RESUMEN
INTRODUÇÃO A mutação do fator V de Leiden é uma condição genética que acomete um ponto único no sítio de inativação do fator V impedindo a ligação com a proteína C ativada, resultando em um estado pró-trombótico. A fibrilação atrial (FA) é a arritmia mais comum do mundo com predomínio na população idosa, e está relacionada com elevado risco de eventos tromboembólicos. A oclusão do apêndice atrial esquerdo (OAA) é um procedimento minimamente invasivo, visando a tromboprofilaxia em pacientes com FA e contraindicação de anticoagulação oral (ACO). DESCRIÇÃO DO CASO Paciente M.S.F.R.S., octogenária com fragilidade severa, dependente para atividades básicas e instrumentais da vida diária, portadora da mutação heterozigótica do fator V de Leiden, dislipidêmica, ex-tagabista, obesidade sarcopênica e apresenta FA permanente em uso inicial de varfarina. Antecedentes de trombose venosa profunda em membro inferior direito, comunicação interatrial corrigida por atriosseptoplastia, quatro eventos prévios de acidente vascular encefálico (AVE) com sequela motora à direita, e osteoporose associado a múltiplas fraturas de vértebras com correção cirúrgica. Além disso, apresentava má adesão ao uso de varfarina com acompanhamento irregular do controle de INR, associado com episódios de sangramentos gastrointestinais. Por isso, optou-se pela realização da oclusão do apêndice atrial esquerdo para prevenção secundária de eventos tromboembólicos. A paciente fez uso de ácido acetilsalicílico (AAS) 100mg e clopidogrel 75mg durante 6 meses pós-procedimento, seguido da suspensão dessas medicações e introdução da rivaroxabana 15mg, devido ao risco elevado de eventos tromboembólicos propiciados pela trombofilia. Atualmente em uso de metoprolol 200mg/dia; digoxina 0,125mg/dia; omeprazol 20mg/dia; clonazepam 2mg/dia e rivaroxabana 15mg/dia. CONCLUSÃO Segundo ensaios clínicos randomizados, a OAA não mostrou-se inferior ao uso de ACO quanto a ocorrência de AVE e embolismo sistêmico, como também demonstrou superioridade quanto a menores taxas de mortalidade cardiovascular. O estudo PROTECT-AF recomenda o uso de ACO associado ao AAS por 45 dias, seguido da dupla antiagregação plaquetária durante 6 meses e após isso, uso indeterminado de AAS isolado. Porém a anticoagulação ideal pós-intervenção permanece um desafio. O futuro da OAA está relacionado com a experiência do operador, evolução da tecnologia dos dispositivos, consenso da terapia antitrombótica e manejo das principais complicações.
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Humanos , Femenino , Anciano de 80 o más Años , Fibrilación Atrial , Factor V , Apéndice Atrial , Arritmias Cardíacas , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular , Defectos del Tabique InteratrialRESUMEN
INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) and venous thromboembolism (VTE) are thought to share many common risk factors. Our study aimed to determine the frequencies of 5 thrombosis-related gene single nucleotide polymorphisms (SNPs) associated with VTE in patients with CTEPH (n 129) compared with a control group of healthy individuals without a history of VTE (n 2637). METHODS: The SNPs of the following genes were investigated: F5 (F V Leiden, rs6025), F2 prothrombin (rs1799963), fibrinogen gamma (FGG, rs2066865), F11 (rs2289252) and ABO (non-O, rs8176719) in both groups. RESULTS: The study found that the rs1799963 variant was more common in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared to the control group (p < .0001). The GA heterozygous variant showed a significant increase with an odds ratio (OR) of 4.480 (95% CI: 2.344-8.562) or a finding by maximum likelihood analysis (MLA) with p < .0001. Additionally, there was a notable increase in the rs8176719 variant with p < .0001 in CTEPH patients. Both the homozygous G/G variant and the heterozygous -/G variant also showed an increase, with OR of 4.2317 (95% CI: 2.45571-7.2919) and 2.4324 (95% CI: 1.46435-4.0403) respectively, or MLA (p < .0001 and p .0006). The study also revealed a higher prevalence of the heterozygous C/T variant of rs2289252 in CTEPH patients, with an OR of 1.5543 (95% CI: 1.02503-2.3568) or MLA (p .0379). CONCLUSION: The study suggests that the observed gene polymorphisms F2 (rs1799963), ABO (rs8176719), and F11 (rs2289252) may play a role as independent heritable risk factors in the development of CTEPH.
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Hipertensión Pulmonar , Polimorfismo de Nucleótido Simple , Humanos , Hipertensión Pulmonar/genética , Femenino , Masculino , Persona de Mediana Edad , Embolia Pulmonar/genética , Enfermedad Crónica , Factor V/genética , Anciano , Adulto , Tromboembolia Venosa/genética , Protrombina/genética , Incidencia , Fibrinógeno/genética , Sistema del Grupo Sanguíneo ABO/genética , Trombofilia/genéticaRESUMEN
Prothrombinase complex, composed of coagulation factors Xa (FXa) and Va (FVa) is a major enzyme of the blood coagulation network that produces thrombin via activation of its inactive precursor prothrombin (FII) on the surface of phospholipid membranes. However, pathways and mechanisms of prothrombinase formation and substrate delivery are still discussed. Here we designed a novel mathematical model that considered different potential pathways of FXa or FII binding (from the membrane or from solution) and analyzed the kinetics of thrombin formation in the presence of a wide range of reactants concentrations. We observed the inhibitory effect of large FVa concentrations and this effect was phospholipid concentration-dependent. We predicted that efficient FII activation occurred via formation of the ternary complex, in which FVa, FXa and FII were in the membrane-bound state. Prothrombin delivery was mostly membrane-dependent, but delivery from solution was predominant under conditions of phospholipid deficiency or FXa/FVa excess. Likewise, FXa delivery from solution was predominant in the case of FVa excess, but high FII did not switch the FXa delivery to the solution-dependent one. Additionally, the FXa delivery pathway did not depend on the phospholipid concentration, being the membrane-dependent one even in case of the phospholipid deficiency. These results suggest a flexible mechanism of prothrombinase functioning which utilizes different complex formation and even inhibitory mechanisms depending on conditions.
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Factor Xa , Protrombina , Cinética , Humanos , Factor Xa/metabolismo , Protrombina/metabolismo , Modelos Biológicos , Fosfolípidos/metabolismo , Coagulación Sanguínea/fisiología , Trombina/metabolismo , Factor Va/metabolismo , Tromboplastina/metabolismo , Especificidad por Sustrato , Factor VRESUMEN
Cancer-associated thrombosis (CAT) is a common complication and a major cause of morbidity and mortality in patients with active cancers. CAT is common in various malignancies, particularly pancreatic, ovarian, gastric, colorectal, and hematologic cancers. In fact, CAT is a complicated multifactorial complication that may be influenced by the type of cancer as well as by the genetic background and inheritance of thrombophilic variants and elevated concentrations of coagulation factors. Several studies have shown the prominent role of inherited thrombophilias, such as prothrombin 20210, factor V Leiden, factor XIII Val34Leu, MTHFR C677T, in the occurrence of CAT, while others have found no correlation between them and CAT. In the present review, we have attempted to investigate the possible role of inherited thrombophilia in the occurrence of CAT.
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Neoplasias , Trombofilia , Trombosis , Humanos , Trombofilia/complicaciones , Trombofilia/genética , Trombofilia/sangre , Neoplasias/complicaciones , Neoplasias/genética , Neoplasias/sangre , Trombosis/etiología , Factor V/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genéticaRESUMEN
The hemostatic response to vascular injury entails a sequence of proteolytic events where several inactive zymogens of the trypsin family are converted to active proteases. The cascade starts with exposure of tissue factor from the damaged endothelium and culminates with conversion of prothrombin to thrombin in a reaction catalyzed by the prothrombinase complex composed of the enzyme factor Xa, cofactor Va, Ca2+, and phospholipids. This cofactor-dependent activation is paradigmatic of analogous reactions of the blood coagulation and complement cascades, which makes elucidation of its molecular mechanism of broad significance to the large class of trypsin-like zymogens to which prothrombin belongs. Because of its relevance as the most important reaction in the physiological response to vascular injury, as well as the main trigger of pathological thrombotic complications, the mechanism of prothrombin activation has been studied extensively. However, a molecular interpretation of this mechanism has become available only recently from important developments in structural biology. Here we review current knowledge on the prothrombin-prothrombinase interaction and outline future directions for the study of this key reaction of the coagulation cascade.
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Coagulación Sanguínea , Protrombina , Tromboplastina , Humanos , Protrombina/metabolismo , Protrombina/química , Tromboplastina/metabolismo , Tromboplastina/química , Coagulación Sanguínea/fisiología , Animales , Unión Proteica , Factor Xa/metabolismo , Factor VRESUMEN
The aim of this study is to characterize zebrafish coagulation cofactors fviii and fv mutant fish and assess if they phenocopy classical hemophilia A and factor V deficiency in humans. The embryos from fviii and fv zebrafish heterozygote mutants generated by ENU mutagenesis were purchased from the ZIRC repository. They were reared to adulthood and genotyped. The heterozygote male and female were crossed to get homozygote, heterozygote, and wild-type fish. Functional kinetic coagulation assays and bleeding assays were performed on normal and mutant adult fish, and venous laser injury assays were performed on the larvae. The DNA from fviii and fv mutants were sequenced to confirm if they have a premature stop codon in exon 19, and in exon 2, respectively, and in both mutants, the amino acid glutamine is replaced with a stop codon. Homozygous and heterozygous 5âdays post fertilization (dpf) larvae for fviii and fv deficient mutants exhibited prolonged time to occlusion after venous laser injury compared to wild-type controls. The homozygous and heterozygous fviii adult mutants showed modest bleeding and delayed fibrin formation in the kinetic partial thromboplastin time (kPTT) assay with their plasma. fv homozygous larvae had poor survival beyond 12 dpf. However, heterozygous fv mutants exhibited heavy bleeding and prolonged fibrin formation in the kPTT and kPT assay compared with wild-type siblings. Our characterization showed fviii and fv mutants from ZIRC phenocopied to a considerable extent classical hemophilia A and factor V deficiency in humans, respectively. These models should be useful in studying and developing novel drugs that reverse the phenotype and in generating suppressor mutations to identify novel factors that compensate for these deficiencies.
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Modelos Animales de Enfermedad , Deficiencia del Factor V , Factor VIII , Hemofilia A , Pez Cebra , Animales , Hemofilia A/genética , Hemofilia A/sangre , Factor VIII/genética , Factor VIII/metabolismo , Deficiencia del Factor V/genética , Factor V/genética , Mutación , Femenino , Masculino , Coagulación Sanguínea , HumanosRESUMEN
Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at determining the risk factors involved recognizes a group of "traditional" risk factors, but also more recent studies identified over 100 "novel" ones which may have a role in the disease. Among the latter is the thrombophilia profile of a patient, a pathology well-established for its involvement in venous thromboembolism, but with less studied implications in arterial thrombosis. This paper reviews the literature, explaining the pathophysiology of the thrombophilia causes associated most with coronary thrombosis events. Results of several studies on the subject, including a meta-analysis with over 60,000 subjects, determined the significant involvement of factor V Leiden, prothrombin G20210A mutation, plasminogen activator inhibitor-1 and antiphospholipid syndrome in the development of coronary artery disease. The mechanisms involved are currently at different stages of research, with some already established and used as therapeutic targets.
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Enfermedad de la Arteria Coronaria , Factor V , Trombofilia , Trombosis , Humanos , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/patología , Trombofilia/genética , Trombofilia/etiología , Trombosis/genética , Trombosis/etiología , Trombosis/patología , Factor V/genética , Protrombina/genética , Protrombina/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Factores de Riesgo , Predisposición Genética a la Enfermedad , MutaciónRESUMEN
BACKGROUND: The clinically significant Factor V Leiden (FVL) point mutation (1691 G/A) causes replacement of Arg with Gln (glutamine), preventing activated protein C from inactivating Factor V leading to a lengthened clotting process. Individuals with the Factor V Leiden mutations have an increased risk for venous thrombosis. The aim of this study is to compare an unlabeled probe high-resolution melting analysis (HRMA) assay for Factor V Leiden mutation to a TaqMan hydrolysis assay (fluorogenic 5' nuclease PCR hydrolysis assay). HRMA is a post-PCR, homogenous, closed-tube system for the detection of sequence variants. Post-PCR, the amplicons are heated gradually until the melting temperature is reached and the fluorescent dye unbinds from the amplicon and exhibits low fluorescence. A melt-curve analysis is generated that is characteristic of a particular sequence variant. Therefore, HRMA allows for comparison of one base changes in genetic sequences based on their differences in melting rate. METHODS: Blood samples were collected in EDTA tubes and DNA extracted using the Roche MagNaPure. Reactions of both HRMA and TaqMan were carried out on 3 controls (1691 G/G, 1691 G/A, and 1691 G/G and G/A) and 20 samples. RESULTS: The genotypes for 3 reference controls purchased from Coriell (F5 1691 G/G, FVL 1691 G/A, and Heterozygote 1691 G/G and G/A) were confirmed by both the HRMA and TaqMan FVL assays. All 20 samples were confirmed to be F5 1691 G/G by both HRMA and TaqMan assays. CONCLUSIONS: Comparing the results of the unlabeled probe HRMA FVL assay with a real-time TaqMan probe end point genotyping assay resulted in 100% sensitivity and 100% specificity for both assays.
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Factor V , Reacción en Cadena de la Polimerasa , Factor V/genética , Humanos , Reacción en Cadena de la Polimerasa/métodos , Colorantes Fluorescentes/química , Mutación Puntual , Desnaturalización de Ácido Nucleico , Hidrólisis , Temperatura de TransiciónRESUMEN
Background and Objectives: This retrospective cohort study investigates the role of genetic thrombophilia in pregnant women experiencing early pregnancy loss compared to those with late pregnancy loss. Materials and Methods: Participants were categorized into early and late pregnancy loss groups based on gestational age. A total of 156 patients were included, out of which 103 had early-trimester pregnancy losses and 96 had multiple miscarriages. Results: The study revealed a synergistic effect of Factor V Leiden (FVL G1691A) and Methylenetetrahydrofolate Reductase (MTHFR C677T) mutations (coefficient 3.42). Prothrombin (PT) G20210A and ß-Fibrinogen 455 G>A mutations exhibited a significant interaction (coefficient 1.98). Additionally, MTHFR A1298C and Plasminogen Activator Inhibitor-1 (PAI-1 4G/5G) mutations showed a significant interaction (coefficient 1.65). FVL G1691A and Endothelial Protein C Receptor (EPCR) allele A1/A2 mutations also demonstrated a significant association (coefficient 2.10). Lastly, MTHFR C677T and Glycoprotein IIb/IIIa T1565C mutations interacted significantly (coefficient 1.77). Risk factor analysis identified several mutations associated with early pregnancy loss, including PAI-1 4G/5G homozygous (OR 3.01), FVL G1691A heterozygous (OR 1.85), and MTHFR A1298C heterozygous (OR 1.55). Both homozygous and heterozygous MTHFR C677T mutations were significant risk factors (OR 2.38; OR 2.06), as was PT G20210A homozygous mutation (OR 1.92). The PAI-1 4G/4G homozygous variant posed a risk (OR 1.36). Late pregnancy loss was associated with MTHFR A1298C homozygous mutation (OR 3.79), ß-Fibrinogen 455 G>A heterozygous mutation (OR 2.20), and MTHFR A1298C heterozygous mutation (OR 2.65). Factor XIII G1002T heterozygous mutation (OR 1.18) and PAI-1 4G/5G homozygous mutation (OR 2.85) were also significant risk factors. EPCR allele A1/A2 (OR 1.60) and A2/A3 (OR 1.73) mutations were identified as significant risk factors for late pregnancy loss. Furthermore, FVL G1691A homozygous mutation, PT G20210A homozygous mutation, MTHFR C677T heterozygous mutation, MTHFR A1298C heterozygous mutation, and EPCR allele A1/A2 were identified as significant risk factors for multiple miscarriage. Conclusions: This study highlights significant interactions and risk factors related to genetic thrombophilia mutations in different types of pregnancy loss, contributing valuable insights for miscarriage management guidelines.
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Aborto Espontáneo , Factor V , Metilenotetrahidrofolato Reductasa (NADPH2) , Mutación , Trombofilia , Humanos , Femenino , Embarazo , Trombofilia/genética , Trombofilia/complicaciones , Adulto , Estudios Retrospectivos , Factores de Riesgo , Aborto Espontáneo/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Factor V/genética , Protrombina/genética , Inhibidor 1 de Activador Plasminogénico/genética , Estudios de CohortesRESUMEN
Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5-HIF-1α-COX2 axis could promote endometrial cancer progression.
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Neoplasias Endometriales , Regulación de la Expresión Génica , Humanos , Femenino , Ciclooxigenasa 2/genética , Neoplasias Endometriales/genética , Factores de Transcripción NFATC , Transducción de Señal , Dinoprostona , Factor V , Factores de TranscripciónRESUMEN
Inherited defects in the genes of blood coagulation essentially express the severity of the clinical phenotype that is directly correlated to the number of mutated alleles of the candidate leader gene (e.g., heterozygote vs. homozygote) and of possible additional coinherited traits. The F5 gene, which codes for coagulation factor V (FV), plays a two-faced role in the coagulation cascade, exhibiting both procoagulant and anticoagulant functions. Thus, defects in this gene can be predisposed to either bleeding or thrombosis. A Sanger sequence analysis detected a premature stop-codon in exon 13 of the F5 gene (c.3481C>T; p.R1161Ter) in several members of a family characterised by low circulating FV levels and contrasting clinical phenotypes. The propositus, a 29 y.o. male affected by recurrent haemorrhages, was homozygous for the F5 stop-codon and for the F5 c.1691G>A (p.R506Q; FV-Leiden) inherited from the heterozygous parents, which is suggestive of combined cis-segregation. The homozygous condition of the stop-codon completely abolished the F5 gene expression in the propositus (FV:Ag < 1%; FV:C < 1%; assessed by ELISA and PT-based one-stage clotting assay respectively), removing, in turn, any chance for FV-Leiden to act as a prothrombotic molecule. His father (57 y.o.), characterised by severe recurrent venous thromboses, underwent a complete molecular thrombophilic screening, revealing a heterozygous F2 G20210A defect, while his mother (56 y.o.), who was negative for further common coagulation defects, reported fully asymptomatic anamnesis. To dissect these conflicting phenotypes, we performed the ProC®Global (Siemens Helthineers) coagulation test aimed at assessing the global pro- and anticoagulant balance of each family member, investigating the responses to the activated protein C (APC) by means of an APC-sensitivity ratio (APC-sr). The propositus had an unexpectedly poor response to APC (APC-sr: 1.09; n.v. > 2.25), and his father and mother had an APC-sr of 1.5 and 2.0, respectively. Although ProC®Global prevalently detects the anticoagulant side of FV, the exceptionally low APC-sr of the propositus and his discordant severe-moderate haemorrhagic phenotype could suggest a residual expression of mutated FV p.506QQ through a natural readthrough or possible alternative splicing mechanisms. The coagulation pathway may be physiologically rebalanced through natural and induced strategies, and the described insights might be able to track the design of novel treatment approaches and rebalancing molecules.
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Factor V , Hemorragia , Fenotipo , Trombosis , Adulto , Femenino , Humanos , Masculino , Codón de Terminación/genética , Factor V/genética , Dosificación de Gen , Hemorragia/genética , Heterocigoto , Linaje , Trombosis/genéticaRESUMEN
ABSTRACT: The factor V Leiden (FVL; rs6025) and prothrombin G20210A (PTGM; rs1799963) polymorphisms are 2 of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with previous studies showing marked disagreement regarding thrombosis risk conferred by the DH genotype. Using multidimensional data from the UK Biobank (UKB) and FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937 939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared with wild-type individuals (odds ratio [OR] = 5.24; 95% confidence interval [CI], 4.01-6.84; P = 4.8 × 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N = 445 144) found that effect size estimates for the DH genotype remained largely unchanged (OR = 4.53; 95% CI, 3.42-5.90; P < 1 × 10-16) after adjustment for commonly cited VTE risk factors, such as body mass index, blood type, and markers of inflammation. In contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic data sets to conduct, to our knowledge, the largest study to date on the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and may confer a similarly increased risk of VTE.
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Bancos de Muestras Biológicas , Factor V , Heterocigoto , Protrombina , Humanos , Protrombina/genética , Factor V/genética , Femenino , Masculino , Persona de Mediana Edad , Reino Unido/epidemiología , Anciano , Factores de Riesgo , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiología , Adulto , Trombosis/genética , Trombosis/epidemiología , Trombosis/etiología , Predisposición Genética a la Enfermedad , Genotipo , Polimorfismo de Nucleótido Simple , Biobanco del Reino UnidoRESUMEN
OBJECTIVE: The global incidence of thrombosis is increasing. However, research on thrombosis in the context of Korea is scarce. We aimed to analyze the relationship between factor V and protein C test results and thrombosis in Koreans through a domestic commissioned testing institution conducting mass examinations. METHODS: Results of factor V and protein C tests of 1386 individuals referred simultaneously to EONE Laboratories (Incheon, Republic of Korea) from January 2017 to July 2023 were analyzed retrospectively to identify the association with thrombotic disease. The tests were performed using a STAR MAX (Diagnostica Stago, Asnieres, France) automatic blood coagulation analyzer. The results were analyzed by age and sex. RESULTS: The inspection rate increased gradually from 2017 to 2022. Women (70.0%) demonstrated a higher test rate than did men (30.0%). Young women reported high test rates; the test rate and age distribution differed by sex. Women aged between 20 and 49âyears reported lower factor V and higher protein C concentrations than did men between 20 and 49âyears of age. CONCLUSIONS: The tests were more commonly performed in women than in men. Women aged between 20 and 49âyears reported lower factor V concentrations and higher protein C concentrations than men between 20 and 49âyears of age. This study will facilitate recognizing and preventing thrombotic diseases in women.
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Factor V , Proteína C , Trombosis , Humanos , Femenino , Proteína C/análisis , Masculino , Adulto , Persona de Mediana Edad , República de Corea/epidemiología , Adulto Joven , Estudios Retrospectivos , Factor V/análisis , Trombosis/sangre , Pruebas de Coagulación Sanguínea/métodos , Anciano , Factores SexualesRESUMEN
OBJECTIVES: Patients with COVID-19 infection appear to develop virus-induced hypercoagulability resulting in numerous thrombotic events. The aim of the present study was to determine the relationship between the thrombophilia genes mutations (prothrombin G20210A, factor V Leiden, and methyltetrahydrofolate reductase (MTHFR)) and the severity of COVID-19 patients. DESIGN: Prospective cross-sectional study. METHOD: One hundred and forty patients (80 adults and 60 children) were included in the current study. They were divided into the severe COVID-19 group and the mild COVID-19 group, with each group comprising 40 adults and 30 children. The patients were assessed for FV R506Q, FV R2H1299R, MTHFR A1298C, MTHFR C677T, and prothrombin gene G20210A polymorphisms. CBC, D-dimer, renal and liver function tests, hs-CRP, ferritin, and LDH were also assessed. Thrombotic events were clinically and radiologically documented. RESULTS: Severe COVID-19 cases were significantly more frequent to have a heterozygous mutation for all the studied genes compared to mild COVID-19 cases (p<0.05 for all). Being mutant to gene FV R506Q carried the highest risk of developing a severe disease course (p<0.0001). Patients with abnormally high D-dimer levels were significantly more frequent to be heterozygous for FV R506Q, FV R2H1299R, and prothrombin gene G20210A (p = 0.006, 0.007, and 0.02, respectively). CONCLUSION: We concluded that there is an evident relationship between severe COVID-19 and inherited thrombophilia. In the current study, FV R506Q gene mutation carried the highest risk of developing a severe COVID-19 disease course.
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COVID-19 , Trombofilia , Trombosis , Adulto , Niño , Humanos , Estudios Prospectivos , Protrombina/genética , Estudios Transversales , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , COVID-19/genética , Mutación , Trombofilia/complicaciones , Trombofilia/genética , Trombosis/genética , Gravedad del Paciente , Factor V/genéticaRESUMEN
BACKGROUND: Patients with cancer are at an increased risk of developing coagulation complications, and chemotherapy treatment increases the risk. Tumor progression is closely linked to the hemostatic system. Breast cancer tumors express coagulation factor V (FV), an essential factor in blood coagulation. The functional role of FV during treatment with chemotherapy is poorly understood and was explored in this study. OBJECTIVES: We aimed to investigate the role of FV in breast cancer progression by exploring associations with treatment response, gene regulation, and the functional effects of FV. METHODS: The receiver operating characteristic plotter was used to explore the predictive value of FV mRNA (F5) expression for treatment with FEC (5-fluorouracil, anthracycline, and cyclophosphamide). Breast cancer cohorts were analyzed to study treatment response to FEC. The effect of chemotherapy on F5 expression, the regulation of F5, and the functional effects of FV dependent and independent of chemotherapy were studied in breast cancer cell lines. RESULTS: F5 tumor expression was significantly higher in responders to FEC than in nonresponders. In vitro experiments revealed that anthracycline treatment increased the expression of F5. Inhibition and knockdown of p53 reduced the anthracycline-induced F5 expression. Mutation of a p53 half-site (c.158+1541/158+1564) in a luciferase plasmid reduced luciferase activity, suggesting that p53 plays a role in regulating F5. FV overexpression increased apoptosis and reduced proliferation slightly during anthracycline treatment. CONCLUSION: Our study identified F5 as a p53-regulated tumor suppressor candidate and a promising marker for response to chemotherapy. FV may have functional effects that are therapeutically relevant in breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Ciclofosfamida , Factor V , Fluorouracilo , Regulación Neoplásica de la Expresión Génica , Proteína p53 Supresora de Tumor , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Fluorouracilo/uso terapéutico , Fluorouracilo/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Factor V/genética , Factor V/metabolismo , Resultado del Tratamiento , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Células MCF-7 , Epirrubicina/farmacología , Epirrubicina/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Mutación , ARN Mensajero/metabolismo , ARN Mensajero/genéticaRESUMEN
An elderly woman with light chain myeloma presented with prolonged epistaxis and extensive cutaneous haematomas: her kappa/lambda ratio was high at 395, her coagulation screen, thrombin and reptilase times were abnormal, her FV and FX were in the low range in the absence of specific inhibitors, her Clauss fibrinogen was low at 0.95âg/l but antigenic FNG was 1.58âg/l. The patient denied treatment and died of progressive renal failure. We wish to describe the unusual association of FX and FV deficiency co-existing with an acquired dysfibrinogenaemia.
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Afibrinogenemia , Deficiencia del Factor X , Mieloma Múltiple , Anciano , Femenino , Humanos , Afibrinogenemia/complicaciones , Factor V , Fibrinógeno , Mieloma Múltiple/complicacionesRESUMEN
Age is a significant risk factor for ischemic stroke. However, the influence of aging on coagulation parameters in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOACs) remains unclear. A total of 775 samples were collected from 224 NVAF patients receiving apixaban, edoxaban or rivaroxaban. The samples were categorized into three age groups: (i) ≤ 64 years, (ii) 65-74 years, and (iii) ≥ 75 years (apixaban: N = 48, 108, 119; edoxaban: N = 63, 68, 126; rivaroxaban: N = 115, 90, 38, respectively). Coagulation parameters including fibrinogen (Fbg), factor II, factor V, factor VII, factor X, and D-dimer, were compared between the three age groups for each drug. The slopes in the correlation between drug concentrations and modified diluted prothrombin time (mdPT) were also assessed. Fbg and factor V increased with age, while factor II and factor X decreased. Factor VII and D-dimer showed no significant differences across age categories. The slope in response to drug concentrations was similar between the age groups. In NVAF patients treated with apixaban, edoxaban and rivaroxaban, some coagulation parameters exhibited age-related variation. However, the response of mdPT to drug concentration was consistent across age categories.
Asunto(s)
Fibrilación Atrial , Piridinas , Accidente Cerebrovascular , Tiazoles , Humanos , Persona de Mediana Edad , Rivaroxabán/efectos adversos , Warfarina , Anticoagulantes , Hemorragia/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/inducido químicamente , Dabigatrán/efectos adversos , Factor X/uso terapéutico , Factor VII/uso terapéutico , Protrombina , Factor V , Piridonas/uso terapéutico , Administración OralRESUMEN
BACKGROUND: Epithelial-mesenchymal transition (EMT) is an important biological process by which malignant tumor cells to acquire migration and invasion abilities. This study explored the role of KLF5 in the EMT process of in cervical cancer cell lines. OBJECTIVE: Krüpple-like factor 5 (KLF5) is a basic transcriptional factor that plays a key role in cell-cycle arrest and inhibition of apoptosis. However, the molecular mechanism by which KLF5 mediates the biological functions of cervical cancer cell lines has not been elucidated. Here, we focus on the potential function of ELF5 in regulating the EMT process in in vitro model of cervical cancer cell lines. METHOD: Western-blot and real-time quantitative PCR were used to detect the expression of EMT-related genes in HeLa cells. MTT assays, cell scratch and Transwell assays were used to assess HeLa cells proliferation and invasion capability. Using the bioinformatics tool JASPAR, we identified a high-scoring KLF5-like binding sequence in the SNAI1 gene promoter. Luciferase reporter assays was used to detect transcriptional activity for different SNAI1 promoter truncates. RESULT: After overexpressing the KLF5 gene in HeLa cells, KLF5 not only significantly inhibited the invasion and migration of HeLa cells, but also increased the expression of E-cadherin and decreased the expression of N-cadherin and MMP9. In addition, the mRNA expression of upstream regulators of E-cadherin, such as SNAI1, SLUG, ZEB1/2 and TWIST1 was also decreased. Furthermore, KLF5 inhibiting the expression of the SNAI1 gene via binding its promoter region, and the EMT of Hela cells was promoted after overexpression of the SNAI1 gene. CONCLUSION: These results indicate that KLF5 can downregulate the EMT process of HeLa cells by decreasing the expression of the SNAI1 gene, thereby inhibiting the migration and invasion of HeLa cervical cancer cells.
Asunto(s)
Neoplasias del Cuello Uterino , Femenino , Humanos , Células HeLa , Neoplasias del Cuello Uterino/patología , Línea Celular Tumoral , Factor V/genética , Factor V/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Transición Epitelial-Mesenquimal/genética , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismoRESUMEN
In the general population, individuals with an inherited thrombophilia have a higher risk of thrombosis, but the effect of inherited thrombophilia on the risk of cancer-associated venous thromboembolism (VTE) remains controversial. Our objective was to determine the risk of VTE in cancer patients with inherited thrombophilia. We conducted a systematic review and meta-analysis of studies reporting on VTE after a cancer diagnosis in adult patients who were tested for inherited thrombophilia. In September 2022, we searched Medline, EMBASE, and Cochrane Central. Two reviewers screened the abstracts/full texts and assessed study quality using the Quality in Prognostic Studies tool. We used Mantel-Haenszel random-effects models to estimate pooled odds ratios (OR) of VTE and 95% confidence intervals (95%CI). We included 37 and 28 studies in the systematic review and meta-analysis, respectively. Most studies focused on specific cancer types and hematologic malignancies were rare. The risk of VTE was significantly higher in cancer patients with non-O (compared with O) blood types (OR: 1.56 [95% CI: 1.28-1.90]), Factor V Leiden, and Prothrombin Factor II G20210A mutations compared with wild types (OR: 2.28 [95% CI: 1.51-3.48] and 2.14 [95% CI: 1.14-4.03], respectively). Additionally, heterozygous and homozygous methylenetetrahydrofolate reductase C677T had ORs of 1.50 (95% CI: 1.00-2.24) and 1.38 (95% CI: 0.87-2.22), respectively. Among those with Plasminogen-Activator Inhibitor-1 4G/5G, Vascular Endothelial Growth Factor (VEGF) A C634G, and VEGF C2578A mutations, there was no significant association with VTE. In conclusion, this meta-analysis provided evidence that non-O blood types, Factor V Leiden, and Prothrombin Factor II G20210A mutations are important genetic risk factors for VTE in cancer patients.