Anticoagulação Crônica em Pacientes com Fibrilação Atrial e COVID-19: Uma Revisão Sistemática e Metanálise / Chronic Anticoagulation in Patients with Atrial Fibrillation and COVID-19: A Systematic Review and Meta-Analysis

Resumo Fundamento: A doença por coronavírus 2019 (COVID-19) está associada à hipercoagulabilidade. Permanece incerto se a anticoagulação contínua para fibrilação atrial (FA) em pacientes que posteriormente contraem COVID-19 melhora os desfechos clínicos. Objetivos: Comparar a anticoagulação oral crônica com ausência de anticoagulação prévia em pacientes com FA que contraíram uma infecção por COVID-19 em relação aos desfechos de mortalidade por todas as causas, mortalidade por COVID-19, admissão em unidade de terapia intensiva (UTI) e hospitalização. Métodos: Buscamos sistematicamente no PubMed, Embase e Cochrane Library estudos elegíveis desde o início até dezembro de 2022. Incluímos estudos que compararam desfechos de COVID-19 em pacientes com e sem anticoagulação crônica prévia para FA. Foram agrupadas razões de risco (RR) com intervalos de confiança (IC) de 95% por meio de um modelo de efeitos aleatórios. O nível de significância foi estabelecido em p < 0,05. As avaliações da qualidade e do risco de viés foram realizadas de acordo com as recomendações da Cochrane. Resultados: Foram identificados 10 estudos abrangendo 1.177.858 pacientes com COVID-19 e FA, dos quais 893.772 (75,9%) estavam em anticoagulação crônica prévia para FA. Em pacientes com COVID-19, a anticoagulação crônica para FA reduziu significativamente a mortalidade por todas as causas (RR 0,75; IC 95% 0,57 a 0,99; p = 0,048; I2 = 89%) e a mortalidade relacionada à COVID-19 (RR 0,76; IC 95% 0,72 a 0,79; p < 0,001; I2 = 0%) quando comparada com a ausência de anticoagulação prévia. Em contrapartida, não houve diferença entre os grupos em relação à hospitalização (RR 1,08; IC 95% 0,82 a 1,41; p = 0,587; I2 = 95%) ou internação em UTI (RR 0,86; IC 95% 0,68 a 1,09; p = 0,216; I2 = 69%). Conclusões: Nesta metanálise, a anticoagulação crônica para pacientes com FA que contraíram COVID-19 foi associada a taxas significativamente mais baixas de mortalidade por todas as causas e mortalidade relacionada à COVID-19 em comparação com a ausência de anticoagulação anterior.

Abstract Background: Coronavirus disease 2019 (COVID-19) is associated with hypercoagulability. It remains uncertain whether ongoing anticoagulation for atrial fibrillation (AF) in patients who later contract COVID-19 improves clinical outcomes. Objectives: To compare chronic oral anticoagulation with no previous anticoagulation in patients with AF who contracted a COVID-19 infection concerning the outcomes of all-cause mortality, COVID-19 mortality, intensive care unit (ICU) admission, and hospitalization. Methods: We systematically searched PubMed, Embase, and Cochrane Library for eligible studies from inception to December 2022. We included studies comparing COVID-19 outcomes in patients with versus without prior chronic anticoagulation for AF. Risk ratios (RR) with 95% confidence intervals (CI) were pooled with a random-effects model. The level of significance was set at p < 0.05. Quality assessment and risk of bias were performed according to Cochrane recommendations. Results: Ten studies comprising 1,177,858 patients with COVID-19 and AF were identified, of whom 893,772 (75.9%) were on prior chronic anticoagulation for AF. In patients with COVID-19, being on chronic anticoagulation for AF significantly reduced all-cause mortality (RR 0.75; 95% CI 0.57 to 0.99; p = 0.048; I2 = 89%) and COVID-19-related mortality (RR 0.76; 95% CI 0.72 to 0.79; p < 0.001; I2 = 0%) when compared with no prior anticoagulation. In contrast, there was no difference between groups regarding hospitalization (RR 1.08; 95% CI 0.82 to 1.41; p = 0.587; I2 = 95%) or ICU admission (RR 0.86; 95% CI 0.68 to 1.09; p = 0.216; I2 = 69%). Conclusions: In this meta-analysis, chronic anticoagulation for patients with AF who contracted COVID-19 was associated with significantly lower rates of all-cause mortality and COVID-19-related mortality as compared with no previous anticoagulation.

Prediction model of therapeutic effect on children with idiopathic short stature based on vitamin K2,IGFBP-3 and Omentin-1 / 国际检验医学杂志

Objective To investigate the relationship between vitamin K2,insulin-like growth factor bind-ing protein 3(IGFBP-3),Omentin-1 and the therapeutic effect on children with idiopathic short stature(ISS),and to build a prediction model.Methods A total of 242 ISS children in Jinan Second Maternal and Child Health Hospital from 2019 to 2021 were selected.All of them received recombinant human growth hormone(rhGH)treatment and were divided into effective group and ineffective group according to the therapeutic effect after 12 months of treatment.The general data,vitamin K2,IGFBP-3 and Omentin-1 in the two groups were analyzed.The influencing factors of ISS children's therapeutic effect were analyzed by Logistic regression model and decision tree model.The predictive performance of two models was analyzed by using receiver oper-ating characteristic(ROC)curve.Results There were statistically significant differences in 25-hydroxy vita-min D[25(OH)D],parathyroid hormone(PTH),thyroid stimulating hormone(TSH),vitamin K2,IGFBP-3,Omentin-1,rhGH dosage and weekly outdoor exercise time between the two groups(P＜0.05).Logistic re-gression showed that PTH(OR=7.011,95％CI:2.456-20.014),vitamin K2(OR=0.605,95％CI:.0.465-0.788),IGFBP-3(OR=0.458,95％CI:0.321-0.654),Omentin-1(OR=0.514,95％CI:0.389-0.679)and rhGH dose(OR=0.563,95％CI:0.445-0.712)]were the influential factors for treatment ineffectiveness in ISS children(P＜0.05).The decision tree model showed that vitamin K2,IGFBP-3 and Omentin-1 were the factors influencing the therapeutic effect of ISS,and IGFBP-3 had the most significant impact.ROC curve re-sults showed that the area under the curve of decision tree model and Logistic regression model were 0.922 and 0.908,respectively,with good classification effect.Conclusion The therapeutic effect of ISS children is in-fluenced by factors such as vitamin K2,IGFBP-3,Omentin-1,and so on,and IGFBP-3 has the most significant impact.Logistic regression model and decision tree model could complement each other so as to provide refer-ence for improving the therapeutic effect of ISS children from different aspects.

Investigation and Analysis of Vitamin K Level Distribution in 1177 Infants of Different Age Groups / 昆明医科大学学报

Objective To investigate the distributions of vitamin K1 and K2 in infants of different age groups by comparing the serum levels of vitamin K1 and K2 in them.Methods 1177 infants from 0 to 3 months were divided into 6 age groups.Those born/treated in the subject units(pediatrics,neonatology,child health care,obstetrics)were selected as the study subjects and grouped by age:0～3 days(591 cases),4～7 days(255 cases),8～5 days(104 cases),1 month(118 cases),2 months(40 cases),and 3 months(69 cases).General data of the infants were collected,and the serum vitamin K1 and K2 levels were determined by HPLC-mass spectrometry(LC-MS)on a unified platform,and analyzed from the distribution of vitamin K1 and K2 at different ages.Results The distributions of vitamin K1 and K2 levels were statistically significant(P<0.001);newborns were highly vulnerable to vitamin K1 deficiency,and vitamin K2 deficiency was higher than vitamin K1 with age.Conclusion Maintaining the normal growth of vitamin K1 and K2 is crucial for the normal growth and development of infants of all ages,so we should pay close attention to the monitoring and supplement of vitamin K1 and K2.

Serum vitamin K2 level in children and its correlation with bone mineral density / 中国儿童保健杂志

【Objective】 To analyze the clinical characteristics of serum vitamin K2 in children and its correlation with bone mineral density, so as to provide reference for the prevention of insufficient bone strength in children. 【Methods】 A total of 4 145 children who underwent serum vitamin K2 testing and physical examination at pediatric outpatient clinics of several municipal and county hospitals in Chongqing from January 2020 to March 2023 were retrospectively selected into this study for serum vitamin K2-related analysis.Further 844 school-age children who completed serum 25-(OH)D and lumbar bone densitometry measurements were screened to analyze the correlation between vitamin K2level and bone mineral density 【Results】 The overall serum vitamin K2 deficiency rate was 61.6% (2 553/4 145), and the difference in serum vitamin K2 deficiency rate between different age groups was statistically significant (χ2=39.364, P<0.05).The vitamin K2 level of children was significantly influenced by season and maternal education level (χ2=45.310,9.990, P<0.05).There were significant differences in age (Z=3.416), gender (χ2=9.218) and serum vitamin K2 deficiency rate (χ2=5.826) between normal bone mass development group and insufficient bone mass development group (P<0.05).Multivariate Logistic regression analysis suggested that vitamin K2 deficiency was an independent risk factor for insufficient bone mass development in school-age children (OR=1.37,95%CI:1.03 - 1.83, P=0.030). 【Conclusions】 There is a higher serum vitamin K2 deficiency rate among children, especially infants and school-age children.Decreased bone mineral density in school-age children may be associated with serum vitamin K2 deficiency.

Kinetics and molecular mechanism of vitamin K3 as xanthine oxidase activator / 中国药理学与毒理学杂志

OBJECTIVE To investigate the activation of xanthine oxidase(XO)from the human liver by vitamin K3 and the mechanism.METHODS Using human liver S9(0.1 g·L-1)as the source,XO was incubated with substrate xanthine of 0,2,4,8,and 16 μmol·L-1 at 37℃ for 90 min.The Michaelis constant(Km)of the reaction of xanthine oxidation was determined using the liquid chromatography diode array method.At the concentration of Km,the three-point method(1,10 and 100 μmol·L-1)was used to detect the activity of vitamin K3 activators.The multi-point method(vitamin K3 1,2,5,10,20,50,100,200 and 400 μmol·L-1)was adopted to determine the half effective concentration(EC50)of activated XO.Kinetic parameters(Km and Vmax)and the fit of double reciprocal curves were determined via vitamin K3 of 1/2EC50,EC50 and 2EC50.The changes in kinetic behavior at different concentrations of vitamin K3 were observed and their types of activation were analyzed.The interactions between XO and activator vitamin K3 were explored via molecular docking.RESULTS The Km of XO-mediated xanthine oxidation reac-tion was 4.71 μmol·L-1.As an activator of this reaction,vitamin K3 activated XO in a concentration-dependent manner(according to the logistic fitting formula y=A2+(A1-A2)/(1+(x/x0)

Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulants and Their Use in Special Populations / 中山大学学报(医学科学版)

In the past few decades， heparin and warfarin have been the main anticoagulants used to treat and prevent venous thromboembolism. Recent studies at home and abroad have shown that non-vitamin K antagonist oral anticoagulants （NOACs） have similar or better efficacy and safety in the prevention and treatment of venous thromboembolism and non-valvular atrial fibrillation. NOACs do not require routine coagulation monitoring when used at a fixed dose. However， in special populations or specific scenarios such as emergency surgery， etc.， an overdose or underdose and abnormal metabolism of NOACs may reduce the drug efficacy and safety， so monitoring and evaluating the anticoagulant effect of NOACs is more conducive to the prognosis of patients.This paper briefly reviewed the common laboratory monitoring methods of NOACs and their use in special populations， aiming to explain different monitoring methods for different NOACs and the applicability of NOACs in special populations， and hoping to provide reference for clinical standard monitoring and use of NOACS.

Dynamic changes and influencing factors of vitamin K levels in neonates / 中国新生儿科杂志

Objective:To study the incidences of vitamin K 1 and K 2 deficiency (VKD) in umbilical cord blood (UBC) of neonates and the dynamic changes and influencing factors of serum vitamin K 1 levels after preventive vitamin K 1 supplementation. Methods:From January 2021 to June 2022, neonates born in the Obstetrics Department of our hospital were prospectively enrolled and the levels of vitamin K 1 and K 2 in UBC and serum vitamin K 1 levels at 14 d and 28 d after vitamin K 1 supplementation were measured. The neonates were assigned into hospitalization group and healthy group and further assigned into early-preterm, late-preterm and full-term groups based on gestational age (GA). The incidences of VKD of different GA were studied. Dynamic changes of vitamin K 1 levels were calculated. Multivariate logistic regression was used to analyze the influencing factors of vitamin K 1 levels in hospitalization group at 28 d. Results:A total of 100 neonates were included. 80 neonates were hospitalized, including 25 early-preterm, 25 late-preterm and 30 full-term. 20 were healthy full-term neonates. No significant differences existed in the incidences of VKD of different GA ( P>0.05), however, the overall incidences were high (82.0% and 84.0%, respectively). After preventive vitamin K 1 supplementation, the levels of vitamin K 1 in full-term and preterm groups at 14 d were higher than at birth and 28 d. The levels of vitamin K 1 in hospitalized full-term neonates at 14 d and 28 d were higher than hospitalized preterm neonates. The levels of vitamin K 1 at 28 d in healthy group was significantly higher than hospitalization group ( P<0.05). Multivariate logistic regression analysis showed that maternal complications during pregnancy ( OR=5.889, 95% CI 1.621-21.399, P=0.007) and neonatal antibiotic use ( OR=5.615, 95% CI 1.833-17.221, P=0.003) were risk factors and formula feeding ( OR=0.389, 95% CI 0.193-0.786, P=0.008) was a protective factor for VKD. Conclusions:VKD is common in neonates. The serum vitamin K 1 level increases significantly after preventive vitamin K 1 supplementation. The vitamin K 1 levels of hospitalized full-term neonates at 14 d and 28 d are higher than hospitalized preterm neonates. The levels of vitamin K 1 at 28 d in hospitalized neonates are influenced by feeding methods, maternal complications during pregnancy and neonatal antibiotic use.

Advances in vitamin K and bone metabolism in children / 国际儿科学杂志

Vitamin K(VK)occurs naturally in two forms, including vitamin K 1(VK 1)and vitamin K 2(VK 2). The function of VK is related to the number of its side chains.In addition to the function of coagulation, VK is also gradually found to be involved in bone metabolism, which is closely related to the occurrence of adult osteoporosis.The rapid growth and development in childhood is a period of extremely vigorous bone metabolism.The role of VK in children′s bone metabolic diseases has been gradually recognized in recent years.However, there are still few clinical studies on the level of VK in children of different ages and how VK participates in children′s bone metabolic diseases.This article reviews the types and metabolism of VK, the mechanism of VK regulating bone metabolism, the level of VK and its role in bone metabolic diseases, so as to provide new understanding and ideas for the prevention and treatment of bone health in children.

Effect of calcium carbonate combined with vitamin K on bone metabolism indexes, Th1 cytokines and safety in children with glucocorticoid-induced osteoporosis / 中华内分泌外科杂志

Objective:To investigate the effect of calcium carbonate combined with vitamin K on bone metabolism indexes, Th1 cytokines and safety in children with glucocorticoid-induced osteoporosis.Methods:A total of 96 children with glucocorticoid-induced osteoporosis were enrolled in this study. They were randomly divided into control group and study group, 48 cases in each group. The control group was treated with calcium carbonate, and the study group was treated with calcium carbonate combined with vitamin K. The bone metabolism index serum total bone type Ⅰ collagen N-terminal peptide was compared between the two groups before and after treatment. PINP), serum β-Carboxy I terminal peptide ( β-CTX), osteocalcin (osteocalcin, P<0.05), and serum β-CTX. BGP), serum bone alkaline phosphatase (BALP), Th1 cytokine interferon- γ (IFN- γ), interleukin-2 (IL-2) levels and adverse reactions were also observed. Results:There was no statistical significance in the general data of the two groups (all P>0.05). Compared with that before treatment, bone mineral density of femoral neck increased in both groups after treatment, and the improvement in the study group (-1.02±0.49) was more significant than that in the control group (-1.52±0.65) ( t=4.26, P<0.001). Compared with those before treatment, the levels of PINP, β-CTX, BGP and BALP in 2 groups after treatment were decreased, and compared with those of the those of the control group (PINP: 31.65±6.58; β-CTX: 0.34±0.05; BGP: 4.95±1.28; BALP: 40.54±7.84), all indexes of the study group after treatment (PINP: 26.54±7.06; β-CTX: 0.24±0.03; BGP: 3.05±1.09; BALP: 35.96±7.02) improved significantly ( t=3.67, P<0.001; t=11.88, P<0.001; t=7.83, P<0.001; t=3.02, P<0.003). Compared with that before treatment, IL-2 level was increased while IFN- γ level was decreased in both treatment groups. Additionally, in comparison to the control group (IL-2: 163.89±30.85; IFN- γ: 196.61±21.05), IL-2 level (198.32±32.14) was higher and the IFN- γ level (163.25±18.43) was lower in the study group after treatment ( t=5.35, P<0.001; t=8.26, P<0.001). The incidence of adverse reactions between the two groups was not statistically significant ( χ2=0.15, P=0.695) . Conclusion:Calcium carbonate combined with vitamin K in the treatment of children with glucocorticoid-induced osteoporosis can improve bone metabolism indexes and Th1 cytokine levels in children, and the clinical therapeutic effect is good.

Clinical characteristics of anticoagulant rodenticide poisoning in northern Anhui analysis of the effect of the vitamin K / 中国临床药理学与治疗学

AIM: To analyze the clinical characteristics of anticoagulant rat poisoning and vitamin K

Application progress of non-vitamin K antagonist oral anticoagulants in hypertrophic cardiomyopathy with atrial fibrillation / 中国医师杂志

Atrial fibrillation (AF) is the most common supraventricular arrhythmia in patients with hypertrophic cardiomyopathy. Patients with hypertrophic cardiomyopathy and atrial fibrillation have a significantly increased risk of thromboembolism. Currently, guidelines recommend lifelong anticoagulant therapy for all such patients. The data on the use of non-vitamin K antagonist oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation are limited, and their efficacy and safety are not well established. This article provides a review of the current evidence on this issue.

Development and validation of a mobile application based on a machine learning model to aid in predicting dosage of vitamin K antagonists among Indian patients post mechanical heart valve replacement

Patients who undergo heart valve replacements with mechanical valves need to take Vitamin K Antagonists (VKA) drugs (Warfarin, Nicoumalone) which has got a very narrow therapeutic range and needs very close monitoring using PT-INR. Accessibility to physicians to titrate drugs doses is a major problem in low-middle income countries (LMIC) like India. Our work was aimed at predicting the maintenance dosage of these drugs, using the de-identified medical data collected from patients attending an INR Clinic in South India. We used artificial intelligence (AI) - machine learning to develop the algorithm. A Support Vector Machine (SVM) regression model was built to predict the maintenance dosage of warfarin, who have stable INR values between 2.0 and 4.0. We developed a simple user friendly android mobile application for patients to use the algorithm to predict the doses. The algorithm generated drug doses in 1100 patients were compared to cardiologist prescribed doses and found to have an excellent correlation.

Perioperative Management of Patients with Prosthetic Heart Valves?A Narrative Review

Worldwide, about 13% of the 200,000 annual recipients of prosthetic heart valves (PHV) present for various surgical procedures. Also, more and more females are opting for pregnancies after having PHV. All patients with PHV present unique challenges for the anesthesiologists, surgeons and obstetricians (in case of deliveries). They have to deal with the perioperative management of anticoagulation and a host of other issues involved. We reviewed the English language medical literature relevant to the different aspects of perioperative management of patients with PHV, particularly the guidelines of reputed societies that appeared in the last 20 years. Regression of cardiac pathophysiology following valve replacement is variable both in extent and timeline. The extent to which reverse remodeling occurs depends on the perioperative status of the heart. We discussed the perioperative assessment of patients with PHV, including focused history and relevant investigations with the inferences drawn. We examined the need for prophylaxis against infective endocarditis and management of anticoagulation in such patients in the perioperative period and the guidelines of reputed societies. We also reviewed the conduct of anesthesia, including general and regional anesthesia (neuraxial and peripheral nerve/plexus blocks) in such patients. Finally, we discussed the management of delivery in this group of high?risk patients. From the discussion of different aspects of perioperative management of patients with PHV, we hope to guide in formulating the comprehensive plan of management of safe anesthesia in such patients.

Función de las vitaminas D, E y K en condiciones especiales: salud y enfermedad / Function of vitamins D, E and K in Special Conditions: Health and Disease

Resumen: Antecedentes: se cuenta con recomendaciones de energía y nutrientes para población sana; sin embargo, a nutrientes como las vitaminas D, E, K se les atribuyen funciones importantes en diferentes situaciones de salud. Objetivo: explorar la efectividad de dosis dietarias y de suplementos de las vitaminas D, E y K en condiciones especiales de salud y enfermedad. Materiales y métodos: se realizó una búsqueda de documentos en las bases de datos PubMed, Scopus, ScienceDirect, Lilacs, SciELO, Ebsco y en textos especializados utilizando palabras clave: "vitamin D", "vitamin E", "vitamin K", "health", "disease", "nutritional recommendations". Resultados: hay un importante número de estudios y revisiones sistemáticas que contribuyen a la evidencia y la discusión en cuanto a efecto, dosis y tiempo, los cuales arrojaron tanto desenlaces positivos como nulos. Conclusión: los efectos de la vitamina D dietaria en la salud ósea están bien documentados, y sus suplementos acompañados de calcio están indicados en grupos poblacionales con riesgo de osteoporosis, pero no en otras condiciones clínicas. No hay suficiente evidencia sobre los beneficios de la vitamina E en el manejo o prevención de enfermedad hepática, cardiovascular o cáncer. La vitamina K podría ser importante en la salud ósea, sobre otras condiciones clínicas.

Abstract: Background: There are energy and nutrient recommendations for a healthy population; however, important functions in different health situations are attributed to nutrients such as vitamins D, E, K, E and K. Objective: To explore the effectiveness of dietary doses and supplements of vitamins D, E and K in special conditions of health and disease. Materials and Methods: A document search was carried out in the PubMed, Scopus, Sciencedirect, Lilacs, Scielo and Ebsco databases, and in specialized texts using keywords: "vitamin D", "vitamin E", "vitamin K", "Health", "disease", "nutritional recommendations". Results: There is a significant number of studies and systematic reviews that contribute to the evidence and discussion regarding effect, dose and time, which yielded both positive and null outcomes. Conclusion: The effects of dietary vitamin D in bone health are well documented and its supplementation accompanied by calcium is indicated in population groups at risk for osteoporosis, but not in other clinical conditions. There is insufficient evidence on the benefits of vitamin E in the management or prevention of liver disease, cardiovascular disease, or cancer. Vitamin K could be important in bone health, over other clinical conditions.

Uso de anticoagulantes orales directos en pacientes con fibrilación auricular post implante de TAVI: resultados de una encuesta internacional / Use of anticoagulants in patients with atrial fibrillation undergoing transcatheter aortic valve implantation

BACKGROUND: Transcatheter Aortic Valve Implantation (TAVI) is beneficial in patients with symptomatic severe Aortic Stenosis (AS). There is no consensus about the best anticoagulation strategy for patients with a recent TAVI and with atrial fibrillation (AF). Direct oral anticoagulants (DOACs) are effective to prevent embolic events with a significant lower incidence of bleeding. There is scarce evidence about the use of these drugs in patients undergoing TAVI. AIM: To assess the management of anticoagulation at the moment of discharge of patients with AF and TAVI. Material and Methods: A four question survey was sent to cardiologists involved in TAVI programs in different international centers. Results: The survey was answered by 72 interventional cardiologists. Even with the lack of randomized evidence, in most of the scenarios DOACs are prescribed at discharge in patients with indication for anticoagulation. Also, in patients with high bleeding risk, most cardiologists would perform a left atrial appendage closure. In patients with concomitant coronary artery disease, if a stent was recently implanted, prescription of the combination of a DOAC and one antiplatelet drug was the most common answer. In patients with a former coronary angioplasty, DOAC or Warfarin was the therapy of choice. CONCLUSIONS: In the absence of randomized data, interventional cardiologists prescribe DOACs at discharge to patients with AF and TAVI, without following current guidelines in most cases.

Effect of vitamin K 2 on traumatic brain injury and the relationship with NLRP3 inflammasomes in rats / 中华麻醉学杂志

Objective:To evaluate the effect of vitamin K 2 on traumatic brain injury (TBI) and the relationship with nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes in rats. Methods:Thirty-six SPF healthy male Sprague-Dawley rats, weighing 280-300 g, were divided into 3 groups ( n=12 each) by a random number table method: sham operation group (group Sham), group TBI and TBI plus vitamin K 2 group (group TBI+ VK 2). The TBI model was developed using modified Feeney′s method.In TBI+ VK 2 group, vitamin K 2 400 mg/kg (dissolved in dimethyl sulfoxide) was intraperitoneally injected at 30 min after developing TBI model.The equal volume of dimethyl sulfoxide was intraperitoneally injected in group Sham and group TBI.The modified neurological severity score (mNSS) was measured and open field tests were performed at 24 h after development of TBI.The rats were sacrificed after the end of behavioral testing, and brains were obtained for measurement of brain water content (by wet-dry weight method), percentage of brain injury volume (by TTC assay), contents of interleukin-1β (IL-1β), IL-18 and caspase-1 in cortex on the injured side (by enzyme-linked immunosorbent assay) and expression of NLRP3, caspase-1 and IL-18 in cortex on the injured side (by Western blot). Results:Compared with group Sham, the mNSS score was significantly increased, the total distance travelled was reduced, the time spent in the central zone was shortened, the brain water content and percentage of brain injury volume were increased, the contents of IL-1β, IL-18 and caspase-1 in cortex on the injured side were increased, and the expression of NLRP3, caspase-1 and IL-18 was up-regulated in group TBI ( P<0.05 or 0.01). Compared with group TBI, the mNSS score was significantly decreased, the total distance travelled was increased, the time spent in the central zone was prolonged, the brain water content and percentage of brain injury volume were decreased, the contents of IL-1β, IL-18 and caspase-1 in cortex on the injured side were decreased, and the expression of NLRP3, caspase-1 and IL-18 was down-regulated in group TBI+ VK 2 ( P<0.05 or 0.01). Conclusions:Vitamin K 2 can reduce TBI, and the mechanism may be related to inhibition of the activation of NLRP3 inflammasomes in rats.

Late vitamin K deficiency bleeding in infants: five-year prospective study

Abstract Objective: To study the presenting clinical and demographic features, risk factors, and outcome of infants with late vitamin K deficiency bleeding. Methods: Over a 5-year study period, the presenting clinical features and outcome of all 47 infants observed aged less than 6 months, who were diagnosed with late-onset primary and secondary VKDB by detailed history, physical examination, and laboratory findings were evaluated. Confirmed primary late VKDB was diagnosed when no cause other than breastfeeding could be found, while in the secondary subtype additional risk factors compromising the vitamin K effect were diagnosed. Results: Secondary late VKDB (83%, 39 patients) was more common than the primary subtype. The mean age of patients was 10.50 ± 5.75 and 9.74 ± 6.04 weeks in primary and secondary VKDB subtypes, respectively, and the age of infants did not have a significant difference (> 0.05). The male to female ratio was 2.13:1. The residency, place and mode of delivery, gestational age, and types of feeding of patients did not have a significant difference between VKDB subtypes. The skin and gastrointestinal tract (GIT) (40.4%) followed by intracranial hemorrhage (ICH) (32%), were common sites of bleeding. Neurological complications were seen in 21% of patients; however, lethality was 23%, and the outcome of patients did not have a significant difference (p > 0.05) between VKDB subtypes. Conclusion: Secondary late VKDB is more common than the primary subtypes, and late VKDB is still a serious disease in developing countries, including Iraq, when vitamin K prophylaxis isn't routinely used at birth.

Análisis farmacogenético retrospectivo de una paciente pediátrica en tratamiento anticoagulante: caso clínico / Retrospective pharmacogenetic analysis of a pediatric patient under anticoagulant treatment: Clinical case

Se presenta el caso clínico de una paciente de 10 años diagnosticada con miocardiopatía dilatada, quien registró valores en el índice internacional normalizado (International Normalized Ratio, INR) superiores a 10 con la dosis estándar de acenocumarol, además de otros valores que indicaban el estado incoagulable, lo que obligó a suspender y reiniciar el tratamiento en varias ocasiones. Después de más de 30 días de tratamiento, sorprendentemente se lograron los niveles esperados y estables en el INR con la mitad de la dosis recomendada para una paciente de su edad y peso.Se decidió hacer un análisis farmacogenético retrospectivo del caso mediante RT-PCR con sondas TaqMan™ que incluyó cinco polimorfismos de un solo nucleótido y distinto grado de asociación con la dosis-respuesta a los fármacos antivitamínicos K (AVK): rs2108622 (gen CYP4F2), rs9923231, rs7294 (gen VKORC1), rs1799853 y rs1057910 (gen CYP2C9). La paciente resultó ser homocigota para el rs9923231 (VKORC1) y heterocigota para el rs2108622 (CYP4F2). Se ha evidenciado a nivel nacional e internacional que este perfil genético está fuertemente asociado con una necesidad de dosis menores de antivitamínicos K.En conclusión, el análisis farmacogenético confirmó que la condición genética de la paciente, la cual conlleva una baja expresión de la enzima VKORC1 (blanco terapéutico de los antivitamínicos K), hacía predecible la necesidad de una dosis menor a la establecida según los protocolos clínicos recomendados por la Food and Drug Administration (FDA) y PharmGKB™ para los fármacos cumarínicos. El análisis genotípico previo de la paciente hubiese permitido alcanzar el rango terapéutico más prontamente, evitando potenciales riesgos de hemorragia, lo que demuestra la importancia de los análisis farmacogenéticos en tratamientos de gran variabilidad y estrecho rango terapéutico.

Abstract We present the clinical case of a 10-year-old patient diagnosed with dilated cardiomyopathy who registered INR values above 10 upon receiving standard doses of acenocoumarol, as well as other values reported as uncoagulable, forcing the discontinuation and restart of treatment more than once. Expected and stable INR levels were achieved after more than 30 days of treatment, surprisingly with half the recommended dose for a patient of her age and weight. We decided to conduct a retrospective pharmacogenomic analysis including nucleotide genetic polymorphisms (SNPs) with different degrees of association with the dose/response to antivitamin K (AVK) drugs: rs2108622 (gene CYP4F2), rs9923231, rs7294 (gene VKORC1), rs1799853, and rs1057910 (CYP2C9 gene) using TaqMan® RT-PCR. The patient was homozygous for rs9923231 (VKORC1) and heterozygous for rs2108622 (CYP4F2), a genetic profile strongly associated with a requirement of lower AVK doses as shown by national and international evidence. In conclusion, the pharmacogenetic analysis confirmed that this patient's genetic conditions, involving low expression of the VKA therapeutic target, required a lower dose than that established in clinical protocols as recommended by the Food and Drug Administration (FDA) and the PharmGKB® for coumarin drugs. A previous genotypic analysis of the patient would have allowed reaching the therapeutic range sooner, thus avoiding potential bleeding risks. This shows the importance of pharmacogenetic analyses for highly variable treatments with a narrow therapeutic range.

Análisis de la calidad de la anticoagulación con antagonistas de la vitamina K en tres escenarios clínicos en México / Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico

Resumen Introducción: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. Objetivo: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. Métodos: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. Resultados: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. Conclusiones: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

Abstract Introduction: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. Objective: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. Methods: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. Results: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. Conclusions: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

Mechanical heart valve thrombosis during pregnancy under non / 中南大学学报(医学版)

Anticoagulation drugs should be used for patients with mechanical heart valve (MHV) in case of potential risk of thrombosis. Pregnant women with MHV have to change therapies due to teratogenic effect of some anti-coagulation drugs. European Society of Cardiology clinical guidelines for the management of cardiovascular diseases during pregnancy gives specific suggestions for anticoagulation therapy.We have treated 2 patients with mechanical heart valve thrombosis (MVT) during pregnancy: One received low molecular weight heparin (LMWH) throughout the pregnancy and developed MVT at the third trimester of pregnancy; one developed MVT at the first trimester when replacing vitamin K antagonists (VKA) with LMWH. These patients raised secondary reflection on the balance between clinical guideline and personalized medicine. During LMWH therapy, we should dynamically monitor patients' anti-activated factor X (anti-Xa) level to evaluate coagulation function during pregnancy. When a pregnant woman with MHV develops symptoms of acute heart failure, stuck mechanical valve should be paid attention to and surgery should be promptly performed if necessary.