RESUMEN

BACKGROUND: Acute pulmonary embolism (APE) is a major type of venous thromboembolism (VTE) with a high risk of mortality and disability. There is a lack of biomarkers for APE to indicate deteriorating development and predict adverse outcomes. This study evaluated the significance of miR-150-5p in APE aiming to explore a novel potential biomarker for APE. METHODS: The study enrolled APE (n = 137) and deep wein thrombosis (DVT, n = 67) patients and collected plasma samples from all study subjects. The expression of miR-150-5p was analyzed by PCR and its significance in screening APE and pulmonary arterial hypertension (PAH) was assessed by receiver operating curve (ROC) and logistic analyses. The study established oxidized low-density lipoprotein (ox-LDL)-induced human venous endothelial cells (HUVECs). Through cell transfection combined with cell counting kit-8 (CCK8), flow cytometry, and enzyme-linked immunosorbent assay (ELISA), the effect of miR-150-5p on ox-LDL-induced HUVEC injury was evaluated. RESULTS: Significant downregulation of miR-150-5p was observed in the plasma of APE patients compared with DVT patients (P < 0.0001). The plasma miR-150-5p levels in APE patients occurred PAH was much lower than in patients without PAH (P < 0.0001). Reducing miR-150-5p distinguished APE patients from DVT patients (AUC = 0.912) and was identified as a risk factor for the occurrence of PAH in APE patients (OR = 0.385, P = 0.010). In HUVECs, oxidized low-density lipoprotein (ox-LDL) caused inhibited cell proliferation, enhanced apoptosis, increased pro-inflammatory cytokines, reactive oxygen species (ROS), malondialdehyde (MDA), and decreased superoxide dismutase (SOD). Overexpressing miR-150-5p could promote proliferation, inhibit apoptosis, and alleviate inflammation and oxidative stress of ox-LDL-treated HUVECs. CONCLUSIONS: Downregulated plasma miR-150-5p served as a diagnostic biomarker for APE and predicted the predisposition of PAH in APE patients. Overexpressing miR-150-5p could alleviate ox-LDL-induced endothelial cell injury in HUVECs.

Asunto(s)

Biomarcadores , Lipoproteínas LDL , MicroARNs , Embolia Pulmonar , Humanos , Lipoproteínas LDL/sangre , MicroARNs/genética , MicroARNs/sangre , Embolia Pulmonar/genética , Embolia Pulmonar/sangre , Embolia Pulmonar/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Células Endoteliales de la Vena Umbilical Humana , Apoptosis , Hipertensión Arterial Pulmonar/genética , Células Endoteliales/metabolismo , Adulto , Estrés Oxidativo , Anciano

RESUMEN

Schimke immuno-osseous dysplasia is a rare multisystemic disorder caused by biallelic loss of function of the SMARCAL1 gene that plays a pivotal role in replication fork stabilization and thus DNA repair. Individuals affected from this disease suffer from disproportionate growth failure, steroid resistant nephrotic syndrome leading to renal failure and primary immunodeficiency mediated by T cell lymphopenia. With infectious complications being the leading cause of death in this disease, researching the nature of the immunodeficiency is crucial, particularly as the state is exacerbated by loss of antibodies due to nephrotic syndrome or immunosuppressive treatment. Building on previous findings that identified the loss of IL-7 receptor expression as a possible cause of the immunodeficiency and increased sensitivity to radiation-induced damage, we have employed spectral cytometry and multiplex RNA-sequencing to assess the phenotype and function of T cells ex-vivo and to study changes induced by in-vitro UV irradiation and reaction of cells to the presence of IL-7. Our findings highlight the mature phenotype of T cells with proinflammatory Th1 skew and signs of exhaustion and lack of response to IL-7. UV light irradiation caused a severe increase in the apoptosis of T cells, however the expression of the genes related to immune response and regulation remained surprisingly similar to healthy cells. Due to the disease's rarity, more studies will be necessary for complete understanding of this unique immunodeficiency.

Asunto(s)

Reparación del ADN , Osteocondrodisplasias , Enfermedades de Inmunodeficiencia Primaria , Humanos , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Osteocondrodisplasias/genética , Osteocondrodisplasias/inmunología , Reparación del ADN/genética , ADN Helicasas/genética , Síndrome Nefrótico/etiología , Síndrome Nefrótico/genética , Linfocitos T/inmunología , Arteriosclerosis/genética , Arteriosclerosis/etiología , Arteriosclerosis/inmunología , Masculino , Femenino , Embolia Pulmonar/genética , Embolia Pulmonar/etiología , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/genética , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/etiología , Rayos Ultravioleta/efectos adversos , Niño , Apoptosis/genética , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología

RESUMEN

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.

Asunto(s)

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/genética

RESUMEN

BACKGROUND: Deficiency of natural anticoagulant antithrombin was first reported as a genetic risk factor for venous thromboembolism, antithrombin III (AT III) is encoded by the serpin family C member 1 (SERPINC1) gene, consisting of 432 amino acids, including 3 disulfide bonds and 4 possible glycosylation sites. Studies have shown that hereditary AT deficiency increases the incidence of venous thromboembolism by up to 20 times. CASE PRESENTATION: The case presented a 27-year-old young man with no acquired risk factors and a sudden onset of right lower extremity venous thrombosis and pulmonary embolism. A heterozygous mutation in gene SERPINC1 of c.1154-14G>A was detected in the patient, which is a deleterious mutation resulting in reduced AT III activity and increased risk of thrombotic events. The patient received anticoagulant therapy for approximately 5 months, and the thrombus gradually dissolved and no recurrent thrombotic events occurred during follow-up. DISCUSSION: AT deficiency is a rare autosomal dominant genetic disease, they are mainly divided into 2 types according to the different effects on the structure or function of the encoded protein. The patient had a mutation in the SERPINC1 gene (c.1154-14G>A). Several cases of this type of mutation have been reported since 1991, and it is classified as AT deficiency type I. CONCLUSION: Thrombosis in patients with antithrombin deficiency is often unpredictable and can lead to fatal pulmonary embolism. Early genetic testing for hereditary thrombophilia in venous thromboembolism patients without obvious high-risk factors is critical. Long-term anticoagulation treatment is an effective treatment, for this type of type I AT III deficiency combined with pulmonary embolism patients, warfarin is an effective anticoagulant drug.

Asunto(s)

Antitrombina III , Mutación , Embolia Pulmonar , Humanos , Embolia Pulmonar/genética , Masculino , Adulto , Antitrombina III/genética , Deficiencia de Antitrombina III/genética , Deficiencia de Antitrombina III/complicaciones , Anticoagulantes/uso terapéutico

RESUMEN

BACKGROUND: Ring finger protein 213 (RNF213) p.Arg4810Lys is a susceptibility gene for moyamoya disease, peripheral pulmonary artery stenosis (PPS), and other vascular diseases and thrombosis. We investigated the prevalence and clinical characteristics of RNF213 variant carriers diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: We retrospectively analyzed the prevalence of the RNF213 p.Arg4810Lys variant in patients diagnosed with CTEPH (n=112) and PPS (n=10). Clinical and angiographic characteristics were evaluated between RNF213 variant carriers diagnosed with CTEPH and noncarriers with CTEPH and homozygous variant carriers with PPS. Eight heterozygous RNF213 p.Arg4810Lys variant carriers (7.1%) were identified among patients diagnosed with CTEPH, while 5 patients with PPS (50%) carried the homozygous variant. The clinical characteristics of heterozygous variant carriers with CTEPH were not remarkably different from those of noncarriers with CTEPH. All heterozygous variant carriers with CTEPH showed webs/bands lesions at the segmental/subsegmental level, with 75% showing distal tortuous vessels. None of the heterozygous variant carriers with CTEPH exhibited the string-of-beads pattern or elongated stenosis. Homozygous variant carriers with PPS showed the string-of-beads pattern, elongated stenosis, and distal tortuous vessels without webs/bands lesions. CONCLUSIONS: A subset of patients diagnosed with CTEPH (7.1%) carried the heterozygous RNF213 p.Arg4810Lys variant. Clinical and angiographic characteristics of heterozygous variant carriers were not remarkably different from those of noncarriers of CTEPH. However, both heterozygous variant carriers with CTEPH and homozygous variant carriers with PPS showed tortuous vessels on angiography.

Asunto(s)

Adenosina Trifosfatasas , Predisposición Genética a la Enfermedad , Heterocigoto , Hipertensión Pulmonar , Embolia Pulmonar , Ubiquitina-Proteína Ligasas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Embolia Pulmonar/genética , Embolia Pulmonar/epidemiología , Prevalencia , Enfermedad Crónica , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/diagnóstico , Adenosina Trifosfatasas/genética , Ubiquitina-Proteína Ligasas/genética , Anciano , Adulto , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/diagnóstico por imagen , Estenosis de Arteria Pulmonar/genética , Estenosis de Arteria Pulmonar/fisiopatología , Estenosis de Arteria Pulmonar/epidemiología , Mutación

RESUMEN

Methylenetetrahydrofolate reductase (MTHFR) enzyme is one of the key enzymes involved in the metabolism of folate. Mutations in this enzyme can lead to a procoagulant state. We present a case of a 20-year-old male with no known comorbidities, who presented with fever and hemoptysis and was diagnosed as a case of pulmonary embolism. He was found to have a homozygous mutation in the MTHFR gene that was responsible for his disease state. He was started on unfractionated heparin infusion and underwent catheter-directed thrombolysis. He showed marked improvement in his condition and was discharged on oral anticoagulants with an advice to follow-up.

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RésuméL'enzyme méthylènetétrahydrofolate réductase (MTHFR) est l'une des enzymes clés impliquées dans le métabolisme du folate. Les mutations de cette enzyme peuvent conduire à un état procoagulant. Nous présentons le cas d'un homme de 20 ans sans comorbidités connues, qui s'est présenté avec de la fièvre et une hémoptysie et a été diagnostiqué comme un cas d'embolie pulmonaire. Il s'est avéré qu'il présentait une mutation homozygote du gène MTHFR responsable de son état pathologique. Il a commencé une perfusion d'héparine non fractionnée et a subi une thrombolyse dirigée par cathéter. Il a montré une nette amélioration de son état et a été libéré sous anticoagulants oraux avec un conseil de suivi.

Asunto(s)

Anticoagulantes , Metilenotetrahidrofolato Reductasa (NADPH2) , Mutación , Embolia Pulmonar , Humanos , Masculino , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/genética , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/diagnóstico por imagen , Anticoagulantes/uso terapéutico , Adulto Joven , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Resultado del Tratamiento , Heparina/uso terapéutico , Terapia Trombolítica/métodos , Homocigoto

RESUMEN

BACKGROUND: The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them. METHODS: A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis. RESULTS: A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001-1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002-1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139-1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165-1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004-1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020-1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029-1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females. CONCLUSIONS: Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE.

Asunto(s)

Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/sangre , Factores de Riesgo , Medición de Riesgo , Femenino , Masculino , Tiroxina/sangre , Fenotipo , Biomarcadores/sangre , Trombosis de la Vena/genética , Trombosis de la Vena/epidemiología , Trombosis de la Vena/sangre , Trombosis de la Vena/diagnóstico , Factores Sexuales , Testosterona/sangre , Embolia Pulmonar/genética , Embolia Pulmonar/epidemiología , Embolia Pulmonar/sangre , Embolia Pulmonar/diagnóstico

RESUMEN

Venous thromboembolic disease (VTE) is a prevalent and potentially life-threatening vascular disease, including both deep vein thrombosis and pulmonary embolism. This review will focus on recent insights into the heritable factors that influence an individual's risk for VTE. Here, we will explore not only the discovery of new genetic risk variants but also the importance of functional characterization of these variants. These genome-wide studies should lead to a better understanding of the biological role of genes inside and outside of the canonical coagulation system in thrombus formation and lead to an improved ability to predict an individual's risk of VTE. Further understanding of the molecular mechanisms altered by genetic variation in VTE risk will be accelerated by further human genome sequencing efforts and the use of functional genetic screens.

Asunto(s)

Predisposición Genética a la Enfermedad , Variación Genética , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Factores de Riesgo , Estudio de Asociación del Genoma Completo , Coagulación Sanguínea/genética , Embolia Pulmonar/genética , Fenotipo , Trombosis de la Vena/genética

RESUMEN

TIMP metallopeptidase inhibitor 3 (TIMP-3) may contribute to the pathogenesis of venous thromboembolism (VTE). However, few studies have investigated the effect of TIMP-3 on VTE. Therefore, a two-sample Mendelian randomization (MR) analysis was conducted to investigate the association between TIMP-3 levels and VTE. Seven independent single-nucleotide polymorphisms (SNPs) for TIMP-3 levels were obtained from a published genome-wide association study (the KORA Consortium, including 997 Europeans). We obtained outcome datasets for VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) from the FinnGen Consortium. The primary analytical method used in the MR analysis was the inverse variance weighted (IVW) method. To enhance the robustness of the MR results, some other MR methods including weighted median, MR-Egger, and MR-PRESSO were conducted. Moreover, several sensitivity analyses were performed to identify potential horizontal pleiotropy and heterogeneity. In primary IVW MR analyses, per log increase in genetically predicted TIMP-3 levels were positively associated with the incidence of VTE (odds ratio [OR], 1.03; 95 % confidence interval (CI), 1.01, 1.06; P = 0.010), PE (OR, 1.04; 95 % CI, 1.01, 1.08; P = 0.009), and DVT (OR, 1.06; 95 % CI, 1.02, 1.10; P= 0.003). The results of the weighted median, MR-Egger, and MR-PRESSO were similar to the main findings. No unbalanced pleiotropy or heterogeneity was observed. The study suggests that genetically predicted high levels of TIMP-3 may be associated with an increased risk of VTE. These findings indicate that strategies targeting TIMP-3 may provide a basis for the prevention and treatment of VTE. Further investigation is required to clarify this potential mechanism.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Inhibidor Tisular de Metaloproteinasa-3 , Tromboembolia Venosa , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiología , Inhibidor Tisular de Metaloproteinasa-3/genética , Estudio de Asociación del Genoma Completo/métodos , Predisposición Genética a la Enfermedad , Embolia Pulmonar/genética , Embolia Pulmonar/epidemiología , Embolia Pulmonar/sangre , Factores de Riesgo , Trombosis de la Vena/genética , Trombosis de la Vena/epidemiología

RESUMEN

Venous thromboembolism (VTE) is a complex disease that can be classified into two subtypes: deep vein thrombosis (DVT) and pulmonary embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE. The MR results identified that fatty acid (FA) unsaturation traits (ratio of bis-allylic bonds to double bonds in lipids, and ratio of bis-allylic bonds to total fatty acids in lipids) were associated with VTE (odds ratio [OR]=1.21, 95% confidence interval [CI]: 1.15-1.27; OR=1.21, 95% CI: 1.13-1.30), DVT (OR=1.24, 95% CI: 1.16-1.33; OR= 1.26, 95% CI: 1.16-1.36) and PE (OR=1.18, 95% CI: 1.08-1.29; OR=1.18, 95% CI: 1.09-1.27). Phosphatidylcholines (PC) exhibit potential causal effects on VTE and PE. PC acyl-alkyl C40:4 (PC ae C40:4) was negatively associated with VTE (OR=0.79, 95% CI: 0.73-0.86), while PC diacyl C42:6 (PC aa C42:6) and PC acyl-alkyl C36:4 (PC ae C36:4) were positively associated with PE (OR=1.44, 95% CI: 1.20-1.72; OR=1.22, 95% CI: 1.10-1.35). Additionally, we found that medium LDL had a protective effect on VTE. Our study indicates that higher FA unsaturation may increase the risk of VTE, DVT, and PE. Different types of PC have either promotive or inhibitory effects on VTE and PE, contributing to a better understanding of the risk factors for VTE.

Asunto(s)

Análisis de la Aleatorización Mendeliana , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/etiología , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/sangre , Tromboembolia Venosa/genética , Lípidos/sangre , Factores de Riesgo , Oportunidad Relativa , Embolia Pulmonar/sangre , Embolia Pulmonar/genética , Embolia Pulmonar/etiología , Embolia Pulmonar/epidemiología , Femenino

RESUMEN

The treatment of patients with acute pulmonary embolism (APE) is extremely challenging due to the complex clinical presentation and prognosis of APE related to the patient's hemodynamic status and insufficient arterial blood flow and right ventricular overload. Protective efficacy against cardiovascular diseases of curcumin, a common natural polyphenolic compound, which has antithrombotic properties and reduces platelet accumulation in the circulation by inhibiting thromboxane synthesis has been demonstrated. However, the direct effect of curcumin on APE has rarely been studied. Therefore, the present study aimed to investigate the therapeutic potential of curcumin in APE and associated myocardial injury to provide new insights into curcumin as a promising competitive new target for the treatment of APE. A suspension of 12 mg/kg microspheres was injected intravenously into rats. An APE rat model was built. Before modeling, intragastric 100 mg/kg curcumin was given, and/or lentiviral plasmid vector targeting microRNA-145-5p or insulin receptor substrate 1 (IRS1) was injected. Pulmonary artery pressure was measured to assess right ventricular systolic pressure (RVSP). Hematoxylin and eosin (H&E) staining was performed on liver tissues and myocardial tissues of APE rats. TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling) staining and immunohistochemical (IHC) staining were conducted to measure apoptosis and CyPA-CD147 expression in the myocardium, respectively. Inflammatory indices interleukin-1beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured by ELISA in cardiac tissues. RT-qPCR and Western blot were performed to determine the expression levels of related genes. In addition, by dual luciferase reporter assay and RIP assay, the relationship between microRNA-145-5p and insulin receptor substrate 1 (IRS1) was confirmed. In results: curcumin improved APE-induced myocardial injury, reduced myocardial tissue edema, and thrombus volume. It attenuated APE-induced myocardial inflammation and apoptosis, as well as reduced lung injury and pulmonary artery pressure. Curcumin promoted microRNA-145-5p expression in APE rat myocardium. MicroRNA-145-5p overexpression protected against APE-induced myocardial injury, and microRNA-145-5p silencing abolished the beneficial effects of curcumin in APE-induced myocardial injury. IRS1 was targeted by microRNA-145-5p. IRS1 silencing attenuated APE-induced myocardial injury, and enhanced therapeutic effect of curcumin on myocardial injury in APE rats. In conclusion, curcumin alleviates myocardial inflammation, apoptosis, and oxidative stress induced by APE by regulating microRNA-145-5p/IRS1 axis.

Asunto(s)

Curcumina , Hominidae , MicroARNs , Miocarditis , Embolia Pulmonar , Humanos , Ratas , Animales , MicroARNs/genética , MicroARNs/metabolismo , Curcumina/farmacología , Curcumina/uso terapéutico , Proteínas Sustrato del Receptor de Insulina/metabolismo , Interleucina-6/metabolismo , Apoptosis , Inflamación/tratamiento farmacológico , Estrés Oxidativo , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/genética , Hominidae/genética , Hominidae/metabolismo

RESUMEN

OBJECTIVE: To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. METHODS: The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. RESULTS: Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). CONCLUSION: The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity.

Asunto(s)

Linaje , Deficiencia de Proteína C , Proteína C , Humanos , Deficiencia de Proteína C/genética , Deficiencia de Proteína C/complicaciones , Femenino , Masculino , Adulto , Proteína C/genética , Persona de Mediana Edad , Estudios Retrospectivos , Trombosis de la Vena/genética , Trombosis de la Vena/sangre , Mutación Missense , Embolia Pulmonar/genética , Mutación

RESUMEN

BACKGROUND: Thrombophilia is a coagulation disorder closely associated with venous thromboembolism. Hereditary antithrombin III (AT III) deficiency is a type of genetic thrombophilia. In China, genetic thrombophilia patients mainly suffer from deficiencies in AT III, protein S, and protein C. Multiple mutations in the serpin family C member 1 (SERPINC1) can affect AT III activity, resulting in thrombosis. CASE PRESENTATION: This case presented a 17-year-old adolescent female who developed lower extremity venous thrombosis and subsequently pulmonary embolism (PE) following a right leg injury. A missense mutation in gene SERPINC1 of c.331 T > C, p.S111P was detected on the patient, resulting in a decreased AT III activity and an elevated risk of thrombosis. The patient received anticoagulation treatment for approximately 5 months. During follow-up, the blood clot gradually dissolved, and there have been no recurrent thrombotic events reported thus far. DISCUSSION: Hereditary AT deficiency can be classified into two types based on the plasma levels of the enzymatic activity and antigen. Type I is a quantitative defect, while Type II is a qualitive defect. Until 2021, 486 SERPINC1 gene mutations have been registered, more than 18% of which are point mutations. The SERPINC1 mutation c.331 T > C in was firstly reported in 2017, which was classified into type I AT III deficiency. CONCLUSION: Hereditary thrombophilia is a coagulation disorder with a high omission diagnostic rate. Minor mutations in the SERPINC1 gene can also lead to hereditary AT III deficiency, which in turn can cause PE. We emphasized the importance of etiological screening for hereditary thrombophilia in venous thromboembolism patients without obvious high-risk factors. Long-term anticoagulation treatment and avoidance of potential thrombosis risk factors are critical for such patients.

Asunto(s)

Deficiencia de Antitrombina III , Embolia Pulmonar , Trombofilia , Trombosis , Tromboembolia Venosa , Adolescente , Humanos , Femenino , Deficiencia de Antitrombina III/complicaciones , Deficiencia de Antitrombina III/genética , Tromboembolia Venosa/genética , Trombosis/genética , Embolia Pulmonar/genética , Anticoagulantes/uso terapéutico

RESUMEN

Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.

Asunto(s)

Estudio de Asociación del Genoma Completo , Hipertensión Pulmonar , Embolia Pulmonar , Humanos , Embolia Pulmonar/genética , Embolia Pulmonar/complicaciones , Hipertensión Pulmonar/genética , Masculino , Femenino , Persona de Mediana Edad , Enfermedad Crónica , Genómica , Predisposición Genética a la Enfermedad , Adulto , Estudios de Casos y Controles , Anciano , Trombosis de la Vena/genética

Asunto(s)

Hipertensión Pulmonar , Embolia Pulmonar , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Embolia Pulmonar/genética , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/complicaciones , Enfermedad Crónica , Masculino , Femenino , Persona de Mediana Edad

RESUMEN

BACKGROUND: Given the current debate in clinical research about the relationship between tobacco smoking and the risk of venous thromboembolism (VTE), a Mendelian randomization (MR) study was conducted aimed at elucidating the causal associations of current and past tobacco smoking with the risk of VTE, from the perspective of genetics. METHODS: Two-sample univariate and multivariable MR analyses were designed, using summary-level data from large genome-wide association studies involving European individuals. Causality was primarily assessed using multiplicative fixed-effects or random-effects model and inverse variance weighting, supplemented by MR-Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out for sensitivity analysis to test the reliability of the results. RESULTS: In the univariate MR analysis, no significant causal effects were found between current tobacco smoking and the risk of VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE). Similarly, no significant causal effects were found between past smoking and VTE, DVT, and PE. As for the multivariable MR analysis, results were consistent with univariate MR analysis, with no significant causal effect of either current or past tobacco smoking on the risk of VTE, DVT, and PE. CONCLUSION: Evidence from both univariate and multivariable MR analyses demonstrated no significant causal relationships between current and past tobacco smoking and VTE, DVT, and PE. This contradicts positive correlations reported in some previous observational studies, which may be explained by other confounding factors. This provided genetic evidence for the conclusion reported in other observational studies that smoking did not affect VTE risk.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Embolia Pulmonar , Fumar Tabaco , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Fumar Tabaco/efectos adversos , Fumar Tabaco/genética , Embolia Pulmonar/genética , Embolia Pulmonar/epidemiología , Embolia Pulmonar/etiología , Factores de Riesgo , Trombosis de la Vena/genética , Trombosis de la Vena/epidemiología , Trombosis de la Vena/etiología , Predisposición Genética a la Enfermedad , Causalidad , Polimorfismo de Nucleótido Simple , Análisis Multivariante

RESUMEN

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54-0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH.

Asunto(s)

Hipertensión Pulmonar , MicroARNs , Embolia Pulmonar , Tromboembolia Venosa , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/complicaciones , Ecocardiografía/efectos adversos , MicroARNs/genética , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/genética , Biomarcadores , Tromboembolia Venosa/complicaciones , Enfermedad Crónica

RESUMEN

BACKGROUND: Lower limb deep vein thrombosis (DVT) concurrent with pulmonary embolism (PE) is perilous, particularly in the elderly, exhibiting heterogeneity with thrombophilia mutations. Tailored treatment is essential, yet sudden deaths complicate causative factor elucidation. This report emphasizes genetic testing necessity in PE patients with thrombophilia indicators, facilitating cause identification, personalized treatment guidance, and family education. CASE PRESENTATION: This study details a 75-year-old Chinese woman with DVT and PE, where genetic testing identified thrombophilia, guiding personalized treatment decisions. RESULTS: Upon admission, the patient, after over 10 days of bed rest, presented chest tightness, shortness of breath, and unilateral leg swelling. Diagnostic measures revealed DVT and a substantial PE. Genetic testing identified a PROS1 gene C200A>C mutation, reducing protein S activity. Following 2 weeks of anticoagulation and inferior vena cava filter insertion, the patient, discharged, initiated lifelong anticoagulant therapy. A 1-year follow-up showed no recurrent thrombotic events. Family members carrying the mutation received informed and educational interventions. CONCLUSION: Genetic testing for thrombophilic predisposition post-PE is crucial, elucidating etiology, guiding individualized treatment, and playing a pivotal role in family education.

Asunto(s)

Deficiencia de Proteína S , Embolia Pulmonar , Trombosis , Filtros de Vena Cava , Trombosis de la Vena , Femenino , Humanos , Anciano , Deficiencia de Proteína S/complicaciones , Deficiencia de Proteína S/genética , Embolia Pulmonar/genética , Embolia Pulmonar/complicaciones , Trombosis de la Vena/genética , Trombosis de la Vena/complicaciones , Trombosis/complicaciones , Mutación , Filtros de Vena Cava/efectos adversos

RESUMEN

Atrial fibrillation (AF) can increase thrombosis, especially arterial thrombosis, and some studies show that AF patients have a higher risk of developing pulmonary embolism (PE). The objective of our study is to investigate whether there is a direct causal effect of AF on PE. A two-sample Mendelian randomization (MR) approach was utilized to determine whether there is a causal relationship between AF and PE. European population-based consortia provided statistical data on the associations between Single Nucleotide Polymorphisms (SNPs) and relevant traits. The AF dataset was obtained from genome-wide association studies (GWAS) comprising 60,620 cases and 970,216 controls, while a GWAS of 1846 cases and 461,164 controls identified genetic variations associated with PE. Estimation of the causal effect was mainly performed using the random effects inverse-variance weighted method (IVW). Additionally, other tests such as MR-Egger intercept, MR-PRESSO, Cochran's Q test, "Leave-one-out," and funnel plots were conducted to assess the extent of pleiotropy and heterogeneity. Using 70 SNPs, there was no evidence to suggest an association between genetically predicted AF and risk of PE with multiplicative random-effects IVW MR analysis (odds ratio = 1.0003, 95% confidence interval: 0.9998-1.0008, P = 0.20). A null association was also observed in other methods. MR-Egger regression and MR-PRESSO respectively showed no evidence of directional (intercept, - 2.25; P = 0.94) and horizontal(P-value in the global heterogeneity test = 0.99) pleiotropic effect across the genetic variants. No substantial evidence was found to support the causal role of AF in the development of PE.

Asunto(s)

Fibrilación Atrial , Embolia Pulmonar , Trombosis , Humanos , Fibrilación Atrial/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Nonoxinol , Embolia Pulmonar/genética

RESUMEN

BACKGROUND: Thrombin-activatable fibrinolysis inhibitor (TAFI) levels are positively correlated with the risk of thrombosis. The mechanism of how TAFI affects venous thromboembolism (VTE) remains uncertain. In addition, the role of sex on the risk of VTE has also been studied. However, their association also remains unclear. OBJECTIVES: To investigate how TAFI and/or sex affect venous thrombus stability and consequent pulmonary embolism (PE). METHODS: Ferric chloride-induced thrombi were formed within the femoral veins of male and female wild-type (WT) or TAFI-knockout (Cpb2-/-) mice. Thrombi were imaged over 2 hours using intravital videomicroscopy to quantify embolization and thrombus size over time. Lungs were examined by immunohistochemistry to quantify (a) emboli and (b) fibrin composition of these emboli. RESULTS: Embolization events in female mice were higher than in males (7.9-fold in WT and 3.1-fold in Cpb2-/- mice). Although the maximal thrombus sizes were not different across groups, Cpb2-/- mice had thrombi that were, on average, 24% smaller at the end of the 2-hour experiment than WT mice. Loss of TAFI led to a 4.0- and 2.8-fold increase in PE burden in males and females, respectively, while sex had no influence. Pulmonary emboli in Cpb2-/- mice had higher fibrin composition compared with WT mice. CONCLUSION: Female mice had less stable venous thrombi than male mice, suggesting a higher risk of PE in females with deep vein thrombosis. Mice lacking TAFI had more thrombus degradation and higher PE burden than WT mice. These results confirm the role of TAFI in venous thrombosis.

Asunto(s)

Carboxipeptidasa B2 , Embolia Pulmonar , Trombosis , Tromboembolia Venosa , Masculino , Femenino , Ratones , Animales , Carboxipeptidasa B2/genética , Modelos Animales de Enfermedad , Embolia Pulmonar/genética , Embolia Pulmonar/metabolismo , Fibrina , Fibrinólisis