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INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII Ë 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.
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Factor VIII , Hemofilia A , Tolerancia Inmunológica , Hemofilia A/genética , Hemofilia A/inmunología , Hemofilia A/tratamiento farmacológico , Humanos , Factor VIII/inmunología , Factor VIII/genética , Factor VIII/uso terapéutico , Tolerancia Inmunológica/genética , Masculino , Niño , Preescolar , Adulto , Adolescente , Femenino , Adulto Joven , Isoanticuerpos/inmunología , Isoanticuerpos/sangre , Mutación INDELRESUMEN
Background: Severe yellow fever infection (YFI) may be complicated by a hemorrhagic diathesis. However, the hemostasis profile of YFI has rarely been reported. Objectives: The aim of this study was to characterize the hemostatic features of YFI by using a rotational thromboelastometry (ROTEM). Methods: We evaluated clinical, laboratory, and ROTEM parameters in adults with severe YFI and their correlation with hemostatic variables according to bleeding and death. Results: A total of 35 patients were included (median age, 49 years). ROTEM was performed in 22 patients, of whom 21 (96%) presented bleeding and 4 (18%) died. All patients who died had major bleeding. Patients who died presented prolonged clotting time (CT; median, 2326 seconds; IQR, 1898-2986 seconds) and reduced alpha angle (median, 12°; IQR, 12°-15°) in comparison with patients who had minor (median CT, 644 seconds; IQR, 552-845 seconds and alpha angle, 47°; IQR, 28°-65°) and major (median CT, 719 seconds; IQR, 368-1114 seconds and alpha angle, 43°; IQR, 32°-64°) bleeding who survived. In patients who had bleeding, CT showed a strong negative correlation with factor (F)V (r = -.68), FIX (r = -.84), and FX (r = -.63) as well as alpha angle showed a strong negative correlation with FIX (r = -.92). In patients who died, the correlations were even stronger. A total of 19/21 (90%) patients presented hypocoagulability assessed by ROTEM. Conclusion: Hypocoagulabitity is the hallmark of the bleeding diathesis of severe YFI. Abnormal CT and alpha angle associated with death and could be used as potential predictors of adverse outcome in severe YFI.
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This article discusses the impacts of the COVID-19 pandemic on health systems and its effects on the working conditions and mental health of health professionals and invisible health workers. It presents data on deaths among health professionals, highlighting the need for better and safer working conditions and improvements in public management. We emphasize WHO/PAHO recommendations and the need for equitable vaccine distribution, including poor countries and vulnerable populations. We also highlight the impacts of interrupting essential health services, such as the treatment of chronic conditions and infectious disease prevention, and the damage caused by the dissemination of fake news, stressing the need to improve access to correct and safe health information.
Este artigo apresenta os impactos da pandemia nos sistemas de saúde e as repercussões nas condições de trabalho e saúde mental dos profissionais de saúde e trabalhadores invisíveis da saúde no contexto da COVID-19. Apresenta a mortalidade entre os profissionais da saúde destacando a necessidade de melhores condições de trabalho e de segurança para os trabalhadores da saúde e melhora da gestão pública. Enfatiza as recomendações da OMS/OPAS, a necessidade de vacinação equânime, incluindo os países mais pobres e as populações mais vulneráveis. Relata os impactos da interrupção dos serviços essenciais em saúde, como para as doenças crônicas e infecciosas, e os prejuízos causados pela disseminação de informações falsas pela rede social, e lembra da necessidade de veiculação de informações corretas e seguras na saúde.
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COVID-19 , Humanos , Pandemias/prevención & control , Condiciones de Trabajo , Brasil/epidemiología , Personal de Salud/psicologíaRESUMEN
Resumo Este artigo apresenta os impactos da pandemia nos sistemas de saúde e as repercussões nas condições de trabalho e saúde mental dos profissionais de saúde e trabalhadores invisíveis da saúde no contexto da COVID-19. Apresenta a mortalidade entre os profissionais da saúde destacando a necessidade de melhores condições de trabalho e de segurança para os trabalhadores da saúde e melhora da gestão pública. Enfatiza as recomendações da OMS/OPAS, a necessidade de vacinação equânime, incluindo os países mais pobres e as populações mais vulneráveis. Relata os impactos da interrupção dos serviços essenciais em saúde, como para as doenças crônicas e infecciosas, e os prejuízos causados pela disseminação de informações falsas pela rede social, e lembra da necessidade de veiculação de informações corretas e seguras na saúde.
Abstract This article discusses the impacts of the COVID-19 pandemic on health systems and its effects on the working conditions and mental health of health professionals and invisible health workers. It presents data on deaths among health professionals, highlighting the need for better and safer working conditions and improvements in public management. We emphasize WHO/PAHO recommendations and the need for equitable vaccine distribution, including poor countries and vulnerable populations. We also highlight the impacts of interrupting essential health services, such as the treatment of chronic conditions and infectious disease prevention, and the damage caused by the dissemination of fake news, stressing the need to improve access to correct and safe health information.
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Yellow fever (YF) is an acute tropical infectious disease caused by an arbovirus and can manifest as a classic hemorrhagic fever. The mechanism of the bleeding diathesis in YF is not well understood. We assessed clinical and laboratory data (including a panel of coagulation tests) from 46 patients with moderate (M) and severe (S) YF admitted to a local hospital between January 2018 and April 2018. Among 46 patients, 34 had SYF of whom 12 (35%) patients died. A total of 21 (45%) patients developed some type of bleeding manifestation and 15 (32%) presented severe bleeding. Patients with SYF had more severe thrombocytopenia (p = 0.001); prolonged activated partial thromboplastin time (aPTT) and thrombin time (TT) (p = 0.03 and p = 0.005, respectively); reduced plasma levels of coagulation factor (F) II (p < 0.01), FIX (p = 0.01), and FX (p = 0.04); and D-dimer levels almost 10 times higher (p < 0.01) when compared with patients with MYF. Patients who died had more bleeding (p = 0.03), more major bleeding (p = 0.03), prolonged international normalized ratio (INR) and aPTT (p = 0.003 and p = 0.002, respectively), as well as lower activity of FII (p = 0.02), FV (p = 0.001), FVII (p = 0.005), FIX (p = 0.01), and protein C (p = 0.01) than the ones who survived. FVIII levels were either normal or increased in all patients studied. Our results suggest that the bleeding diathesis of SYF is associated with the deficiency of coagulation factors produced by the liver. Prolonged INR and aPTT and reduced FII, FV, FVII, FIX, and protein C were associated with death.
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Trastornos de la Coagulación Sanguínea , Fiebre Amarilla , Humanos , Proteína C , Susceptibilidad a Enfermedades , Factores de Coagulación Sanguínea/metabolismo , Pruebas de Coagulación Sanguínea/métodosRESUMEN
OBJECTIVE: to analyze the influence of socioeconomic inequality on COVID-19 distribution in larger Brazilian municipalities, controlling for effect of hospital infrastructure, comorbidities and other variables. METHODS: this was an ecological study of COVID-19 hospitalizations and deaths in 2020; outcome data were obtained from the Ministry of Health; incidence ratios were estimated using a generalized linear model. RESULTS: we identified 291,073 hospitalizations and 139,953 deaths; we found higher mortality rates in municipalities with a higher proportion of non-White people (95%CI 1.01;1.16) and with more households with more than two people per room (95%CI 1.01;1.13); presence of sewerage systems was protective for both outcomes (hospitalizations: 95%CI 0.87;0.99 - deaths: 95%CI 0.90;0.99), while a higher proportion of the population in subnormal housing clusters was a risk factor (hospitalizations: 95%CI 1.01;1.16 - deaths: 95%CI 1.09;1.21), with this variable interacting with the proportion of people receiving Emergency Aid (hospitalizations: 95%CI 0.88;1.00 - deaths: 95%CI 0.89;0.98). CONCLUSION: socioeconomic conditions affected illness and death due to COVID-19 in Brazil.
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COVID-19 , Humanos , Ciudades , Brasil/epidemiología , COVID-19/epidemiología , Composición Familiar , HospitalizaciónRESUMEN
Objetivo analisar a influência da desigualdade socioeconômica na distribuição da covid-19 nos maiores municípios brasileiros (> 100 mil habitantes), controlando, pelo efeito da infraestrutura hospitalar, comorbidades e outras variáveis. Métodos estudo ecológico sobre internações e óbitos por covid-19 em 2020; dados de desfecho obtidos do Ministério da Saúde; a razão de incidência foi estimada via modelo linear generalizado. Resultados identificados 291.073 internações e 139.953 óbitos; encontrou-se maior taxa de mortalidade nos municípios com maior população não branca (IC95% 1,01;1,16) e nos domicílios com mais de duas pessoas por cômodo (IC95% 1,01;1,13); para ambos os desfechos, esgotamento sanitário foi protetivo (internações: IC95% 0,87;0,99 - óbitos: IC95% 0,90;0,99), e população em aglomerados subnormais revelou-se fator de risco (internações: IC95% 1,01;1,16 - óbitos: IC95% 1,09;1,21) com interação, com a proporção de pessoas a receber auxílio emergencial (internações: IC95% 0,88;1,00 - óbitos: IC95% 0,89;0,98). Conclusão condições socioeconômicas afetaram o adoecimento e morte por covid-19 no Brasil.
Objetivo: analizar la influencia de la desigualdad socioeconómica en la distribución de COVID-19 en los mayores municipios brasileños (> 100 mil habitantes), controlando, por la infraestructura hospitalaria, comorbilidades y otras variables. Métodos: estudio ecológico sobre hospitalizaciones y muertes por COVID-19 en 2020; datos del resultado fueran obtenidos del Ministerio de Salud; razón de incidencia estimada a través del modelo lineal generalizado. Resultados: 291.073 hospitalizaciones y 139.953 muertes; mayor tasa de mortalidad en municipios con mayor proporción de población no blanca (IC95% 1,01;1,16) y con más hogares con más de dos personas por habitación (IC95% 1,01;1,13); el alcantarillado sanitario resultó protector (hospitalizaciones: IC95% 0,87;0,99 - muertes: IC95% 0,90;0,99) y la mayor proporción de población en aglomeraciones subnormales fue un factor de riesgo (hospitalizaciones: IC95% 1,01;1,16 - muertes: IC95% 1,09;1,21), interactuando con proporción de personas con asistencia de emergencia (hospitalizaciones IC95% 0,88;1,00, defunciones IC95% 0,89;0,98). Conclusión: las condiciones socioeconómicas afectaron la enfermedad y la muerte por COVID-19.
Objective: to analyze the influence of socioeconomic inequality on COVID-19 istribution in larger Brazilian municipalities, controlling for effect of hospital infrastructure, comorbidities and other variables. Methods: this was an ecological study of COVID-19 hospitalizations and deaths in 2020; outcome data were obtained from the Ministry of Health; incidence ratios were estimated using a generalized linear model. Results: we identified 291,073 hospitalizations and 139,953 deaths; we found higher mortality rates in municipalities with a higher proportion of non-White people (95%CI 1.01;1.16) and with more households with more than two people per room (95%CI 1.01;1.13); presence of sewerage systems was protective for both outcomes (hospitalizations: 95%CI 0.87;0.99 - deaths: 95%CI 0.90;0.99), while a higher proportion of the population in subnormal housing clusters was a risk factor (hospitalizations: 95%CI 1.01;1.16 - deaths: 95%CI 1.09;1.21), with this variable interacting with the proportion of people receiving Emergency Aid (hospitalizations: 95%CI 0.88;1.00 - deaths: 95%CI 0.89;0.98). Conclusion: socioeconomic conditions affected illness and death due to COVID-19 in Brazil.
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Humanos , COVID-19/mortalidad , COVID-19/epidemiología , Hospitalización , Factores Socioeconómicos , Brasil/epidemiología , Determinantes Sociales de la SaludRESUMEN
BACKGROUND: Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI (∆tinhi-ITI ) is debatable. OBJECTIVE: The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. METHODS: Severe (factor VIII activity level <1%) PwHA-HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA-HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). RESULTS: Median ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6-8.1) and 6.9 years [IQR, 2.6-20.1), respectively. PwHA-HRi were stratified according to ∆tinhi-ITI quartiles: first (0.0-0.6 year), second (>0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. CONCLUSION: In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.
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Hemofilia A , Hemostáticos , Humanos , Lactante , Preescolar , Niño , Isoanticuerpos , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , Hemofilia A/complicaciones , Tolerancia Inmunológica , Hemorragia/complicacionesRESUMEN
Hemophilia A (HA) is an inherited bleeding disorder which requires continuous replacement with factor (F) VIII concentrate. The main complication of HA is the development of neutralizing alloantibodies which inhibit FVIII activity (inhibitors). The objective of this study was to investigate the effect of the first FVIII infusions on immunological biomarkers in previously untreated patients with HA. Plasma samples were collected at enrollment before any FVIII infusion (T0) and at inhibitor development (INB +/T1) or up to 35 exposure days without inhibitors (INB -/T1). Anti-FVIII antibodies (immunoglobulin M, immunoglobulin G [IgG] 1, IgG3, and IgG4), chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10), and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, interferon-γ, tumor necrosis factor, and IL-17) were assessed. A total of 71 children with severe HA were included, of whom 28 (39.4%) developed inhibitors. Plasma levels of anti-FVIII IgG4, IL-6, and CXCL8 were higher at INB +/T1 when compared with INB -/T1. This group presented a mixed cytokine profile and higher plasma levels of CXCL9 and CXL10 when compared with INB +/T1. We conclude that exposure to FVIII triggers a proinflammatory response mediated by IL-6 and CXCL8 in patients with HA who developed inhibitors. Regardless of inhibitor status, the immune system of all HA patients is stimulated after infusions of FVIII.
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Biomarcadores/sangre , Quimiocina CXCL10/sangre , Factor VIII/administración & dosificación , Hemofilia A/sangre , Hemofilia A/inmunología , Anticuerpos Neutralizantes/química , Quimiocina CXCL9/sangre , Quimiocinas/metabolismo , Citocinas/metabolismo , Hemostáticos , Humanos , Sistema Inmunológico , Inmunoglobulina G/sangre , Lactante , Inflamación , Isoanticuerpos/química , MasculinoRESUMEN
ABSTRACT Background: In order to standardize a thrombin generation() protocol, we analyzed the analytical variables and sensitivity of this test to hypo/hypercoagulability states. Methods: The effect of the tissue factor concentration and the intra- and interassay precision were analyzed. To evaluate the hypercoagulability status, the plasma of women under an oral contraceptive was tested, while plasma from hemophilia A patients at 1, 3 and 7 days after recombinant FVIII infusion, and lyophilized plasma deficient in FVII or FVIII were used for the evaluation of hypocoagulability. Results: The intra-assay coefficient of variation was <10% with 1 and 5 pM of low and high TF. The oral contraceptive users showed increased thrombin generation in comparison to non-users, which was more pronounced with low TF (endogenous thrombin potential ETP) p = 0.0009; peak p = 0.0009; lagtime p = 0.0008). In relation to the FVIII-deficient plasma, a higher TG was observed as FVIII levels were increased and a better discrimination was obtained for different concentrations of FVIII with low TF (ETP p < 0.0001; peak p < 0.0001; lagtime p = 0.0004). Using low TF, plasma from hemophilia A patients showed higher TG values after 1 day of recombinant FVIII infusion vs after 3 days (ETP p < 0.0001; peak p < 0.0001; lagtime p = 0.0407), while the lowest values were observed after 7 days. With FVII-deficient plasma, thrombin generation was lower than normal plasma and a more pronounced difference was observed with high TF compared to low TF (ETP p < 0.0001; peak p < 0.0001; lagtime p < 0.0001). Conclusion: Under our conditions the thrombin generation test seems to be sensitive to evaluation of hyper/hypocoagulability states. Standardization of the thrombin generation test may have an application in the evaluation of bleeding and thrombotic disorders.
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Humanos , Masculino , Femenino , Adulto , Trombina , TrombofiliaRESUMEN
BACKGROUND: In order to standardize a thrombin generation() protocol, we analyzed the analytical variables and sensitivity of this test to hypo/hypercoagulability states. METHODS: The effect of the tissue factor concentration and the intra- and interassay precision were analyzed. To evaluate the hypercoagulability status, the plasma of women under an oral contraceptive was tested, while plasma from hemophilia A patients at 1, 3 and 7 days after recombinant FVIII infusion, and lyophilized plasma deficient in FVII or FVIII were used for the evaluation of hypocoagulability. RESULTS: The intra-assay coefficient of variation was <10% with 1 and 5pM of low and high TF. The oral contraceptive users showed increased thrombin generation in comparison to non-users, which was more pronounced with low TF (endogenous thrombin potential ETP) p=0.0009; peak p=0.0009; lagtime p=0.0008). In relation to the FVIII-deficient plasma, a higher TG was observed as FVIII levels were increased and a better discrimination was obtained for different concentrations of FVIII with low TF (ETP p<0.0001; peak p<0.0001; lagtime p=0.0004). Using low TF, plasma from hemophilia A patients showed higher TG values after 1 day of recombinant FVIII infusion vs after 3 days (ETP p<0.0001; peak p<0.0001; lagtime p=0.0407), while the lowest values were observed after 7 days. With FVII-deficient plasma, thrombin generation was lower than normal plasma and a more pronounced difference was observed with high TF compared to low TF (ETP p<0.0001; peak p<0.0001; lagtime p<0.0001). CONCLUSION: Under our conditions the thrombin generation test seems to be sensitive to evaluation of hyper/hypocoagulability states. Standardization of the thrombin generation test may have an application in the evaluation of bleeding and thrombotic disorders.
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INTRODUCTION: Brazil has the fourth largest world population of patients with haemophilia. However, mortality rates in this population are unknown. AIM: To analyse mortality and its causes in Brazilian patients with haemophilia from 2000 to 2014. METHODS: The number of deceased patients with haemophilia and causes of death were obtained from the Brazilian National Mortality Information System (SIM), according to the 10th International Classification of Diseases (ICD-10). Standardized mortality ratios (SMR) were calculated to estimate the rate of overall death of patients with haemophilia relative to that of the Brazilian general male population. RESULTS: A total of 784 deaths were identified in the period of 15 years. Mortality of patients with haemophilia was 13% higher when compared with the general male population (SMR 1.13, 95% CI: 1.01-1.16). Haemorrhage was the main cause of death (n = 254; 32.4%) of which 137 (54%) was intracranial haemorrhage. The total number of deaths due to HIV decreased over the years, and an increase in deaths due to cancer and cardiovascular disease was observed. A total of 129 deaths (16.5%) were related to hepatitis infection, of whom, 109 (86.5%) patients also presented with cirrhosis and hepatocellular carcinoma or other liver diseases. CONCLUSION: Mortality rate of Brazilian patients with haemophilia decreased over the evaluated period. Intracranial haemorrhage is still an important cause of death in these patients, which requires major effort for prevention. Death due to age-related cardiovascular disease and cancer has increased over the years, following the same tendency observed in developed countries.
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Hemofilia A/mortalidad , Hemofilia B/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , Causas de Muerte , Niño , Preescolar , Femenino , Hemofilia A/complicaciones , Hemofilia A/diagnóstico , Hemofilia B/complicaciones , Hemofilia B/diagnóstico , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Preeclampsia (PE) is a multisystem disease characterized by the development of hypertension and proteinuria. Although PE etiology is not fully known, the placenta seems to play a central role in the development of disease. The inadequate placentation process results in a change in angiogenic factors levels, such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble form of endoglin (s-Eng) and soluble form of vascular endothelial growth factor receptor type 1 (sFlt-1). OBJECTIVE: The aim of this review was to clarify if the imbalance between pro-angiogenic and anti-angiogenic factors is associated with PE. CONCLUSION: It is known that inadequate placentation process is the primary mechanism suggested for PE occurrence and angiogenic factors are involved in this process. The state-of-the-art suggests that progress in grasp the imbalance of pro-angiogenic and anti-angiogenic factors is essential for the improvement of knowledge about PE. The development of prospective, longitudinal studies with serial determinations of these factors throughout pregnancy is needed to better assess the relevance of these markers for understanding the etiology, prevention, diagnosis, prognosis and treatment of this challenging disease.
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Neovascularización Patológica , Preeclampsia/fisiopatología , Animales , Biomarcadores/metabolismo , Femenino , Humanos , Preeclampsia/metabolismo , Preeclampsia/terapia , EmbarazoRESUMEN
Preeclampsia (PE) is characterized by hypertension and proteinuria, occurring after the 20th week of pregnancy in women who have had no previous symptoms. The disease progresses with generalized vasoconstriction and endothelial dysfunction. Clinically, it is important to diagnose the severe form of the disease (sPE), in which blood pressure and proteinuria are much higher. Recently, the gestational age (GA) of the onset of PE has led to the classification of this disease as early (GA <34 weeks) and late (GA ≥34 weeks). Several genetic polymorphisms affecting endothelial nitric oxide synthase (eNOS) levels or function were described, including G894T (Glu298Asp), VNTR b/a (variable-number 27-bp tandem repeat) and T-786C (promoter) polymorphisms. Thus, the aim of this study was to compare the distribution of G894T, VNTR b/a and T-786C polymorphisms and their haplotypes in Brazilian early and late sPE, as well as in normotensive pregnant. A total of 201 women were evaluated, 53 with early sPE, 45 with late sPE and 103 as normotensive pregnant women. The frequency of 894T allele was higher in late sPE vs normotensive pregnant, and 894TT genotype was higher in late sPE vs early sPE and normotensive pregnant. For VNTR b/a polymorphism, higher frequencies of aa genotype and a allele were observed in early sPE vs late sPE and normotensive pregnant. Besides, the frequency of haplotype T-b-C was higher in late sPE vs early sPE and normotensive pregnant. Considering the results found for eNOS polymorphisms, it is possible to suggest that the functional alterations induced by these two polymorphisms may influence the time of severe PE onset, although both alterations are putatively associated with low NO bioavailability. However, other studies are necessary to validate these findings and clarify this issue.