Evaluating the effects of anticoagulant rodenticide bromadiolone in Wistar rats co-exposed to vitamin K: impact on blood-liver axis and brain oxidative status.

The aim of this study was to investigate the beneficial effects of vitamin K relate to protection against detrimental effects of bromadiolone. Wistar rats (n = 30) were divided in three groups (n = 10): control group and two groups treated with bromadiolone (0.12 mg/kg) and bromadiolone + vitamin K (0.12 mg/kg + 100 mg/kg) over the period of four days. The main findings in the bromadiolone-exposed rats, such as damaged hepatocytes, high levels of globulin, total proteins and lymphocytes, and altered albumin/globulin ratio, collectively indicate an acute inflammatory process. Morphological changes in erythrocytes include microcytosis, hypochromia, hyperchromia, hemolysis, stomatocytosis, and spherocytosis. Significantly low values of RBC, Hct, and hemoglobin concentrations indicate impairments of the hematopoietic pathway causing combined anemia. The selected dose of bromadiolone caused a non-significant increase of catalase activity and a significant increase of the total protein content in brain tissue homogenates. Vitamin K supplementation reduced many of the harmful effects of bromadiolone. The cytoprotective role of vitamin K was proved to be of great importance for the preservation of structural changes on the membranes of hepatocytes and erythrocytes, in addition to the known role in the treatment of coagulopathies. The results of the study suggest valuable properties of vitamin K in the prevention and treatment of various types of anemia caused by bromadiolone toxicity. Future research is necessary to determine the adequate dose and treatment duration with vitamin K in disorders caused by the cumulative action of bromadiolone and possibly other pesticides.

P-glycoprotein (ABCB1) is involved in vitamin K efflux.

ABCB1 (P-glycoprotein/MDR1) is a multidrug efflux transporter that has previously been involved in cholesterol and vitamin D metabolism. Our aim was to explore whether ABCB1 is also involved in vitamin K efflux. Vitamin K apical efflux was significantly decreased in presence of ABCB1 inhibitor in Caco-2 cells (-20.4%; p < 0.05) and increased in Griptite cells overexpressing ABCB1 (+40.7%; p < 0.05). In vivo, the vitamin K postprandial response was higher in male Abcb1-/- mice after gavage compared to control animals (+115%; p < 0.05), but was unchanged in female mice. Finally, a vitamin K transintestinal efflux and a biliary vitamin K efflux were observed, but the specific involvement of ABCB1 could not be confirmed in these pathways. Overall, we showed for the first time that ABCB1 is involved in enterocyte vitamin K efflux in both cell and mouse models and regulates vitamin K absorption in mice.

Discovery of the First Vitamin K Analogue as a Potential Treatment of Pharmacoresistant Seizures.

Despite the availability of more than 25 antiseizure drugs on the market, approximately 30% of patients with epilepsy still suffer from seizures. Thus, the epilepsy therapy market has a great need for a breakthrough drug that will aid pharmacoresistant patients. In our previous study, we discovered a vitamin K analogue, 2h, which displayed modest antiseizure activity in zebrafish and mouse seizure models. However, there are limitations to this compound due to its pharmacokinetic profile. In this study, we develop a new series of vitamin K analogues by modifying the structure of 2h. Among these, compound 3d shows full protection in a rodent pharmacoresistant seizure model with limited rotarod motor toxicity and favorable pharmacokinetic properties. Furthermore, the brain/plasma concentration ratio of 3d indicates its excellent permeability into the brain. The resulting data shows that 3d can be further developed as a potential antiseizure drug in the clinic.

Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates: A Study With the Modified Cooperstown 5+1 Cocktail.

The aim of this study was to characterize the effects of upadacitinib, a Janus kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) enzymes using a cocktail approach. Healthy subjects (n = 20) received single oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 (all other probes) of a 15-day regimen of upadacitinib 30 mg once daily (extended-release formulation). Serial blood samples and 12-hour urine samples were collected for assays of the probe substrates and select metabolites. The ratio (90%CI) of area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) central values when the cocktail drugs were administered with upadacitinib relative to when administered alone were 0.74 (0.68-0.80) for midazolam, 1.22 (1.15-1.29) for caffeine, 1.11 (1.07-1.15) for S-warfarin, 1.07 (0.95-1.22) for dextromethorphan, and 0.82 (0.72-0.94) for omeprazole. The ratio (90%CI) was 1.09 (1.00-1.19) for 5-hydroxy-omeprazole to omeprazole AUCinf ratio and 1.17 (0.97-1.41) for dextromethorphan to dextrorphan 12-hour molar urinary ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. No clinically relevant changes in plasma exposures are expected for drugs that are substrates for the evaluated CYP enzymes when coadministered with upadacitinib.

Factors associated to adequate time in therapeutic range with oral vitamin K antagonists in Tunisia.

INTRODUCTION:   The quality of chronic anticoagulation and predictor factors of poor anticoagulant control in patients under acenocoumarol were unknown in North Africa. METHODS: It is an observational study, carried out between November 2015 and November 30, 2016. The international normalized ratio (INR) values were prospectively obtained, and TTR was calculated using the Rosendaal method. RESULTS: Overall, 215 patients were included in this study, with a mean age of 63±0,8 years. The prevalence of poor anticoagulation control was 78.1%; 95% CI [72.2-83.2] (168 patients with TTR less than 65%). The median TTR with the Rosendaal method was 44.4%. After multivariate adjustment, variables significantly associated with adequate anticoagulation level were: history of ischemic stroke (Adjusted OR equal to 4.3, 95% CI: 1.4-12.9), associated prescription of antiplatelet therapy (Adjusted OR equal to 3.5, 95% CI: 1.1-11.2), daily prescribed dose of coumarins less than 6 mg (Adjusted OR equal to 6.4, 95% CI: 1.1- 36) and lower risk of bleeding assessed as HAS-BLED score (Adjusted OR: 0.5, 95% CI: 0.3-0.8). CONCLUSION: The quality of anticoagulation management with VKA among outpatients who received acenocoumarol was suboptimal. Strategies should be undertaken by clinicians and patients to improve the quality of anticoagulation, to address challenges to adverse cardiovascular outcomes in individuals treated with chronic anticoagulation.

Transdermal delivery of vitamin K using dissolving microneedles for the prevention of vitamin K deficiency bleeding.

Vitamin K deficiency within neonates can result in vitamin K deficiency bleeding. Ensuring that newborns receive vitamin K is particularly critical in places where access to health care and blood products and transfusions is limited. The World Health Organization recommends that newborns receive a 1 mg intramuscular injection of vitamin K at birth. Evidence from multiple surveillance studies shows that the introduction of vitamin K prophylaxis reduces the incidence of vitamin K deficiency bleeding. Despite these recommendations, coverage of vitamin K prophylactic treatment in low-resource settings is limited. An intramuscular injection is the most common method of vitamin K administration in neonates. In low- and middle-income countries, needle sharing may occur, which may result in the spread of bloodborne diseases. The objective of our study was to investigate the manufacture of microneedles for the delivery of vitamin K. Following microneedle fabrication, we performed insertion studies to assess the microneedle's mechanical properties. Results indicate that vitamin K in a microneedle array was successfully delivered in vitro across neonatal porcine skin with 1.80 ±â€¯0.08 mg delivered over 24 h. Therefore, this initial study shows that microneedles do have the potential to prevent vitamin K deficiency bleeding. Future work will assess delivery of vitamin K in microneedle array in vivo.

Effect of ramadan fasting on acenocoumarol-induced antocoagulant effect.

Eating patterns, food intake and type of alimentation vary greatly during the month of ramadan. Furthermore, fasting, which practiced during the month of ramadan, can have an impact on drug's metabolism. These two factors, fasting and eating habits changes during the month of ramadan, may impact acenocoumarol anticoagulant effect, translated by variations of INR values. The aim of our study was to see ramadan fasting effects on INR variations in patients treated by acenocoumarol. A prospective monocentric study was conducted during the ramadan month on fasting outpatients that were treated by acenocoumarol. Baseline INR values (e.i. most recent available value before the month of ramadan) were compared to INR values obtained during the month of ramadan. All patients were monitored for signs of secondary haemorrhagic complications linked to treatment by anti-vitamin K (AVK). Thirty patients were included in the study with a sex ratio 1. Patients mean age was 65 years. Around two thirds of the patients were treated by AVK for atrial fibrillation. The majority of patients (94%) have been treated by AVK for more than a year. Mean INR was significantly higher during the month of ramadan than baseline (3.51 vs 2.52; p< 0.0001). There were also more overdoses during the month of ramadan than baseline (9 vs. 0; p=0.014). The increased INR values highlights the need of a close monitoring of INR values during the month of ramadan, particularly in patients with a high haemorrhagic risk.

US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K.

Vitamin K plays important biological roles in maintaining normal blood coagulation, bone mineralization, soft tissue physiology, and neurological development. Menaquinone-7 is a form of vitamin K2 that occurs naturally in some animal-derived and fermented foods. It is also available as an ingredient of dietary supplements. Menaquinone-7 has greater bioavailability than other forms of vitamin K, which has led to increasing sales and use of menaquinone-7 supplements. This special article reviews the chemistry, nomenclature, dietary sources, intake levels, and pharmacokinetics of menaquinones, along with the nonclinical toxicity data available and the data on clinical outcomes related to safety (adverse events). In conclusion, the data reviewed indicate that menaquinone-7, when ingested as a dietary supplement, is not associated with any serious risk to health or with other public health concerns. On the basis of this conclusion, US Pharmacopeia monographs have been developed to establish quality standards for menaquinone-7 as a dietary ingredient and as a dietary supplement in various dosage forms.

Effect of Vitamin K Intake on the Stability of Treatment with Vitamin K Antagonists: A Systematic Review of the Literature.

Vitamin K antagonists (VKA) are highly effective for the primary and secondary prevention of arterial and venous thromboembolic events. However, patients treated with VKA have on average only 60% of their international normalized ratio (INR) values within the therapeutic range and INR instability is associated with an increased risk of thrombosis and bleeding events. Recent evidence suggests that poor dietary vitamin K intake may affect anticoagulation control, but the role of vitamin K in INR stability remains to be established. We performed a systematic review of the literature to assess the role of vitamin K dietary intake on the stability of VKA and the potential effect of daily vitamin K supplementation on VKA therapy. After a search in Medline and EMBASE databases, 15 studies for a total of 1,838 patients were included in our systematic review. Observational studies suggest an increased risk of unstable anticoagulation control in patients with lower daily vitamin K intake. On the other hand, the role of daily vitamin K supplementation or a diet with controlled vitamin K content in patients on VKA treatment remains to be established. Use of daily vitamin K supplementation may be associated with a clinically relevant increase in the time in therapeutic range in patients with unstable anticoagulation control. Conversely, this effect appears small and not clinically relevant when vitamin K was administered to an unselected population receiving VKA. Other large prospective studies are necessary to confirm our preliminary findings.

Modelling of vitamin K half-life in patients treated with vitamin K antagonists before hip fracture surgery.

BACKGROUND: Guidelines recommend treatment with vitamin K in patients requiring reversal of the effect of vitamin K antagonists (VKA) before semi-urgent surgery. In clinical practice, the time for reversal of the international normalized ratio (INR) to values adequate for surgery is often reported longer than the expected 12-24 hours, which may delay surgery and increase the risk of complications. METHODS: In order to optimize the management of elderly patients treated with VKA and undergoing hip fracture surgery, we aimed to model the vitamin K half-life in this specific population. Files for patients admitted between 2006 and 2008 for hip fracture surgery and chronically treated with VKA were retrospectively studied. Only patients with an INR superior to 1.5 upon arrival were included in the study. The effect of vitamin K on the decrease in INR was modelled after a PK/PD analysis using NONMEM. Thirty-one patients' files were analysed. RESULTS: Despite management in accordance with guidelines, 31% of the patients had a delayed return to INR values<1.5 resulting in delayed surgery. Time to INR<1.5 was longer than 24 hours in 50% of the patients. The calculated half-life of vitamin K was 24.7 hours in this population. CONCLUSION: The vitamin K half-life in elderly patients treated with VKA and undergoing hip fracture surgery was prolonged. The use of vitamin K or of a more rapid acting alternative should be discussed, depending on the urgency of the surgery.

Fat-soluble vitamin intestinal absorption: absorption sites in the intestine and interactions for absorption.

The interactions occurring at the intestinal level between the fat-soluble vitamins A, D, E and K (FSVs) are poorly documented. We first determined each FSV absorption profile along the duodenal-colonic axis of mouse intestine to clarify their respective absorption sites. We then investigated the interactions between FSVs during their uptake by Caco-2 cells. Our data show that vitamin A was mostly absorbed in the mouse proximal intestine, while vitamin D was absorbed in the median intestine, and vitamin E and K in the distal intestine. Significant competitive interactions for uptake were then elucidated among vitamin D, E and K, supporting the hypothesis of common absorption pathways. Vitamin A also significantly decreased the uptake of the other FSVs but, conversely, its uptake was not impaired by vitamins D and K and even promoted by vitamin E. These results should be taken into account, especially for supplement formulation, to optimise FSV absorption.

A global quality control system to check PT-INR portable monitor for Antivitamin K antagonists.

INTRODUCTION: Although most guidelines for quality assessment of INR PMs recommend specific procedures, no clear regulation or methodology is required for outpatients in our country. We have developed a specific INR portable monitor (PM) quality control system within our telemedicine organization to check over time quality performances and plan corrective actions. METHODS: Based on current guidelines for laboratory QC, the following aspects were assessed: suitability of PM, defined in terms of imprecision and accuracy; intra-assay imprecision, defined according to monthly revision of Levey-Jennings cards with data from each peripheral healthcare unit (PHU), using an internal QC provided by the manufacturer (CV ± 20% considered as acceptable); quarterly accuracy study, for assessing agreement between analytical instruments, based on duplicate analysis of three samples with INR values reflecting different therapeutic ranges (differences ± 0.5 considered as acceptable); external quality assessment (NEQAS). RESULTS: In the nine PHU, 18 portable monitors were used to perform 22 929 test during year 2010. Analytical imprecision was low, showing CVs always <5%. Accuracy check showed two of 216 results out of range (0.92%), thus providing timely indication for instrument replacement. The external QC NEQAS showed optimal performance. CONCLUSION: The current protocol for INR PMs quality assessment was effective to establish and maintain a reliable control of devices, ensuring the quality of analytical data over time. National authorities should be prompted to guarantee and apply correct protocols for INR-PM use.

Uso da vitamina K como rastreador de eventos adversos hemorrágicos por varfarina: um estudo de caso / Use of vitamin K to track hemorrhagic adverse events caused by warfarin: a case study

The medical use of warfarin requires close monitoring because of its narrow therapeutic index. Thus, methods that enable effective monitoring to detect any adverse events (AEs) associated with this drug are necessary to improve the quality of health care. Many authors have proposed the use of triggers to search actively for possibleAEs. The aim of this study was to assess the possible use of vitamin K as a tracker of adverse bleeding events caused by warfarin in a public hospital specialized in cardiology in Rio de Janeiro. We applied the method of trigger tools (Institute for Healthcare Improvement, 2004; Rozichet al., 2003), which retrospectively analyzed the results of the use of vitamin K (phytomenadione), to screen for adverse bleeding events caused by warfarin, from October 2010 to March 2011. From an analysis of 46 medical records, 14 possible AEs were found. In 23 cases, internal bleeding was the cause of hospitalization. Despite difficulties, especially those related to poor access to data and quality of hospital records, the application of vitamin K as a trigger was found to be of great use in detecting hemorrhagic AEs associated with warfarin. This method has potential applications for monitoring the results of interventions, with a view to reducing the incidence of hemorrhagic adverse events...

O uso de varfarina requer monitoramento rigoroso devido a seu índice terapêutico estreito. Da mesma forma, a aplicação de métodos que permitam o monitoramento adequado de eventos adversos a este medicamento é necessária para que se possa contribuir com a qualidade do cuidado em saúde. O uso de marcadores para o processo de busca ativa de eventos adversos tem sido proposto por muitos autores. Neste trabalho, buscou-se avaliar o potencial de utilização do uso da vitamina K como rastreador de eventos adversos hemorrágicos causados por varfarina em um hospital público de alta complexidade em cardiologia do Rio de Janeiro. O método dos rastreadores ou trigger tools foi aplicado para análise retrospectiva da utilização da vitamina K (fitomenadiona) como rastreador de eventos adversos hemorrágicos causados por varfarina, no período de outubro de 2010 a março de 2011. Com base na análise de 46 prontuários, foram encontrados 14 possíveis eventos adversos. Em 23 casos, a hemorragia foi a causa da internação. Apesar das dificuldades, sobretudo relacionadas ao acesso às informações e à qualidade dos registros, a aplicação da vitamina K como rastreador se mostrou bastante útil na detecção de eventos adversos hemorrágicos por varfarina. A aplicação deste método como estratégia de monitoramento de eventos adversos, tem potencial para uso no acompanhamento dos resultados de intervenções visando à redução da incidência dos eventos adversos hemorrágicos...

Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 µM) and the more potent and specific P-gp inhibitor valspodar (5 µM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 µM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

Matrix gla protein and alkaline phosphatase are differently modulated in human dermal fibroblasts from PXE patients and controls.

Mineralization of elastic fibers in pseudoxanthoma elasticum (PXE) has been associated with low levels of carboxylated matrix gla protein (MGP), most likely as a consequence of reduced vitamin K (vit K) availability. Unexpectedly, vit K supplementation does not exert beneficial effects on soft connective tissue mineralization in the PXE animal model. To understand the effects of vit K supplementation and in the attempt to interfere with pathways leading to the accumulation of calcium and phosphate within PXE-mineralized soft connective tissues, we have conducted in vitro studies on dermal fibroblasts isolated from control subjects and from PXE patients. Cells were cultured in standard conditions and in calcifying medium (CM) in the presence of vit K1 and K2, or levamisole, an alkaline phosphatase (ALP) inhibitor. Control and PXE fibroblasts were characterized by a similar dose-dependent uptake of both vit K1 and vit K2, thus promoting a significant increase of total protein carboxylation in all cell lines. Nevertheless, MGP carboxylation remained much less in PXE fibroblasts. Interestingly, PXE fibroblasts exhibited a significantly higher ALP activity. Consistently, the mineralization process induced in vitro by a long-term culture in CM appeared unaffected by vit K, whereas it was abolished by levamisole.

Dietary vitamin K intake and stability of anticoagulation with coumarins; evidence derived from a clinical trial / El consumo de vitamina K y la estabilidad de la anticoagulación con cumarínicos; evidencia derivada de ensayo clínico

Background: Dietary vitamin K intake has been considered a major factor that influences stability of oral anticoagulation (OA) with coumarins. Few studies have evaluated the relationship between amounts of dietary vitamin K intake and stability of anticoagulation. Objective: To assess whether high dietary vitamin K intake is associated to stability of International Normalized Ratio (INR) of the prothrombin time. Methods: We performed a sub-analysis of a randomized clinical trial involving outpatients from the anticoagulation clinic of a university hospital. INR and vitamin K intake were prospectively collected at baseline, 15, 30, 60 and 90 days after randomization. Patients were considered with a stable anticoagulation when their INR coefficient of variation was less than 10%. Dietary vitamin K intake was assessed by a food frequency questionnair and a score of intake was derived. Results: We studied 132 patients on chronic OA (57 ± 13 years; 55% males); 23 patients (17%) were achieved stable anticoagulation. Stable and unstable patients had no significant differences in baseline characteristics. The dietary vitamin K score over the entire follow-up for stable patients was significantly lower than that for unstable patients (p = 0.012). Discussion: Our findings suggest that INR stability could be achieved with relatively low amounts of dietary vitamin K (AU)

Introducción: El consumo dietético de vitamina K ha sido considerado un factor importante que influye en la estabilidad de la anticoagulación oral (AO) con cumarina. Pocos estudios han evaluado la relación entre el consumo dietético de vitamina K y la estabilidad de la anticoagulación. Objetivo: Evaluar la relación existente entre la alta ingesta de vitamina K y el mantenimiento de la estabilidade del la Razón Normalizada Internacional RNI. Métodos: Se realizó una subanálisis de un ensayo clínico aleatorizado con pacientes ambulatórios de la clínica de anticoagulación de un hospital universitario. Los datos acerca del RNI y la ingesta de vitamina K fueron recogidos prospectivamente al inicio del estudio, y en los días 15, 30, 60 y 90. Los pacientes fueron considerados estables cuando su coeficiente de variación del RNI fue menor de 10%. La evaluacion de la dieta y la ingesta de vitamina K se obtuvo mediante un cuestionario de frecuencia alimentaria y un sistema de puntuación fue creado para esto. Resultados: Se estudiaron 132 pacientes en tratamiento crónico (57 ± 13 años, el 55% masculino), 23 pacientes (17%) lograron anticoagulación estable. Con relación a las características basales, no hubo diferencias entre los sujetos con anticoagulación estable o inestable. La puntuación de la vitamina K de la dieta durante todo el seguimiento de los pacientes se mantuvo significativamente menor entre aquellos con RNI estable cuándo comparado con los inestables (p = 0,012). Discusión: Nuestros hallazgos sugieren que con cantidades relativamente bajas de vitamina K podremos obtener la estabilidad de RNI (AU)

Vitamin K nutrition, metabolism, and requirements: current concepts and future research.

In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults.

"The end of good luck''--long-term survival without anticoagulation: a case report and review of the literature.

Long-term anticoagulation in patients with metallic prosthetic valve disease is required according to current guidelines. We describe a patient with a functioning mitral mechanical valve without anticoagulation for 27 years. A 46-year-old man admitted to the emergency department with complains of palpitation. The patient had a mitral valve replacement because of severe mitral stenosis. He discontinued warfarin treatment 1 month after surgery because of the unavailability of this drug in Turkey. Transthoracic echocardiography revealed functioning metalic mitral valve with a mean gradient of 9 mm Hg. Fluoroscopy showed normal excursions of the mechanical mitral valve. Transesophageal echocardiography was performed and revealed fresh thrombus formation in the left atrial appendix. Admission international normalized ration (INR) level was 1.79. Due to the higher INR level and long-term survival, genetic analysis of warfarin polymorphism was performed. There was a homozygous mutation in the vitamin K epoxide reductase complex 1 (VKORC1) 1173C>T and 1639G>A genotypes. The possible explanations of long-term survival and baseline higher INR level were linked to the mutation in warfarin metabolism. We also briefly review the literature.