RESUMO
For many years, the left atrial appendage (LAA) was considered a dormant embryological remnant; however, it is a structurally complex and functional organ that contributes to cardiac haemodynamic changes and volume homeostasis through both its contractile properties and neurohormonal peptide secretion. When dysfunctional, the LAA contributes to thrombogenesis and subsequent increased predisposition to cardioembolic events. Consequently, the LAA has gained much attention as a therapeutic target to lower this risk. In addition, attention has focused on the LAA in its role as an electrical trigger for atrial tachycardia and atrial fibrillation with ablation of the LAA to achieve electrical isolation showing promising results in the maintenance of sinus rhythm. This in-depth review explores the structure, physiology and pathophysiology of the LAA, as well as LAA intervention and their sequelae.
Assuntos
Apêndice Atrial , Fibrilação Atrial , Ablação por Cateter , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Causalidade , HumanosRESUMO
Extracranial-to-intracranial (EC-IC) bypass surgery is an effective treatment for patients with moyamoya disease and other conditions. Some patients with moyamoya disease have a risk of acute thrombogenesis at the anastomotic site just after bypass surgery. The purpose of this study was to study risk factors of acute thrombogenesis and determine effective countermeasures. This study included 48 patients (66 EC-IC bypass procedures) with moyamoya disease and 52 controls (54 procedures) without moyamoya disease. The development of acute thrombogenesis was compared between the moyamoya disease and control groups. In the moyamoya disease group, clinical and radiological characteristics were assessed with respect to acute thrombogenesis. In the patients with acute thrombogenesis, causes of technical problems were retrospectively examined. The incidence of acute thrombogenesis was significantly higher in the moyamoya disease group than those in the control group. In the moyamoya disease group, acute thrombogenesis was observed in seven patients. In the moyamoya disease group, the magnetic resonance angiography (MRA) scores were significantly higher in patients with acute thrombogenesis than those in the patients without acute thrombogenesis. In the multivariate analysis, the predictive factor of acute thrombogenesis in moyamoya disease was a high MRA score (odds ratio, 2.336; p = 0.009). During EC-IC bypass surgery for moyamoya disease, acute thrombogenesis should be considered to obtain a high patency rate, particularly in patients with high MRA scores. Acute thrombogenesis will not influence morbidity if proper countermeasures are followed; therefore, the prediction and recognition of white thrombus are important for a successful bypass surgery.
Assuntos
Revascularização Cerebral/efeitos adversos , Trombose Intracraniana/epidemiologia , Doença de Moyamoya/cirurgia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Incidência , Trombose Intracraniana/diagnóstico por imagem , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/complicações , Doença de Moyamoya/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Clot formation within membrane oxygenators (MOs) remains a critical problem during extracorporeal membrane oxygenation (ECMO). The composition of the clots-in particular, the presence of von Willebrand factor (vWF)-may be an indicator for prevalent nonphysiological flow conditions, foreign body reactions, or coagulation abnormalities in critically ill patients. Mats of interwoven gas exchange fibers from randomly collected MOs (PLS, Maquet, Rastatt, Germany) of 21 patients were stained with antibodies (anti-vWF and anti-P-selectin) and counterstained with 4',6-diamidino-2-phenylindole. The extent of vWF-loading was correlated with patient and technical data. While 12 MOs showed low vWF-loadings, 9 MOs showed high vWF-loading with highest accumulations close to crossing points of adjacent gas fibers. The presence and the extent of vWF-fibers/"cobwebs," leukocytes, platelet-leukocyte aggregates (PLAs), and P-selectin-positive platelet aggregates were independent of the extent of vWF-loading. However, the highly loaded MOs were obtained from patients with a significantly elevated SOFA score, severe thrombocytopenia, and persistent liver dysfunction. The coagulation abnormalities of these critically ill patients may cause an accumulation of the highly thrombogenic and elongated high-molecular-weight vWF multimers in the plasma which will be trapped in the MOs during the ECMO therapy.
Assuntos
Oxigenação por Membrana Extracorpórea/efeitos adversos , Trombose/etiologia , Fator de von Willebrand/análise , Adulto , Idoso , Coagulação Sanguínea , Estado Terminal/terapia , Desenho de Equipamento , Oxigenação por Membrana Extracorpórea/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigenadores de Membrana/efeitos adversos , Ativação PlaquetáriaRESUMO
Recently, it has been shown in the murine model that platelet maturation takes place, to some extent, in the lungs. The extrapolation of these findings to humans leads to the possibility that chronic lung diseases could affect platelet maturation and, consequently, the platelet count. The aim of this study was to investigate whether there are changes in the platelet count in patients with chronic obstructive disease (COPD). The study included 44 patients, aged 66.5 ± 5.5 years, in stage II-IV COPD. The control group consisted of 48 age- and gender-matched patients without any respiratory diseases. We failed to find a significant difference in the platelet count between the two groups: 231 ± 80 vs. 223 ± 63 x 103/µL, respectively (p = 0.61). However, the number of platelets in the COPD patients was inversely associated with hemoglobin content (r = -0.57; p < 0.001), hematocrit (r = -0.40; p = 0.006), and the red cell count (r = -0.51; p < 0.001); the blood morphology indices that are typically increased in severe COPD. Such associations were absent in the control non-COPD group. We conclude that COPD has no influence on the platelet count in humans.
Assuntos
Plaquetas , Doença Pulmonar Obstrutiva Crônica , Idoso , Plaquetas/citologia , Doença Crônica , Contagem de Eritrócitos , Feminino , Hematócrito , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Doença Pulmonar Obstrutiva Crônica/sangueRESUMO
BACKGROUND: It has been suggested that ethnicity can make a significant difference to the likelihood of thromboembolic stroke related to atrial fibrillation. Ethnic differences have been shown to alter inflammatory and haemostatic factors; however, this may all be confounded by differences in cardiovascular risk factors between different ethnicity. The impact of different ethnicities on the thrombogenic profile is not known. The aim of this study was to investigate differences in markers of inflammation, endothelial function and tissue remodelling between Caucasian and Indian populations with supraventricular tachycardia (SVT). METHODS: Patients with structurally normal hearts undergoing catheter ablation for SVT were studied. This study included 23 Australian (Caucasian) patients from the Royal Adelaide Hospital, Adelaide, Australia and 24 Indian (Indian) patients from the Christian Medical College, Vellore, India. Blood samples were collected from the femoral vein, and right and left atria. Blood samples were analysed for the markers of endothelial function (ADMA, ET-1), inflammation (CD40L, VCAM-1, ICAM-1), and tissue remodelling (MMP-9, TIMP-1) using ELISA. RESULTS: The study populations were well matched for cardiovascular risk factors and the absence of structural heart disease. No difference in the echocardiographic measurements between the two ethnicities was found. In this context, there was no difference in markers of inflammation, endothelial function or tissue remodelling between the two SVT populations. CONCLUSION: Caucasian and Indian populations demonstrate similar inflammatory, endothelial function or tissue remodelling profiles. This study suggests a lack of an impact of different ethnicity in these populations in terms of thrombogenic risk.
RESUMO
OBJECTIVE: Introduction: One of the major complications of stage V chronic kidney disease (CKD), treated by program hemodialysis, are hemostatic system disturbances resulting in thrombosis development. To detect early predictors of potential thrombosis in study category of patients is rather difficult because of inflammatory process, accumulation of antibodies, continuous damage of blood elements. The aim: To estimate potential applicability of activators and inhibitors of thrombogenesis as thrombophilia markers in the patients with stage V CKD, treated by program hemodialysis. PATIENTS AND METHODS: Materials and methods:88 patients (52 males and 36 females) with stage V CKD, treated by program hemodialysis, were studied. Hemostatic profile was estimated in all the patients (soluble fibrin, D-dimer, protein C, fibrinogen). RESULTS: Results: Two thirds of the patients with stage V CKD, treated by program hemodialysis, had significant increase in soluble fibrin and fibrinogen concentration against the background of decrease of natural anticoagulant - protein C and disparate response of D-dimer (tendency to decrease). It was established that comprehensive estimation of activators and inhibitors of thrombogenesis can become an indicator of thrombophilias in the patients with stage V CKD, treated by long term hemodialysis. CONCLUSION: Conclusions: The majority of patients (68.2%) with stage VD CKD, treated by long term hemodialysis, had significant increase of soluble fibrin level (Ñ <0.02) along with decreased D-dimer to borderline values. In general group of patients there was significant decrease of protein C (Ñ<0.05) on the background of great increase of fibrinogen concentration in the majority of patients (62%) (Ñ <0.001). The females were found to have significant increase of D-dimer level (Ñ <0.05) along with the increase of soluble fibrin concentration. Comprehensive determination of activators and inhibitors of thrombogenesis can serve an indicator of thrombophilias in the patients with stage VD CKD, treated by program hemodialysis.
Assuntos
Proteínas Sanguíneas/análise , Insuficiência Renal Crônica/sangue , Trombose/sangue , Idoso , Biomarcadores/sangue , Feminino , Fibrina/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/análise , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Proteína C/análise , Insuficiência Renal Crônica/complicações , Trombose/etiologiaRESUMO
Thrombogenesis (blood clot formation) is a major barrier to the development of biomedical devices that interface with blood. Although state-of-the-art chemically and pharmacologically mediated clot mitigation strategies are effective, some limitations of such approaches include depletion of active agents, or adverse reactions in patients. Increased clotting protein adsorption and platelet adhesion, which occur when artificial surfaces are exposed to blood result in enhanced clot formation on artificial surfaces. It is hypothesized that repelling proteins and platelets using dielectrophoresis (DEP), a contact-free particle manipulation technique, will reduce clot formation in biomedical devices. In this paper, the effect of DEP on thrombogenesis in human blood is investigated. Undiluted whole blood from human donors is pumped through microchannels at a physiological shear rate (400 s-1 ). Experiments are performed by applying 0 V, 0.5 Vrms , 2 Vrms , and 3 Vrms to electrodes in the channel. Clot formation is observed to decrease in experiments in which DEP electrodes are active (average of 6% coverage @ 0V reduced to 0.08% coverage @ 3 Vrms ). Repulsion is more effective at higher voltages. DEP causes a quantifiable reduction in microscopic and macroscopic clot formation in PDMS microchannels.
Assuntos
Coagulação Sanguínea/fisiologia , Eletroforese/métodos , Técnicas Analíticas Microfluídicas/métodos , Eletroforese/instrumentação , Desenho de Equipamento , Humanos , Técnicas Analíticas Microfluídicas/instrumentação , Modelos BiológicosRESUMO
BACKGROUND: Inflammation markers have been associated with cardiovascular diseases including atrial fibrillation. This arrhythmia is the most frequent, with an incidence of 38/1000 person-years. PURPOSE OF REVIEW: The aims of this study are to discuss the association between inflammation, atherosclerosis and atrial fibrillation and its clinical implications. Atherosclerosis is a chronic inflammatory disease and inflammation is a triggering factor of atherosclerotic plaque rupture. In addition to coronary artery disease, clinical conditions identified as risk factors for atrial fibrillation (AF) are also associated with the inflammatory state such as obesity, diabetes mellitus, hypertension, heart failure, metabolic syndrome and sedentary lifestyle. Biomarkers of inflammation, oxidative stress, coagulation, and myocardial necrosis have been identified in patients with atrial fibrillation and these traditional risk factors. Some markers of inflammation were identified as predictors of recurrence of this arrhythmia, subsequent myocardial infarction, stroke by embolism, and death. Thus, approaches to manipulate the inflammatory pathways may be therapeutic interventions, benefiting patients with AF and increased inflammatory markers.
Assuntos
Aterosclerose/complicações , Fibrilação Atrial/etiologia , Inflamação/complicações , Animais , Humanos , Metabolismo dos Lipídeos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
The aim of this study is to investigate thrombogenesis and the hypercoagulable changes in pregnant women affected by thrombophilia who received low-molecular-weight heparin (LWMH) prophylaxis. We included 21 pregnant women affected by thrombophilia treated with LWMH and 20 nontreated normal pregnant women as the control group. The sample group of thrombophilic pregnant women included different conditions (factor V Leiden mutation, protein C deficiency, protein S deficiency, antiphospholipid antibodies syndrome, and combined defects). Three blood samples were collected during pregnancy (i.e., at 16, 20, and 24 weeks) and tested for activated partial thromboplastin time and prothrombin fragment F1 + 2 (F1 + 2); anti-FXa activity was tested only in treated thrombophilic pregnant women. F1 + 2 levels progressively increased during pregnancy in both study groups. However, the F1 + 2 increase in women exposed to heparin prophylaxis was significantly lower than that in normal pregnant women in all 3 measurements carried out during gestation (p < 0.05); a statistically significant inverse correlation between F1 + 2 levels and anti-Xa activity (R = -0.8575, p < 0.05) was observed in treated women during pregnancy. Our findings suggest that F1 + 2 in addition to anti-Xa measurement could be used to adjust LWMH prophylaxis, at least in high-risk pregnant women.
Assuntos
Heparina de Baixo Peso Molecular/uso terapêutico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Trombofilia/tratamento farmacológico , Trombose/prevenção & controle , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Estudos de Casos e Controles , Inibidores do Fator Xa/sangue , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Humanos , Nadroparina/administração & dosagem , Nadroparina/uso terapêutico , Tempo de Tromboplastina Parcial , Fragmentos de Peptídeos/sangue , Projetos Piloto , Gravidez , Complicações Hematológicas na Gravidez/sangue , Protrombina , Trombofilia/sangue , Trombofilia/complicações , Trombose/sangue , Trombose/complicaçõesRESUMO
Pigment epithelium-derived factor (PEDF) has anti-inflammatory and anti-thrombogenic properties both in cell culture and animal models. Although adipose triglyceride lipase (ATGL) and laminin receptor (LR) are two putative receptors for PEDF, which receptor mainly mediates the beneficial effects of PEDF is largely unknown. In this study, we addressed the issue. siRNA raised against LR (siLR) and siATGL transfection dramatically decreased LR and ATGL levels in human cultured myeloma cells, respectively. Ten nM PEDF significantly reduced vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels in siCon- or siATGL-transfected myeloma cells, whereas PEDF increased rather than decreased these gene expressions in siLR-transfected cells. Neutralizing antibody directed against LR (LR-Ab) or LR antagonist actually bound to LR and reduced mRNA levels of VEGF, MCP-1, ICAM-1 and PAI-1 in myeloma cells. Further, pre-treatment of LR-Ab or LR antagonist suppressed the binding of PEDF to LR and resultantly blocked the effects of PEDF in myeloma cells. In addition, high concentration of LR agonist mimicked the actions of PEDF on these gene expressions in myeloma cells. This study indicates that PEDF causes anti-angiogenic, anti-inflammatory and anti-thrombogenic reactions in myeloma cells through the interaction with LR. Target domain of LR agonist and antagonist might be involved in the PEDF-signaling to gene suppression in myeloma cells.
Assuntos
Anti-Inflamatórios/metabolismo , Proteínas do Olho/metabolismo , Fibrinolíticos/metabolismo , Mieloma Múltiplo/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores de Laminina/metabolismo , Serpinas/metabolismo , Animais , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Proteínas do Olho/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Lipase/metabolismo , Camundongos , Mieloma Múltiplo/patologia , Fatores de Crescimento Neural/farmacologia , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores de Laminina/antagonistas & inibidores , Serpinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Activation of the complement cascade is an important mechanism for antiphospholipid antibody-mediated thrombosis. We examined the effects of rEV576 (coversin), a recombinant protein inhibitor of complement factor 5 activation, on antiphospholipid antibody-mediated tissue factor up-regulation and thrombosis. Groups of C57BL/6J mice (n=5) received either IgG from a patient with antiphospholipid syndrome (APS) or control IgG from normal human serum (NHS). Each of these groups of mice had IgG administration preceded by either rEV576, or phosphate buffer control. For each of the four treatment groups, the size of induced thrombus, tissue factor activity in carotid homogenates, anticardiolipin and anti-ß2glycoprotein I (anti-ß2GPI) levels were measured 72 h after the first injection. Mice treated with IgG-APS had significantly higher titers of anticardiolipin antibodies and anti-ß2GPI at thrombus induction compared with those treated with IgG-NHS. The IgG-APS/phosphate buffer treatment induced significantly larger thrombi and tissue factor activity compared with other groups. Mice treated with IgG-APS/rEV576 had significantly smaller thrombi and reduced tissue factor activity than those treated with IgG-APS/phosphate buffer. The data confirm involvement of complement activation in antiphospholipid antibody-mediated thrombogenesis and suggest that complement inhibition might ameliorate this effect.
Assuntos
Anticorpos Antifosfolipídeos/imunologia , Complemento C5/antagonistas & inibidores , Trombose/prevenção & controle , Animais , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/farmacologia , Tromboplastina/análise , Trombose/etiologia , beta 2-Glicoproteína I/imunologiaRESUMO
Stroke is the third leading cause of human death. Endothelial dysfunction, thrombogenesis, inflammatory and oxidative stress damage, and angiogenesis play an important role in cerebral ischemic pathogenesis and represent a target for prevention and treatment. Statins have been found to improve endothelial function, modulate thrombogenesis, attenuate inflammatory and oxidative stress damage, and facilitate angiogenesis far beyond lowering cholesterol levels. Statins have also been proved to significantly decrease cardiovascular risk and to improve clinical outcome. Could statins be the new candidate agent for the prevention and therapy in ischemic stroke? In recent years, a vast expansion in the understanding of the pathophysiology of ischemic stroke and the pleiotropic effects of statins has occurred and clinical trials involving statins for the prevention and treatment of ischemic stroke have begun. These facts force us to revisit ischemic stroke and consider new strategies for prevention and treatment. Here, we survey the important developments in the non-lipid dependent pleiotropic effects and clinical effects of statins in ischemic stroke.
RESUMO
BACKGROUND: Combined oral contraceptives (COCs) are considered for their thrombogenicity and the risk of premature atherosclerosis and the stroke caused by them. The aim of this study was to evaluate the relationship between chronic use of low-dose COCs (ethinyl estradiol 30 mcg + levonorgestrel 150 mcg) and endothelial dysfunction and intima-media thickness. METHODS: In a cross-sectional study, in 2011-2012, 60 healthy premenopausal women (30 cases of COC consumers and 30 controls as nonconsumers), aged between 25 and 45 years, participated in this study. They were current users for at least a 3-year period. Brachial artery flow-mediated dilatation (FMD) and common carotid artery intima-media thickness (CCA-IMT) were measured for the patients. RESULTS: The mean duration of COC consumption was 54.03 ± 27.27 months in the case group. There was a significant FMD% difference between 2 groups of cases and controls: 11 ± 3.53 versus 15.80 ± 9.22 (P = .01). In addition, a significant mean CCA-IMT thickness difference was detected: .53 ± .07 versus .44 ± .08 (P = .00). However, after multiple regression analysis and adjusting for body mass index (BMI), in COC users, no significant association between COC consumption duration and FMD% and mean CCA-IMT was observed. CONCLUSIONS: Prolonged used of low-dose COCs may cause changes in both endothelial function (measured by FMD%) and endothelial structure (measured by CCA-IMT). There was a nonsignificant inverse relationship between the duration of COC ingestion and FMD% and a nonsignificant positive relationship with CCA-IMT. Our results are in favor of early atherosclerotic changes in prolonged users of COCs.
Assuntos
Artéria Braquial/fisiopatologia , Artérias Carótidas/fisiopatologia , Espessura Intima-Media Carotídea , Anticoncepcionais Orais Combinados/efeitos adversos , Endotélio Vascular/fisiopatologia , Adulto , Aterosclerose/induzido quimicamente , Aterosclerose/patologia , Pressão Sanguínea/efeitos dos fármacos , Artéria Braquial/diagnóstico por imagem , Artérias Carótidas/diagnóstico por imagem , Combinação de Medicamentos , Endotélio Vascular/diagnóstico por imagem , Etinilestradiol/efeitos adversos , Feminino , Humanos , Levanogestrel/efeitos adversos , Adulto JovemRESUMO
In this paper, we propose a model that connects two standard inflammatory responses to viral infection, namely, elevation of fibrinogen and the lipid drop shower, to the initiation of non-thrombin-generated clot formation. In order to understand the molecular basis for the formation of non-thrombin-generated clots following viral infection, human epithelial and Madin-Darby Canine Kidney (MDCK, epithelial) cells were infected with H1N1, OC43, and adenovirus, and conditioned media was collected, which was later used to treat human umbilical vein endothelial cells and human lung microvascular endothelial cells. After direct infection or after exposure to conditioned media from infected cells, tissue surfaces of both epithelial and endothelial cells, exposed to 8 mg/mL fibrinogen, were observed to initiate fibrillogenesis in the absence of thrombin. No fibers were observed after direct viral exposure of the endothelium or when the epithelium cells were exposed to SARS-CoV-2 isolated spike proteins. Heating the conditioned media to 60 °C had no effect on fibrillogenesis, indicating that the effect was not enzymatic but rather associated with relatively thermally stable inflammatory factors released soon after viral infection. Spontaneous fibrillogenesis had previously been reported and interpreted as being due to the release of the alpha C domains due to strong interactions of the interior of the fibrinogen molecule in contact with hydrophobic material surfaces rather than cleavage of the fibrinopeptides. Contact angle goniometry and immunohistochemistry were used to demonstrate that the lipids produced within the epithelium and released in the conditioned media, probably after the death of infected epithelial cells, formed a hydrophobic residue responsible for fibrillogenesis. Hence, the standard inflammatory response constitutes the ideal conditions for surface-initiated clot formation.
Assuntos
Fibrinogênio , Humanos , Cães , Animais , Fibrinogênio/química , Fibrinogênio/metabolismo , Trombina/metabolismo , Trombina/farmacologia , Células Madin Darby de Rim Canino , Células Endoteliais da Veia Umbilical Humana , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Coagulação Sanguínea , COVID-19/virologia , COVID-19/metabolismo , Meios de Cultivo Condicionados/farmacologia , Meios de Cultivo Condicionados/química , Células Endoteliais/metabolismo , Células Endoteliais/virologia , Células Epiteliais/virologia , Células Epiteliais/metabolismoRESUMO
Oxidative stress and iron accumulation-induced ferroptosis occurs in injured vascular cells and can promote thrombogenesis. Transferrin receptor 1 (encoded by the TFRC gene) is an initial element involved in iron transport and ferroptosis and is highly expressed in injured vascular tissues, but its role in thrombosis has not been determined. To explore the potential mechanism and therapeutic effect of TFRC on thrombogenesis, a DVT model of femoral veins (FVs) was established in rats, and weighted correlation network analysis (WGCNA) was used to identify TFRC as a hub protein that is associated with thrombus formation. TFRC was knocked down by adeno-associated virus (AAV) or lentivirus transduction in FVs or human umbilical vein endothelial cells (HUVECs), respectively. Thrombus characteristics and ferroptosis biomarkers were evaluated. Colocalization analysis, molecular docking and coimmunoprecipitation (co-IP) were used to evaluate protein interactions. Tissue-specific TFRC knockdown alleviated iron overload and redox stress, thereby preventing ferroptosis in injured FVs. Loss of TFRC in injured veins could alleviate thrombogenesis, reduce thrombus size and attenuate hypercoagulability. The protein level of thrombospondin-1 (THBS1) was increased in DVT tissues, and silencing TFRC decreased the protein level of THBS1. In vitro experiments further showed that TFRC and THBS1 were sensitive to erastin-induced ferroptosis and that TFRC knockdown reversed this effect. TFRC can interact with THBS1 in the domain spanning from TSR1-2 to TSR1-3 of THBS1. Amino acid sites, including GLN320 of TFRC and ASP502 of THBS1, could be potential pharmacological targets. Erastin induced ferroptosis affected extracellular THBS1 levels and weakened the interaction between TFRC and THBS1 both in vivo and in vitro, and promoted the interaction between THBS1 and CD47. This study revealed a linked relationship between venous ferroptosis and coagulation cascades. Controlling TFRC and ferroptosis in endothelial cells can be an efficient approach for preventing and treating thrombogenesis.
Assuntos
Ferroptose , Trombose , Animais , Humanos , Ratos , Ferroptose/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Ferro/metabolismo , Simulação de Acoplamento Molecular , Receptores da Transferrina/genética , Trombose/genética , Trombose/metabolismoRESUMO
Background: Congenital fibrinogen disorders are classified based on both fibrinogen levels and the clinical phenotype. For dysfibrinogenemia, normal fibrinogen levels are typical. Key Clinical Question: We highlight the importance of comprehensive thrombotic risk assessment, including lipoprotein a (Lp[a]) and hypertriglyceridemia in association with severe thrombosis and poor wound healing in dysfibrinogenemia. Clinical Approach: We report the case of a 42-year-old male patient with a rare congenital thrombotic-related dysfibrinogenemia (fibrinogen Naples) and multiple thrombotic episodes throughout his life and an unhealing ankle wound. Despite all thrombotic episodes and surgery, the patient had undetectable D-dimer, suggestive of fibrinolytic defect, further supported by over 4-fold elevated Lp(a) levels. The last arterial thrombosis was preoperatively managed by plasma exchange, antithrombotics, and thereafter continued fibrinogen replacement therapy, under which the chronic wound has healed. Conclusion: The combination of thrombogenesis, abnormal fibrinogen, and high Lp(a) levels is a clinical and research topic deserving more attention.
RESUMO
The concept that the mammalian glycoprotein vitronectin acts as a biological 'glue' and key controller of mammalian tissue repair and remodelling activity is emerging from nearly 50 years of experimental in vitro and in vivo data. Unexpectedly, the vitronectin-knockout (VN-KO) mouse was found to be viable and to have largely normal phenotype. However, diligent observation revealed that the VN-KO animal exhibits delayed coagulation and poor wound healing. This is interpreted to indicate that VN occupies a role in the earliest events of thrombogenesis and tissue repair. VN is the foundation upon which the thrombus grows in an organised structure. In addition to sealing the wound, the thrombus also serves to protect the underlying tissue from oxidation, is a reservoir of mitogens and tissue repair mediators, and provides a provisional scaffold for the repairing tissue. In the absence of VN (e.g., VN-KO animal), this cascade is disrupted before it begins. A wide variety of biologically active species associate with VN. Although initial studies were focused on mitogens, other classes of bioactives (e.g., glycosaminoglycans and metalloproteinases) are now also known to specifically interact with VN. Although some interactions are transient, others are long-lived and often result in multi-protein complexes. Multi-protein complexes provide several advantages: prolonging molecular interactions, sustaining local concentrations, facilitating co-stimulation of cell surface receptors and thereby enhancing cellular/biological responses. We contend that these, or equivalent, multi-protein complexes facilitate VN polyfunctionality in vivo. It is also likely that many of the species demonstrated to associate with VN in vitro, also associate with VN in vivo in similar multi-protein complexes. Thus, the predominant biological function of VN is that of a master controller of the extracellular environment; informing, and possibly instructing cells 'where' to behave, 'when' to behave and 'how' to behave (i.e., appropriately for the current circumstance).
Assuntos
Coagulação Sanguínea/genética , Matriz Extracelular/metabolismo , Complexos Multiproteicos/genética , Vitronectina/genética , Animais , Glicosaminoglicanos/metabolismo , Camundongos , Camundongos Knockout , Vitronectina/metabolismo , Cicatrização/genéticaRESUMO
Catheter ablation is an effective and durable treatment option for patients with atrial fibrillation (AF). Ablation outcomes vary widely, with optimal results in patients with paroxysmal AF and diminishing results in patients with persistent or long-standing persistent AF. A number of clinical factors including obesity, hypertension, diabetes, obstructive sleep apnea, and alcohol use contribute to AF recurrence following ablation, likely through modulation of the atrial electroanatomic substrate. In this article, we review the clinical risk factors and the electro-anatomic features that contribute to AF recurrence in patients undergoing ablation for AF.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Fibrilação Atrial/tratamento farmacológico , Resultado do Tratamento , Átrios do Coração , Fatores de Risco , Ablação por Cateter/métodos , Recidiva , Veias Pulmonares/cirurgiaRESUMO
BACKGROUND AND OBJECTIVE: Studies on the association between blood fibrinogen levels and adverse outcomes in patients with acute ischemic stroke have produced controversial results. This meta-analysis aimed to examine the association of elevated fibrinogen levels with adverse outcomes in acute ischemic stroke patients. METHODS: Two authors comprehensively searched the articles indexed in PubMed and Embase databases until December 31, 2021. All cohort studies that assessed the value of fibrinogen level in predicting poor functional outcomes or all-cause mortality in acute ischemic stroke patients were included. RESULTS: Nine studies reporting on ten articles involving 16,998 patients met the inclusion criteria. For the highest versus lowest fibrinogen group, the pooled adjusted risk ratio (RR) was 1.48 (95% confidence intervals [CI] 1.17-1.87) for poor functional outcomes defined by the modified Rankin Scale ≥ 3. In addition, elevated fibrinogen was not significantly associated with an increased risk of all-cause mortality (RR 1.76; 95% CI 1.42-2.20). Subgroup analysis suggested that there was no clear association between elevated fibrinogen levels and PFO in younger acute ischemic stroke patients (RR 1.16; 95% CI 0.87-1.53). CONCLUSION: Elevated fibrinogen level at baseline is possibly an independent predictor of short-term poor functional outcome and long-term all-cause mortality, particularly in elderly acute ischemic stroke patients. Blood fibrinogen level may serve as a useful biomarker for risk classification of acute ischemic stroke patients.
Assuntos
Isquemia Encefálica , Fibrinogênio , AVC Isquêmico , Humanos , Biomarcadores , AVC Isquêmico/complicações , Fibrinogênio/análiseRESUMO
BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site-specificity remain poorly understood. Here, we present a comparative single-cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber-specific properties of the main cell types. METHODS: Single-cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S-transferase pull-down assays, coimmunoprecipitation (Co-IP), cleavage assays and shear stress experiments in vitro. RESULTS: In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up-regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down-regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (Tbx5+/- ) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs. CONCLUSIONS: This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.