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BACKGROUND: SARS-CoV-2 is a systemic disease that affects endothelial function and leads to coagulation disorders, increasing the risk of mortality. Blood levels of endothelial biomarkers such as Von Willebrand Factor (VWF), Thrombomodulin or Blood Dendritic Cell Antigen-3 (BDCA3), and uUokinase (uPA) increase in patients with severe disease and can be prognostic indicators for mortality. Therefore, the aim of this study was to determine the effect of VWF, BDCA3, and uPA levels on mortality. METHODS: From May 2020 to January 2021, we studied a prospective cohort of hospitalized adult patients with polymerase chain reaction (PCR)-confirmed COVID-19 with a SaO2 ≤ 93% and a PaO2/FiO2 ratio < 300. In-hospital survival was evaluated from admission to death or to a maximum of 60 days of follow-up with Kaplan-Meier survival curves and Cox proportional hazard models as independent predictor measures of endothelial dysfunction. RESULTS: We recruited a total of 165 subjects (73% men) with a median age of 57.3 ± 12.9 years. The most common comorbidities were obesity (39.7%), hypertension (35.4%) and diabetes (30.3%). Endothelial biomarkers were increased in non-survivors compared to survivors. According to the multivariate Cox proportional hazard model, those with an elevated VWF concentration ≥ 4870 pg/ml had a hazard ratio (HR) of 4.06 (95% CI: 1.32-12.5) compared to those with a lower VWF concentration adjusted for age, cerebrovascular events, enoxaparin dose, lactate dehydrogenase (LDH) level, and bilirubin level. uPA and BDCA3 also increased mortality in patients with levels ≥ 460 pg/ml and ≥ 3600 pg/ml, respectively. CONCLUSION: The risk of mortality in those with elevated levels of endothelial biomarkers was observable in this study.
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Biomarcadores , COVID-19 , Trombomodulina , Ativador de Plasminogênio Tipo Uroquinase , Fator de von Willebrand , Humanos , COVID-19/mortalidade , COVID-19/sangue , Masculino , Fator de von Willebrand/metabolismo , Fator de von Willebrand/análise , Pessoa de Meia-Idade , Feminino , Biomarcadores/sangue , Idoso , Ativador de Plasminogênio Tipo Uroquinase/sangue , Trombomodulina/sangue , Estudos Prospectivos , Prognóstico , SARS-CoV-2 , Adulto , Endotélio Vascular/fisiopatologia , Mortalidade Hospitalar , Modelos de Riscos ProporcionaisRESUMO
Clinical interpretation of genetic variants in the context of the patient's phenotype is a time-consuming and costly process. In-silico analysis using in-silico prediction tools, and molecular modeling have been developed to predict the influence of genetic variants on the quality and/or quantity of the resulting translated protein, and in this way, to alert clinicians of disease likelihood in the absence of previous evidence. Our objectives were to evaluate the success rate of the in-silico analysis in predicting the disease-causing variants as pathogenic and the single-nucleotide variants as neutral, and to establish the reliability of in-silico analysis for determining pathogenicity or neutrality of von Willebrand factor gene-associated genetic variants. Using in-silico analysis, we studied pathogenicity in 31 disease-causing variants, and neutrality in 61 single-nucleotide variants from patients previously diagnosed as type 2 von Willebrand disease. Disease-causing variants and non-synonymous single-nucleotide variants were explored by in-silico tools that analyze the amino acidic sequence. Intronic and synonymous single-nucleotide variants were analyzed by in-silico methods that evaluate the nucleotidic sequence. We found a consistent agreement between predictions achieved by in-silico prediction tools and molecular modeling, both for defining the pathogenicity of disease-causing variants and the neutrality of single-nucleotide variants. Based on our results, the in-silico analysis would help to define the pathogenicity or neutrality in novel genetic variants observed in patients with clinical and laboratory phenotypes suggestive of von Willebrand disease.
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Doenças de von Willebrand , Fator de von Willebrand , Humanos , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo , Relevância Clínica , Reprodutibilidade dos Testes , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genética , NucleotídeosRESUMO
Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder that can precede the diagnosis of multiple myeloma. MGUS is characterized by the presence of a monoclonal paraprotein without evidence of multiple myeloma or other lymphoplasmacytic malignancies. Even though MGUS is an asymptomatic condition that does not require management strategies other than periodic follow-up to prevent complications, secondary nonmalignant diseases may arise, requiring control of the plasma cell clone. Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that occurs in patients with no prior personal or family history of bleeding. It is associated with several other disorders, such as neoplasia, mainly hematological (including MGUS and other lymphoproliferative disorders), autoimmune, infectious and cardiac diseases. At diagnosis, patients usually present with cutaneous and mucosal bleeding, including gastrointestinal bleeding. Here, we report a case of a patient with MGUS who developed AVWS after one year of follow-up. The patient was refractory to glucocorticoids and cyclophosphamide and achieved remission only after monoclonal paraprotein was eradicated following treatment with bortezomib and dexamethasone. Our report sdemonstrates that, for refractory cases, eradication of the monoclonal paraprotein may be necessary to treat bleeding complications due to MGUS-associated AVWS.
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Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Paraproteinemias , Doenças de von Willebrand , Humanos , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/tratamento farmacológico , Bortezomib/uso terapêutico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Paraproteinemias/complicações , Paraproteinemias/tratamento farmacológico , Doenças de von Willebrand/complicações , Doenças de von Willebrand/tratamento farmacológico , Proteínas do MielomaRESUMO
La enfermedad de von Willebrand (EVW) es el trastorno hemorrágico hereditario más común, y se caracteriza por presentar disminución de la capacidad del factor von Willebrand (FVW) de unirse a las plaquetas y al colágeno de la matriz extracelular durante la hemostasia primaria, debido a defectos cuantitativos o cualitativos. La EVW se clasifica en tres fenotipos principales: el 1 y el 3 que son trastornos cuantitativos, y el 2 que se subclasifica en 2A, 2B, 2M y 2N, y refleja los trastornos cualitativos. Para su diagnóstico son necesarios varios pasos: 1) la evaluación del historial de sangrado personal y familiar del paciente, 2) detección inicial de trastornos hemorrágicos, 3) pruebas para la detección de la EVW, 4) pruebas para la tipificación de la EVW, y 5) el análisis molecular. Tanto la subclasificación de la EVW como su diagnóstico continúan planteando desafíos importantes, motivo por el cual se realiza esta revisión, de manera que los profesionales de la salud tengan una guía que los oriente al momento de tener pacientes con algún trastorno hemorrágico que amerite descartar una EVW e implementar un tratamiento adecuado
von Willebrand disease (VWD) is the most common hereditary bleeding disorder, and is characterized by a decreased ability of the von Willebrand factor (VWF) to bind to platelets and extracellular matrix collagen during primary hemostasis, due to quantitative or qualitative defects. VWD is classified into three main phenotypes: 1 and 3, which are quantitative disorders, and 2 (2A, 2B, 2M and 2N) that reflects qualitative disorders. Several steps are necessary for its diagnosis: 1) evaluation of the patient's personal and family bleeding history, 2) initial screening tests for bleeding disorders, 3) tests for the detection of VWD, 4) tests for the classification of VWD, and 5) molecular analysis. Both the subclassification of VWD and its diagnosis continue to represent important challenges, which we aimed to describe in this review, so that health professionals have a guide to assist them when they have patients with a bleeding disorder that requires exclusion of VWD, and implementation of an appropriate treatment.
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Humanos , Doenças de von Willebrand , Fator de von Willebrand , Ristocetina , Agregação Plaquetária , Genética , Hemorragia , Hemostasia , AntígenosRESUMO
The von Willebrand disease (vWD) is the most common hereditary bleeding disorder caused by defects of the von Willebrand Factor (vWF), a large extracellular protein in charge of adhering platelets to sites of vascular lesions. vWF performs this essential homeostatic task via specific protein-protein interactions between the vWF A1 domain and the platelet receptor, the glycoprotein Ib alpha (GPIBα). The two naturally occurring vWF A1 domain mutations G1324A and G1324S, near the GPIBα binding site, induce a dramatic decrease in platelet adhesion, resulting in a bleeding disorder classified as type 2M vWD. However, the reason for the drastic phenotypic response induced by these two supposedly minor modifications remains unclear. We addressed this question using a combination of equilibrium-molecular dynamics (MD) and nonequilibrium MD-based free energy simulations. Our data confirms that both mutations maintain the highly stable Rossmann fold of the vWF A1 domain. G1324A and G1324S mutations hardly changed the per-residue flexibility of the A1 domain but induced a global conformational change affecting the region near the binding site to GPIBα. Furthermore, we observed two significant changes in the vWF A1 domain upon mutation, the global redistribution of the internal mechanical stress and the increased thermodynamic stability of the A1 domain. These observations are consistent with previously reported mutations increasing the melting temperature. Overall, our results support the idea of thermodynamic conformational restriction of A1-before the binding to GPIBα-as a crucial factor determining the loss-of-function of the G1324A(S) vWD mutants.
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Doenças de von Willebrand , Fator de von Willebrand , Humanos , Sítios de Ligação , Plaquetas/metabolismo , Ligação Proteica , Termodinâmica , Doenças de von Willebrand/genética , Fator de von Willebrand/química , Fator de von Willebrand/genéticaRESUMO
Obesity (OB) is a major healthcare problem that results from long-term energy imbalance. Adipokines and pro-inflammatory cytokines facilitate adipose tissue (AT) remodeling to safely store excess nutrients. B-cell activating factor (BAFF) is a newly described adipokine whose role in enhancing adipogenesis has been reported. The present study aimed to evaluate serum BAFF association with adiposity distribution, serum adipokines, pro-inflammatory cytokines, and metabolic and endothelial dysfunction markers. The study included 124 young Mexican adults with no diagnosed comorbidities, divided according to their BMI. Anthropometric measurements, blood counts, and serum molecules (i.e., glucose, lipid profile, insulin, leptin, pro- and anti-inflammatory cytokines, von Willebrand factor (vWF), and BAFF) were assessed. The analysis showed positive correlation between BAFF and increased fat mass in all anthropometric measurements (p < 0.0001). BAFF augmentation was related to systemic inflammatory environment (p < 0.05), and linked with insulin resistance status (p < 0.05). BAFF increment was also correlated with early endothelial damage markers such as vWF (p < 0.0001). Linear regression analysis showed a role for BAFF in predicting serum vWF concentrations (p < 0.01). In conclusion, our data show that BAFF is an adipokine dynamically related to OB progression, insulin resistance status, and systemic inflammatory environment, and is a predictor of soluble vWF augmentation, in young overweight and obese Mexican subjects.
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Archaebacterias are considered a unique source of novel biomaterials of interest for nanomedicine. In this perspective, the effects of nanoarchaeosomes (ARC), which are nanovesicles prepared from polar lipids extracted from the extreme halophilic Halorubrum tebenquinchense, on human umbilical vein endothelial cells (HUVEC) were investigated in physiological and under inflammatory static conditions. Upon incubation, ARC (170 nm mean size, -41 mV ζ) did not affect viability, cell proliferation, and expression of intercellular adhesion molecule-1 (ICAM-1) and E-selectin under basal conditions, but reduced expression of both molecules and secretion of IL-6 induced by lypopolysaccharide (LPS), Pam3CSK4 or Escherichia coli. Such effects were not observed with TNF-α or IL-1ß stimulation. Interestingly, ARC significantly decreased basal levels of von Willebrand factor (vWF) and levels induced by all stimuli. None of these parameters was altered by liposomes of hydrogenated phosphatidylcholine and cholesterol of comparable size and concentration. Only ARC were endocytosed by HUVEC and reduced mRNA expression of ICAM-1 and vWF via NF-ĸB and ERK1/2 in LPS-stimulated cells. This is the first report of the anti-inflammatory effect of ARC on endothelial cells and our data suggest that its future use in vascular disease may hopefully be of particular interest.
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Apicomplexan parasites transmitted by vectors, including Babesia spp. and Plasmodium spp., cause severe disease in both humans and animals. These parasites have a complex life cycle during which they migrate, invade, and replicate in contrasting hosts such as the mammal and the invertebrate vector. The interaction of parasites with the host cell is mediated by adhesive proteins which play a key role in the different cellular processes regarding successful progression of the life cycle. Thrombospondin related anonymous protein (TRAP) is a superfamily of adhesins that are involved in motility, invasion and egress of the parasite. These proteins are stored and released from apical organelles and have either one or two types of adhesive domains, namely thrombospondin type 1 repeat and von Willebrand factor type A, that upon secretion are located in the extracellular portion of the molecule. Proteins from the TRAP superfamily have been intensively studied in Plasmodium species and to a lesser extent in Babesia spp., where they have proven to be functionally relevant throughout the entire parasite's journey both in the arthropod vector and in the mammalian host. In recent years new findings provided answers to the role of TRAP proteins and in some cases the function of these adhesins during the parasite's life cycle was redefined. In this review we will discuss the current knowledge of the diverse roles of the TRAP superfamily in vector-borne parasites from Class Aconoidasida. We will focus on the varied approaches that allowed the understanding of protein function and the relevance of TRAP- superfamily throughout the entire parasite's cell cycle.
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Babesia , Parasitos , Plasmodium , Animais , Babesia/genética , Mamíferos/metabolismo , Parasitos/metabolismo , Plasmodium/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , TrombospondinasRESUMO
The utility of mouse models to dissect the molecular basis of hemostasis and thrombosis is now well established. The anucleate properties of circulating blood platelet and their specialized release from mature megakaryocytes makes the use of in vivo models all the more informative and powerful. Indeed, they are powerful but there do exist limitations. Here, we review the contributions of mouse models to the pathogenesis of the Bernard-Soulier syndrome, their use in platelet-specific gene expression, the recent development of mice expressing both human GPIb-IX and human von Willebrand factor (VWF), and finally the use of GPIb-IX mouse models to examine the impact of platelet biology beyond clotting. The humanization of the receptor and ligand axis is likely to be a major advancement in the characterization of therapeutics in the complex pathogenesis that drives thrombosis. When appropriate, we highlight some limitations of each mouse model, but this is not to minimize the contributions these models to the field. Rather, the limitations are meant to provide context for any direct application to the important mechanisms supporting human primary hemostasis and thrombosis.
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Síndrome de Bernard-Soulier , Trombose , Animais , Síndrome de Bernard-Soulier/genética , Plaquetas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Trombose/metabolismo , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
RESUMEN La enfermedad von Willebrand es el desorden hemorrágico hereditario más común, que se origina por la deficiencia del factor von Willebrand, la cual provoca una adhesión y agregación plaquetaria defectuosa. Se caracteriza por un tiempo de sangrado y tiempo parcial de tromboplastina prolongados, con bajos valores del factor VIII, y aumento de fragilidad capilar, pero con recuento normal de plaquetas. El tratamiento odontológico en un paciente con enfermedad von Willebrand, debe ser individualizado de acuerdo con la severidad de la condición del paciente, así como coordinado con el hematólogo, quien debe de determinar el tipo de enfermedad y la necesidad de la terapia de reemplazo del factor según diagnóstico específico previo al manejo de este. Mediante esta revisión bibliográfica se desea reforzar el conocimiento al odontólogo de este trastorno hemorrágico, ya que con ello se pueden evitar o minimizar posibles complicaciones de sangrado durante el tratamiento odontológico.
ABSTRACT von Willebrand disease is the most common inherited bleeding disorder, caused by von Willebrand factor deficiency, which causes defective platelet adhesion and aggregation. It is characterized by a prolonged bleeding time and partial thromboplastin time, with low levels of factor VIII, and increased capillary fragility, but with a normal platelet count. Dental treatment in a patient with von Willebrand disease must be individualized according to the severity of the patient's condition, as well as coordinated with the hematologist, who must determine the type of disease and the need for factor replacement therapy, prior to the patient management. Through this bibliographic review, it wants to reinforce the dentist's knowledge of this bleeding disorder, since this can prevent or minimize possible bleeding complications during dental treatment.
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The swine mulefoot (SM) is a rare condition characterized by a non-cloven hoof due to the partial or total fusion of the phalanges. No comprehensive study has been conducted to identify associated markers with this phenotype until now. We aimed to characterize the association between SNP and the mulefoot phenotype using a Genome-Wide Association Study (GWAS). An experimental population was produced using a half-sib mating where the male had the mulefoot phenotype and the females (n = 6) had cloven hoofs. The cross resulted in 27 (47%) animals with the mulefoot characteristic and 30 (53%) normal animals, indicating the possible dominant gene action. Animals were further genotyped using the Illumina PorcineSNP50k BeadChip, and SNPs were tested for associations. Twenty-nine SNPs located on the SSC15, SSC4, and SSCX were associated with the mulefoot phenotype (p-value <5 × 10-5). Six markers were found in the intronic regions of VWC2L, CATIP, PDK3, PCYT1B, and POLA1 genes. The marker rs81277626, on SSC15:116,886,110 bp, is located in the Von Willebrand Factor C Domain (VWC2L), a possible functional candidate gene. The VWC2L is part of a biological process involved with the bone morphogenetic protein (BMP) signaling pathway, previously associated with syndactyly in other species. In conclusion, the identified markers suggest the involvement of the VWC2L gene in the SM phenotype in this population.
Assuntos
Doenças do Pé/veterinária , Estudos de Associação Genética , Casco e Garras/anormalidades , Polimorfismo de Nucleotídeo Único , Animais , Feminino , Doenças do Pé/patologia , Estudos de Associação Genética/veterinária , Genótipo , Masculino , Fenótipo , Suínos/genéticaRESUMO
PURPOSE: Hyperglycemia is one of the factors responsible for the molecular alterations that modify hemostasis. The aim of this study was to determine the levels of circulating molecules that have a prothrombotic impact on the child and adolescent population with type 1 diabetes mellitus. METHODS: There were 35 patients with type 1 diabetes mellitus (11.0±2.5 years of age and a median 3.7±2.0 years of the disease) with no vascular complications and 20 healthy controls with similar age, sex, and body mass index included in the study. The evaluated parameters were fibrinogen, plasminogen activator inhibitor-1 (PAI1), von Willebrand factor antigen, and standard coagulation tests (platelet count, prothrombin time, and activated partial thromboplastin time). Glycemic control was evaluated by hemoglobin A1c and fasting blood glucose tests, and the presence of retinopathy and nephropathy was ruled out. The data obtained were analyzed by IBM SPSS Statistics ver. 20.0 and expressed as mean±standard deviation. The Pearson correlation coefficient was applied to investigate correlations between variables. RESULTS: Diabetic patients showed significantly higher levels of fibrinogen (308±66 mg/dL vs. 246±18 mg/dL, P=0.0001), PAI-1 (41.6±12 ng/mL vs. 11.7±1.0 ng/mL, P=0.0001), and von Willebrand factor antigen (284%±55% vs. 121%±19%, P=0.0001). However, standard coagulation tests did not show differences between the 2 groups. PAI-1 was correlated with glycemia, hemoglobin A1c, fibrinogen, and von Willebrand factor antigen. CONCLUSION: Elevated levels of fibrinogen, PAI-1, and von Willebrand factor antigen were found in the pediatric and adolescent population with type 1 diabetes mellitus, which suggests a prothrombotic state.
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Resumen La presencia o ausencia de los antígenos del sistema ABO entre otros factores se han relacionado con los niveles plasmáticos del factor von Willebrand (VWF) debido a su influencia en la proteólisis por la ADAMTS 13; la actividad de este sistema eritrocitario puede incidir en eventos trombóticos o hemorrágicos. El propósito de este estudio fue determinar si los pacientes diagnosticados con la enfermedad de von Willebrand pertenecían al grupo sanguíneo O y si los niveles de VWF y FVIII eran más bajos que los de los grupos no-O. El grupo sanguíneo fue identificado por un método directo en tubo y el VWF y FVIII se midieron mediante ensayos de coagulación. Se analizó un total de 64 pacientes, el 29,4% eran mayores de 40 años, el 100% presentaron valores más bajos del VWF que los grupos no-O, el 64% de los pacientes presentaron una concentración del FVIII de 6-49% inferior al rango normal establecido y el 78,51% fueron tipificados como del grupo sanguíneo O. El análisis estadístico demostró una relación estadísticamente significativa entre los niveles de VWF y el grupo sanguíneo. Se determinó que existe una relación entre el sistema ABO y el VWF-FVIII (p<0,05); sin embargo, esto no significa que sea la única causa de la existencia de un nivel bajo del factor. Estos datos indican la necesidad de mayores estudios en la población de pacientes con la enfermedad y la necesidad de determinar los tipos de von Willebrand y su relación con el grupo sanguíneo.
Abstract The presence or absence of antigens of the ABO system, among other factors, have been related to plasma levels of von Willebrand factor (VWF) due to its influence on proteolysis by ADAMTS 13. The activity of this erythrocyte system may influence on thrombotic or hemorrhagic events. The purpose of this study was to determine if the patients diagnosed with von Willebrand disease belonged to the O blood group and the VWF and FVIII levels were lower than those of the other blood groups. The blood group was identified by direct tube method and the VWF and FVIII were measured by coagulation tests. A total of 64 patients were analised, 29.4% were older than 40, 100% presented lower values of VWF than the non-O groups. A total of 64% of the patients presented a lower concentration of 6-49% in FVIII at the established normal range and 78.51% were typified as blood group O. Statistical analysis showed a statistically significant relationship between VWF levels and blood group. It was determined that there is a relationship between the ABO system and the VWF-FVIII (p<0.05). However, this does not mean that is the only cause of the existence of a low level of these factors. These data indicate the need for further studies in the population of patients with von Willebrand disease in order to determine the von Willebrand types and their relationship with the blood group.
Resumo A presença ou ausência dos antígenos do sistema ABO, entre outros fatores, tem sido relacionada aos níveis plasmáticos do fator de von Willebrand (VWF) devido à sua influência na proteólise pelo ADAMTS 13; a atividade desse sistema eritrocitário pode afetar eventos trombóticos ou hemorrágicos. O objetivo deste estudo foi determinar se os pacientes com diagnóstico de doença de von Willebrand pertenciam ao grupo sanguíneo O e se os níveis de VWF e FVIII eram inferiores aos dos grupos não-0. O grupo sanguíneo foi identificado por um método direto em tubo e o VWF e o FVIII foram medidos por testes de coagulação. Foram analisados 64 pacientes, 29,4% tinham idade superior a 40 anos, 100% apresentaram valores mais baixos do VWF que os grupos não-O e 64% dos pacientes apresentaram concentração de FVIII 6-49% menor à faixa normal estabelecida, e 78,51% foram tipificados como do grupo sanguíneo O. A análise estatística mostrou uma relação estatisticamente significativa entre os níveis de VWF e o grupo sanguíneo. Foi determinado que existe uma relação entre o sistema ABO e o VWF-FVIII (p<0,05), no entanto, isso não significa que seja a única causa da existência de um baixo nível do fator. Esses dados indicam a necessidade de novos estudos na população de pacientes com a doença e a necessidade de determinar os tipos de von Willebrand e sua relação com o grupo sanguíneo.
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Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Doenças de von Willebrand/etiologia , Sistema ABO de Grupos Sanguíneos/análiseRESUMO
Among COVID-19 hospitalized patients, high incidence of alterations in inflammatory and coagulation biomarkers correlates with a poor prognosis. Comorbidities such as chronic degenerative diseases are frequently associated with complications in COVID-19 patients. The aim of this study was to evaluate inflammatory and procoagulant biomarkers in COVID-19 patients from a public hospital in Mexico. Blood was sampled within the first 48 h after admission in 119 confirmed COVID-19 patients that were classified in 3 groups according to oxygen demand, evolution and the severity of the disease as follows: 1) Non severe: nasal cannula or oxygen mask; 2) Severe: high flow nasal cannula and 3) Death: mechanical ventilation eventually leading to fatal outcome. Blood samples from 20 healthy donors were included as a Control Group. Analysis of inflammatory and coagulation biomarkers including D-dimer, interleukin 6, interleukin 8, PAI-1, P-selectin and VWF was performed in plasma. Routine laboratory and clinical biomarkers were also included and compared among groups. Concentrations of D-dimer (14.5 ± 13.8 µg/ml) and PAI-1 (1223 ± 889.6 ng/ml) were significantly elevated in severe COVID-19 patients (P < 0.0001). A significant difference was found in interleukin-6, PAI-1 and P-selectin in non-severe and healthy donors when compared to Severe COVID-19 and deceased patients (P < 0.001). VWF levels were also significantly different between severe patients (153.5 ± 24.3 UI/dl) and non-severe ones (133.9 ± 20.2 UI/dl) (P < 0.0001). WBC and glucose levels were also significantly elevated in patients with Severe COVID-19. Plasma concentrations of all prothrombotic biomarkers were significantly higher in patients with a fatal outcome.
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Biomarcadores/sangue , COVID-19/sangue , Mediadores da Inflamação/sangue , SARS-CoV-2 , Adulto , Idoso , COVID-19/complicações , COVID-19/epidemiologia , Estudos de Casos e Controles , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hospitalização , Humanos , Interleucina-6/sangue , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Selectina-P/sangue , Pandemias , Inibidor 1 de Ativador de Plasminogênio/sangue , Prognóstico , Índice de Gravidade de Doença , Trombose/sangue , Trombose/etiologia , Fator de von Willebrand/metabolismoRESUMO
Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.
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COVID-19/complicações , Placenta/irrigação sanguínea , Placenta/patologia , Complicações Cardiovasculares na Gravidez/etiologia , Complicações Infecciosas na Gravidez/etiologia , Trombose/etiologia , Adulto , Antígenos CD/análise , COVID-19/patologia , COVID-19/virologia , Caderinas/análise , Claudina-5/análise , Endotélio/irrigação sanguínea , Endotélio/patologia , Endotélio/virologia , Feminino , Humanos , Recém-Nascido , Microvasos/patologia , Microvasos/virologia , Gravidez , Complicações Cardiovasculares na Gravidez/patologia , Complicações Cardiovasculares na Gravidez/virologia , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , SARS-CoV-2/isolamento & purificação , Trombose/patologia , Trombose/virologia , Adulto Jovem , Fator de von Willebrand/análiseRESUMO
INTRODUCTION: von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays an important role in haemostasis. von Willebrand disease (VWD) is an inherited heterogeneous bleeding disorder caused by either a quantitative or qualitative defect of VWF. Type 3 VWD, the most severe form of the disease, leads to complete quantitative VWF deficiency. AIM: The present study aims to investigate the molecular pathogenesis of type 3 VWD patients from Southern Brazil. METHODS: The VWF gene was sequenced in 26 cases clinically diagnosed with type 3 VWD by next-generation sequencing using Ion Torrent PGM. RESULTS: In 25 patients, we were able to identify both disease-causing variants. We identified 72 different variants: 31 intronic and 41 exonic. Five novel variants were found: c.6976+5G>T; c.6885_6886insC; c.3378C>T (p.Cys1126); c.3346_3347insCCA; and c.2503G>T (p.Glu835*). Variants p.Pro2063Ser and p.Arg324* co-segregated in 17 patients, 15 of them in homozygosity. CONCLUSION: Our results may contribute to the discussion on whether the variant p.Pro2063Ser is pathogenic or not. Finally, the presence of a common haplotype in patients bearing these two variants suggests a founder effect for this variant in our region.
Assuntos
Doença de von Willebrand Tipo 3 , Fator de von Willebrand , Substituição de Aminoácidos , Brasil , Hemostasia , Humanos , Doença de von Willebrand Tipo 3/genética , Doenças de von Willebrand/genética , Fator de von Willebrand/genéticaRESUMO
Sickle cell disease (SCD) comprises a group of genetic disorders characterized by the presence of the hemoglobin (Hb) S in homozygosis or in heterozygosis with some other Hb variant or in interaction with thalassemia. SCD is characterized by a very complex pathophysiology, which determines a wide variability of clinical manifestations, including a chronic state of hypercoagulability responsible for the increased risk of thromboembolic events. ADAMTS13 and von Willebrand factor (VWF) play an important role in arterial and venous thrombosis. Thus, the aim of this study was to understand how the ADAMTS13-VWF axis behaves in sickle cell disease, as well as whether there is an association of these markers with the use of hydroxyurea (HU). This is a cross-sectional study conducted with 40 patients diagnosed with SCD and 40 healthy individuals. The analysis of the ADAMTS13-VWF axis was comparatively performed between groups of patients and controls and, afterwards, between patients with SCD who were users and non-users of HU. ADAMTS13 activity, ADAMTS13 activity/VWF:Ag, and ADAMTS13:Ag/VWF:Ag ratios were significantly lower and VWF:Ag levels significantly higher in SCD patients when compared to the controls. There was no statistically significant difference in ADAMTS13:Ag and VWF collagen binding (VWF:CB) levels between the groups evaluated. Among the categories of HU use, there was no statistically significant difference in any of the evaluated markers. As a conclusion, we could observe that the ADAMTS13-VWF axis is altered in SCD when compared to healthy individuals and that there is no association between these markers and the use of HU.
Assuntos
Proteína ADAMTS13/sangue , Anemia Falciforme/sangue , Fator de von Willebrand/metabolismo , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Estudos Transversais , Feminino , Humanos , Hidroxiureia/administração & dosagem , Masculino , Trombose Venosa/sangue , Trombose Venosa/etiologiaRESUMO
BACKGROUND: There are only a few reports evaluating the applicability of endothelial-damage markers analysis by immunohistochemistry (IHC) in kidney allograft samples. This study analyzed the expression of Caveolin-1 (Cav), von Willebrand factor (Vwf), and T-cadherin (Cad) in kidney biopsies and their association with antibody-mediated injury. METHODS: In this retrospective study, 114 cases with antibody-mediated changes (Banff, 2020) and 72 with interstitial fibrosis/tubular atrophy were selected. IHC for Cav, Vwf and Cad was performed and evaluated according to their qualitative expression in peritubular capillaries. The cases were grouped according to the presence of microvascular inflammation (MVI), donor-specific antibodies (DSA), C4d positivity and antibody-mediated rejection (AMR). A level of significance < 0.05 was adopted. RESULTS: Vwf expression was associated with MVI (p < 0.001), DSA (p = 0.016), C4d (p < 0.001) and AMR (p < 0.001), and was higher in DSA+/C4d+ cases despite MVI (p < 0.001). The expression of Cad correlated with MVI (p = 0.015), C4d (p = 0.005) and AMR (p = < 0.001). Cad was more expressed in chronic AMR compared with acute/active cases (p = 0.001). Cav expression was associated with MVI (p = 0.029) and AMR (p = 0.016) and was also higher in chronic AMR (p = 0.049). A combined score of Vwf and Cad was higher in AMR when compared with C4d without rejection and IF/TA cases (p < 0.001). CONCLUSION: Vwf, Cad and Cav expression shows association with antibody-mediated injury and may be helpful to support AMR diagnosis.
Assuntos
Caderinas/análise , Caveolina 1/análise , Rejeição de Enxerto/metabolismo , Imuno-Histoquímica , Isoanticorpos/análise , Transplante de Rim/efeitos adversos , Rim/química , Fator de von Willebrand/análise , Adulto , Biomarcadores/análise , Biópsia , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Rim/imunologia , Rim/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 0.1%, characterised by quantitative or functional deficiency of von Willebrand factor (VWF). VWD diagnosis is based on symptomology, biochemical and genetic tests, but limited laboratory resources and VWD heterogeneity still generate an important subdiagnosis gap worldwide and in our country. AIM: To identify the type and subtype of VWD in a cohort of patients with a history of excessive bleeding in Western Mexico. METHODS: This prospective cohort study from 2012 to 2019 included patients with mucocutaneous bleeding or abnormal laboratory tests. A standardised questionnaire and confirmatory tests were applied: FVIII:C, VWF activity, VWF antigen, and VWF multimeric analysis. RESULTS: Of the 297 patients recruited, 207 (69.7%) were excluded because their values exceeded 50% in VWF activity and VWF antigen. Of those 90 remaining, 54 (18.2%) had low VWF, and only 36 patients (12.1%) were diagnosed with VWD. Among them, 17 (47.2%) had quantitative deficiencies, of whom 14 were assigned as type 1 and 3 as type 3.The remaining 19 cases were diagnosed as type 2 (52.8%): type 2A and 2B were the most frequent with 6 and 7 cases respectively; 4 cases were possible type 2M and two suggestive of 2N, however, this was not confirmed. CONCLUSION: This study highlights the challenges of VWD diagnosis using a comprehensive panel of diagnostic tests which should extend to supplemental tests of VWF:CB, VWF:FVIIIB, and sequencing the VWD gene to confirm the results from the panel assays.