple and sensitive method was developed on multiwalled-carbon-nanotube modified ZnCrFeO4 carbon paste electrodes（MWCNT/ZnCrFeO4/CPEs）. Cyclic voltammetry, differential pulse voltammetry, chronoamperometry, and electrochemical impedance spectroscopy were used to investigate the electrochemical behavior of warfarin at the chemically modified electrode. According to the results, MWCNT/ZnCrFeO4/CPEs showed high electrocatalytic activity for warfarin oxidation, producing a sharp oxidation peak current at about ＋0.97 vs Ag/AgCl reference electrode at pH = 4.0. The peak current was linearly dependent on warfarin concentration over the range of 0.02–920.0 μmol/L with a detection limit of 0.003 μmol/L. In addition, chronoamperometry was also used to determine warfarin＇s catalytic rate constant and diffusion coefficient at MWCNT/ZnCrFeO4/CPEs.
文摘BACKGROUND Most of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation(AF)originated from western countries.AIM To systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran,rivaroxaban,and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF.METHODS Medline,Cochrane,and ClinicalTrial.gov databases were reviewed.A randomeffect model meta-analysis was used and I-square was utilized to assess the heterogeneity.The primary outcome was ischemic stroke.The secondary outcomes were all-cause mortality,major bleeding,intracranial hemorrhage,and gastrointestinal bleeding.RESULTS Twelve studies from East Asia or Southeast Asia and 441450 patients were included.Dabigatran,rivaroxaban,and apixaban were associated with a significant reduction in the incidence of ischemic stroke[hazard ratio(HR)=0.78,95%confidence interval(CI):0.65-0.94;HR=0.79,95%CI:0.74-0.85,HR=0.70,95%CI:0.62-0.78;respectively],all-cause mortality(HR=0.68,95%CI:0.56-0.83;HR=0.66,95%CI:0.52-0.84;HR=0.66,95%CI:0.49-0.90;respectively),and major bleeding(HR=0.61,95%CI:0.54-0.69;HR=0.70,95%CI:0.54-0.90;HR=0.58,95%CI:0.43-0.78;respectively)compared to warfarin.CONCLUSION Dabigatran,rivaroxaban,and apixaban appear to be superior to warfarin in both efficacy and safety in Asians with non-valvular AF.
文摘BACKGROUND Heparin is commonly recommended for warfarin-induced skin necrosis;however, there is currently no established therapy for this disease. We present a serious case of warfarin-induced skin necrosis that was successfully treated with oral rivaroxaban, a factor Xa inhibitor.CASE SUMMARY A 48-year-old woman was admitted to the hospital for cellulitis of the right lower extremity. After antibiotic treatment, she developed pain and swelling of the left lower extremity, and deep vein thrombosis of both lower extremities was diagnosed. She was treated with a continuous heparin injection;subsequently,oral warfarin was concomitantly administered. Heparin was terminated after the therapeutic range was reached. On the following day, the patient had swelling and pain in the left lower extremity. In addition to decrease in protein S activity due to systemic lupus erythematosus, warfarin also reduced protein C activity,resulting in further hypercoagulation and skin necrosis. Warfarin was discontinued, and continuous heparin injection was resumed. Although the patient had to undergo amputation of the distal end of her left foot, continuous heparin injection was switched to oral rivaroxaban, and she was eventually discharged from the hospital in remission.CONCLUSION Administration of direct oral anticoagulants instead of warfarin is important in patients with decreased protein S and C activity.
基金supported by the Occupational Health Standards Program (20100304) from Ministry of Health of China
文摘This study aims to establish the occupational exposure limit （OEL） in the air for workplace of warfarin based on the available toxicological studies and field investigations by using questionnaire and air monitoring. The clinical therapeutic dose was used as lowest observed effect level （LOEL）, and no observed effect level （NOEL） was achieved by using a safety factor. The highest concentration of warfarin monitored in the worksite of centrifuge washing, drying and packing were 0.029 mg/m3, 0.052 mg/m3 respectively, which did not exceed the OEL 0.2 mg/m3 recommended by NIOSH and ACGIH. Considering its feasibility for enforcement and protection for workers, we recommend OEL 0.2 mg/m3 of warfarin in China.
基金Acknowledgements This work was supported by grants from the National Natural Science Foundation of China （No. 30971259）, and the Scientific and Technological Innovation Fund for Young Investigation, Chinese PLA General Hospital （No. 09KMM23）.
文摘Warfarin is a commonly used anticoagulant with a narrow therapeutic range and risk of hemorrhagic complications. After CYP2C9 and VKORC1, CYP4F2 was confirmed as the third principle genetic determinant of warfarin dose variability.
基金the Health System Research Institute(59-053)the Heart Association of Thailand under the Royal Patronage of H.M.the King.All authors had no conflicts of interest to disclose.The authors gratefully acknowledge Pontawee Kaewcomdee and Olaree Chaiphet for data management,and all investigators and nurse coordinators of the COOL-AF registry.
文摘Background Asian population are at increased risk of bleeding during the warfarin treatment,so the recommended optimal international normalized ratio(INR)level may be lower in Asians than in Westerners.The aim of this prospective multicenter study was to determine the optimal INR level in Thai patients with non-valvular atrial fibrillation(NVAF).Methods Patients with NVAF who were on warfarin for stroke prevention were recruited from 27 hospitals in the nationwide COOL-AF registry in Thailand.We collected demographic data,medical history,risk factors for stroke and bleeding,concomitant disease,electrocardiogram and laboratory data including INR and antithrombotic medications.Outcome measurements included ischemic stroke/transient ischemic attack(TIA)and major bleeding.Optimal INR level was assessed by the calculation of incidence density for six INR ranges(<1.5,1.5–1.99,2–2.49,2.5–2.99,3–3.49,and≥3.5).Results A total of 2,232 patients were included.The mean age of patients was 68.5±10.6 years.The mean follow-up duration was 25.7±10.6 months.There were 63 ischemic stroke/TIA and 112 major bleeding events.The lowest prevalence of ischemic stroke/TIA and major bleeding events occurred within the INR range of 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.Conclusions The INR range associated with the lowest risk of ischemic stroke/TIA and bleeding in the Thai population was 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.The rates of major bleeding and ischemic stroke/TIA were both higher than the rates reported in Western population.
文摘Background: Interaction between proton pump inhibitors (PPI) and warfarin is controversial. Previous clinical studies have only a short follow-up period. Methods and Results: All patients (n = 716) for whom warfarin was prescribed from November 1, 2010 to October 30, 2011 were extracted from electronic health records. In retrospective analysis for 1 year, PPI were prescribed to 404 patients. Among them, 108 patients were taking warfarin for more than 6 weeks before and after PPI. The profile of these patients was analyzed: 63 patients took lansoprazole;15 patients took omeprazole;30 patients took rabeprazole. No statistical difference was observed among 3 groups in age, body weight, concomitant use of other drugs, and comorbidity. Warfarin dose and INR did not change after PPI. Multivariate stepwise logistic regression analysis revealed that upper quartile of increment of INR was associated with the presence of atrial fibrillation (OR 3.77, 95% CI 1.16 - 12.27). The patients who had warfarin for shorter periods before PPI, or those who had PPI first (n = 141) had similar dose of warfarin and INR. In all patients analyzed (n = 404), including patients whose follow-up periods were shorter than 6 weeks (n = 155), a patient had cerebral bleeding, and 2 patients had cerebral infarction. Conclusions: Unfavorable interaction between warfarin and PPI was negligible in clinical use. Relatively higher INR was achieved after PPI in the presence of atrial fibrillation.
文摘BACKGROUND The quality of warfarin therapy can be determined by the time in the therapeutic range(TTR)of international normalized ratio(INR).The estimated minimum TTR needed to achieve a benefit from warfarin therapy is≥60%.AIM To determine TTR and the predictors of poor TTR among atrial fibrillation patients who receive warfarin therapy.METHODS A retrospective observational study was conducted at a cardiology referral center in Selangor,Malaysia.A total of 420 patients with atrial fibrillation and under follow-up at the pharmacist led Warfarin Medication Therapeutic Adherence Clinic between January 2014 and December 2018 were included.Patients’clinical data,information related to warfarin therapy,and INR readings were traced through electronic Hospital Information system.A data collection form was used for data collection.The percentage of days when INR was within range was calculated using the Rosendaal method.The poor INR control category was defined as a TTR<60%.Predictors for poor TTR were further determined by using logistic regression.RESULTS A total of 420 patients[54.0%male;mean age 65.7(10.9)years]were included.The calculated mean and median TTR were 60.6%±20.6%and 64%(interquartile range 48%-75%),respectively.Of the included patients,57.6%(n=242)were in the good control category and 42.4%(n=178)were in the poor control category.The annual calculated mean TTR between the year 2014 and 2018 ranged from 59.7%and 67.3%.A high HAS-BLED score of≥3 was associated with poor TTR(adjusted odds ratio,2.525;95%confidence interval:1.6-3.9,P<0.001).CONCLUSION In our population,a high HAS-BLED score was associated with poor TTR.This could provide an important insight when initiating an oral anticoagulant for these patients.Patients with a high HAS-BLED score may obtain less benefit from warfarin therapy and should be considered for other available oral anticoagulants for maximum benefit.
文摘VKORC1 and CYP2C9 have been shown to be strongly associated with Warfarin dosing. However, it is still unclear whether other common genetic variants also contribute to the variation in Warfarin dosing. In the present study, we aim to investigate possible effects of single nucleotide polymorphisms （SNPs） in other candidate genes （CYP4F2, CACNAIC and STX4）, as well as several factors, on stable daily Warfarin dosage （DWMD） in Chinese cardiovascular disease patients. 207 cardiovascular disease patients treated with Warfarin were recruited from Beijing Hospital. DNA was extracted from the blood samples collected one day after Warfarin administration. Nine SNPs （i.e. rs9923231, rs9934438, rs7294, rs1799853, rs1057910, rs4086116, rs2108622, rs216013 and rs10871454 in five genes （i.e. VKORC1, CYP2Cg, CYP4F2, CACNA1C and STX4） were analyzed using ligase detection reactions （LDR）. Univariate analyses and multiple linear regression analyses were performed to analyze the associations between SNPs and other factors （i.e. body surface area （BSA）, Statin medication） and DWMD. Four SNPs （i.e. rs9923231, rs9934438, rs7294 in VKORC1 and rsi0871454 in STX4） had significant statistically effects on DWMD. The multiple linear regression model showed that rs10871454 in STX4, BSA, statin medication, and rs1057910 in CYP2C9 were the significant independent covariates of DWMD. SNP （rs10871454） in STX4 had the strongest effect on Warfarin dosing among the examined candidate genes, indicating that it might serve as a key genetic factor for prediciting the Warfarin maintenance dose in Chinese patients.
文摘Management of warfarin-induced major bleeding in patients with mechanical heart valves is challenging. There is vast controversy and confusion in the type of treatment required to reverse anticoagulation and stop bleeding as well as the ideal time to restart warfarin therapy safely without recurrence of bleeding and/or thromboembolism. Presently, the treatments available to reverse warfarin-induced bleeding are vitamin K, fresh frozen plasma, prothrombin complex concentrates and recombinant activated factor VIIa. Currently, vitamin K and fresh frozen plasma are the recommended treatments in patients with mechanical heart valves and warfarin-induced major bleeding. The safe use of prothrombin complex concentrates and recombinant activated factor VIIa in patients with mechanical heart valves is controversial and needs well-designed clinical studies. With regard to restarting anticoagulation in patients with warfarin-induced major bleeding and mechanical heart valves, the safe period varies from 7-14 d after the onset of bleeding for patients with intracranial bleed and 48-72 h for patients with extra-cranial bleed. In this review article, we present relevant literature about these controversies and suggest recommendations for management of patients with warfarin-induced bleeding and a mechanical heart valve. Furthermore, there is an urgent need for separate specific guidelines from major associations/ professional societies with regard to mechanical heart valves and warfarin-induced bleeding.
文摘BACKGROUND The drug interaction between warfarin and rifampicin is widely known,but there are still some difficulties in managing the combination of the two drugs.CASE SUMMARY A patient with brucellosis received strict monitoring from a Chinese pharmacist team during combination of warfarin and rifampicin.The dose of warfarin was increased to 350%in 3 mo before reaching the lower international normalized ratio treatment window.No obvious adverse reaction occurred during the drugadjustment period.This is the first case report of long-term combined use of rifampicin and warfarin in patients with brucellosis and valve replacement in China based on the Chinese lower warfarin dose and international normalized ratio range.CONCLUSION Anticoagulation for valve replacement in Chinese patients differs from that in other races.Establishment of a pharmacist clinic provides vital assistance in warfarin dose adjustment.
基金supported by National Natural Science Foundation of China (No.30772620)Guangdong Medical Science and Technology Research Foundation (NO.A2007048)
文摘Background In recent years, it is found that the polymorphisms of genes which are involved in the pharmacokinetic and pharmacodynamic pathways play important roles in the clinical anticoagulation treatment with warfarin. The aim of the study was to investigate the impact of the genetic polymorphism of r-glutamic acid carboxylase （gamma-glutamyl carboxylase gene, GGCX） on the response of warfarin initial anticoagulant therapy. Methods Seven hundred and ninety-eight Chinese Han patients who received valve replacement surgery and orally taken warfarin in long term for anticoagulant therapy in Guangdong General Hospital from 2000 to 2008 were enrolled in the study, a polymorphic SNPs point （rs699664） of GGCX was selected, and SnaPshot was adopted to perform single nucleotide polymorphism （SNP） test, and by grouping according to genotype, GGCX average daily dose of warfarin, time for PT-INR to reach the target value and differences in the incidence of excessive coagulation between different genotypes were compared respectively. Hardy-Weinberg genetic equilibrium test was applied for population representative test. Results Within the 20 days of warfarin initial therapy, male average daily dose of warfarin （2.92 ± 1.18 mg/d） was apparently higher than that of female （2.64 ± 0.98 mg/d）, while there were no significant differences in the average time required for PT-INR to reach the target value （ 1.8） and the excessive coagulation ratio at the initial therapy stage between male and female. And there were no significant differences in the average daily dose of warfarin, time to reach the target value and excessive coagulation ratio among different GGCX genotypes. Conclusions GGCX genovariation had no significant impact on the warfarin daily dose within the 20-day initial therapy of Chinese Han Population, and for the conventional dosage program, the risk of bleeding in the GGCX mutation individuals did not increase obviously at the initial administration period.
