Resistência insulínica pode prejudicar a redução da espessura mediointimal em adolescentes obesos / Insulin resistance can impair reduction on carotid intima-media thickness in obese adolescents

FUNDAMENTO: O processo aterosclerótico no nível endotelial começa em idade precoce e parece estar associado com a obesidade e suas comorbidades como a resistência insulínica. OBJETIVO: O objetivo deste estudo foi verificar a influência da resistência insulínica em marcadores inflamatórios e subclínicos de aterosclerose em adolescentes obesos. MÉTODOS: Sessenta e seis adolescentes obesos pós-púberes foram divididos em dois grupos de acordo com o índice de resistência insulínica estimado pelo Modelo de Avaliação da Homeostase (HOMA-RI): com resistência insulínica (RI) n = 39 e sem resistência insulínica (NRI) n = 27, e foram submetidos a uma intervenção interdisciplinar ao longo de um ano. A espessura mediointimal da artéria carótida comum (EMIC), e o tecido adiposo visceral e subcutâneo foram determinados por ultrassonografia. A composição corporal, pressão arterial, índice HOMA-RI, perfil lipídico e as concentrações de adipocinas [leptina, adiponectina, e inibidor do ativador do plasminogênio-1 (PAI-1)] foram analisados antes e após a terapia. RESULTADOS: Ambos os grupos apresentaram melhoras significativas na composição corporal, estado inflamatório (redução da concentração de leptina e PAI 1; aumento de adiponectina plasmática) e redução da EMIC. Apenas o grupo NRI mostrou correlação positiva entre as alterações na gordura visceral (∆Visceral) e mudanças na EMIC (∆ EMIC) (r = 0,42, p < 0,05). A análise por regressão linear simples revelou o ∆Visceral ser um preditor independente para a redução da EMIC nesse grupo (R2 ajustado = 0,14, p = 0,04). Os valores finais da EIMC permaneceram significativamente maiores no grupo RI, quando comparado com grupo NRI. CONCLUSÃO: A presença de resistência insulínica pode prejudicar mudanças na EMIC levando ao desenvolvimento precoce da aterosclerose em adolescentes obesos submetidos a uma intervenção interdisciplinar.

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Associação de níveis plasmáticos de PAI-1 e polimorfismo 4G/5G em pacientes com doença arterial coronariana / PAI-1 4G/5G polymorphism and plasma levels association in patients with coronary artery disease

FUNDAMENTO: O polimorfismo 4G/5G do inibidor ativador do plasminogênio tipo 1 (PAI-1) pode influenciar a expressão do PAI-1. Níveis plasmáticos elevados de PAI-1 estão associados com Doença Arterial Coronariana (DAC). OBJETIVO: O presente estudo investigou a influência do polimorfismo 4G/5G do PAI-1 nos níveis plasmáticos de PAI-1 e sua associação com DAC avaliada por angiografia coronária. MÉTODOS: Foi avaliada amostra de sangue de 35 indivíduos com artérias coronárias angiograficamente normais, 31 indivíduos apresentando ateromatose leve/moderada, 57 indivíduos apresentando ateromatose grave e 38 indivíduos saudáveis (controles). Em pacientes e controles, o polimorfismo 4G/5G do PAI-1 foi determinado por amplificação da proteína-C reativa utilizando primers específicos de alelo. Os níveis plasmáticos de PAI-1 foram quantificados pelo ensaio ELISA (American Diagnostica). RESULTADOS: Não houve diferença entre os grupos quanto a sexo, idade e índice de massa corporal. Níveis plasmáticos de PAI-1 e frequência do genótipo 4G/4G mostravam-se significativamente maiores no grupo com ateromatose grave em comparação com os outros grupos (p < 0,001). Além disso, os pacientes com genótipo 4G/4G (r = 0,28, p < 0,001) apresentaram níveis plasmáticos de PAI-1 significativamente maiores do que aqueles com o genótipo 5G/5G (r = 0,02, p = 0,4511). Além disso, em um modelo de regressão logística múltipla, ajustado para todas as outras variáveis, o PAI-1 esteve independentemente associado com DAC > 70 por cento (p < 0,001). CONCLUSÃO: O achado mais importante deste estudo foi a associação entre o genótipo 4G/4G, elevados níveis plasmáticos de PAI-1 e estenose coronariana superior a 70 por cento em indivíduos brasileiros. Ainda não foi estabelecido se elevados níveis plasmáticos de PAI-1 são um fator decisivo para o agravamento da aterosclerose ou se são uma consequência.

BACKGROUND: Type-1 plasminogen activator inhibitor (PAI-1) 4G/5G polymorphism may influence the PAI-1 expression. High plasma levels of PAI-1 are associated with coronary artery disease (CAD). OBJECTIVE: This study investigated the influence of PAI-1 4G/5G polymorphism on plasma PAI-1 levels and its association with CAD assessed by coronary angiography. METHODS: Blood sample of 35 individuals with angiographycally normal coronary arteries, 31 individuals presenting mild/moderate atheromatosis, 57 individuals presenting severe atheromatosis and 38 healthy individuals (controls) were evaluated. In patients and controls, the PAI-1 4G/5G polymorphism was determined by PCR amplification using allele-specific primers. Plasma PAI-1 levels were quantified by ELISA assay (American Diagnostica). RESULTS: No difference was found between groups regarding age, gender and body mass index. Plasma PAI-1 levels and 4G/4G genotype frequency were significantly higher in the severe atheromatosis group compared to the other groups (p<0.001). Furthermore, patients with 4G/4G genotype (r=0.28, p<0.001) had significantly higher plasma PAI-1 levels than those with 5G/5G genotype (r=0.02, p=0.4511). In addition, in a multiple logistic regression model, adjusted for all the other variables, PAI-1 was observed to be independently associated with CAD > 70 percent (p<0.001). CONCLUSION: The most important finding of this study was the association between 4G/4G genotype, high plasma PAI-1 levels and coronary stenosis higher than 70 percent in Brazilian individuals. Whether high plasma PAI-1 levels are a decisive factor for atherosclerosis worsening or it is a consequence remains to be established.

Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 Levels in Patients with Acute Paraquat Intoxication

To investigate the effects of reactive oxygen species (ROS) on tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) plasma levels, and their possible implications on clinical outcome, we measured tPA and PAI-1 levels in 101 patients with acute paraquat (PQ) intoxication. The control group consisted of patients who ingested non-PQ pesticides during the same period. tPA and PAI-1 levels were higher in the PQ group than in the controls. PQ levels were significantly correlated with ingested amount, timelag to hospital, tPA level, and hospitalization duration. tPA levels were correlated with PAI-1, fibrin degradation product (FDP), and D-dimer. D-dimer levels were lower in the PQ group than in the controls. Univariate analysis indicated the following significant determinants of death: age, ingested amount, PQ level, timelag to hospital, serum creatinine, lipase, pH, pCO2, HCO3-, WBC, FDP, PAI-1, and tPA. However, multivariate analysis indicated that only PQ level was significant independent factor predicting death. In conclusion, tPA and PAI-1 levels were higher, while D-dimer levels were lower in the PQ group than in the controls, implying that ROS stimulate tPA and PAI-1, but PAI-1 activity overrides tPA activity in this setting. Decreased fibrinolytic activity appears to be one of the clinical characteristics of acute PQ intoxication.

Atividade pró-trombótica da toxina ExoU de Pseudomonas aeruginosa detectada em modelos experimentais in vivo e in vitro / Prothrombotic activity of the Pseudomonas aeruginosa toxin ExoU detected in experimental models in vivo and in vitro

Pseudomonas aeruginosa é um importante agente de pneumonia, particularmente em pacientes submetidos à ventilação mecânica, que pode evoluir para sepse, com elevadas taxas de letalidade. Na sepse, o processo inflamatório sistêmico exacerbado favorece o desequilíbrio entre as vias de coagulação e fibrinólise e a instalação de um estado pró-coagulante, com o aparecimento de trombose microvascular, coagulação intravascular disseminada e falência de múltiplos órgãos. Conhecendo a potente atividade pró-inflamatória da toxina ExoU produzida por P. aeruginosa, decorrente de sua atividade fosfolipásica A2, o objetivo desta tese foi investigar seu potencial de indução de alterações hemostáticas relacionadas à patogênese da sepse. Utilizando modelo de sepse em camundongos inoculados, por via intratraqueal, com suspensões de P. aeruginosa produtora de ExoU (PA103) ou de cepa com deleção do gene exoU, não produtora da toxina, foi mostrado que ExoU determinou maior gravidade da infecção, maior taxa de letalidade, leucopenia, trombocitose, hiperpermeabilidade vascular e transudação plasmática, evidenciadas, respectivamente, pela maior concentração de proteínas nos lavados broncoalveolares (LBAs) e acúmulo do corante Azul de Evans, previamente inoculado nos animais, por via endovenosa, no parênquima renal. ExoU favoreceu, também, a ativação plaquetária, confirmada pela maior concentração de plaquetas expressando P-seletina em sua supefície, maior número de micropartículas derivadas de plaquetas e maior concentração plasmática de tromboxano A2. A histopatologia dos pulmões e rins dos animais infectados com PA103 confirmou a formação de microtrombos, que não foram detectados nos animais controles ou infectados com a cepa mutante. Nos pulmões, a produção de ExoU determinou intensa resposta inflamatória com maior concentração de leucócitos totais e polimorfonucleados, interleucina-6 e fator de necrose tumoral-alfa nos LBAs. A análise imunohistoquímica mostrou intensa deposição...

Pseudomonas aeruginosa is an important agent of pneumonia, mainly in patients undergoing mechanical ventilation, which can progress to sepsis with high mortality rates. In sepsis, the systemic inflammatory process favors exacerbated imbalance between the coagulation and fibrinolysis pathways and the installation of a procoagulant state, leading to microvascular thrombosis, disseminated intravascular coagulation and multiple organ failure. Knowing the powerful proinflammatory activity of the P. aeruginosa toxin ExoU, secondary to its phospholipase A2 activity, the goal of this study was to investigate the ExoU potential to induce hemostatic changes related to sepsis pathogenesis. By using a murine model of pneumosepsis, obtained by the intratracheal injection of suspensions of the ExoU-producing PA103 P. aeruginosa strain or of its isogenic mutant PA103 exoU, defective in the toxin synthesis, ExoU was shown to enhance the severity of the infection and to induce higher mice mortality rate as well as leukopenia, thrombocytosis, vascular hyperpermeability and plasma transudation, evidenced, respectively, by the higher protein concentration in the bronchoalveolar lavage fluids (BALF) and accumulation of Evans blue dye, previously intravenous infectioned, in mice renal parenchyma. ExoU also favored platelet activation, evidenced by the higher concentration of platelets expressing P-selectin on their surface, greater number of platelet-derived microparticles and increased plasma concentration of thromboxane A2. Histopathology of the lungs and kidneys of PA103 - infected animals confirmed the formation of microthrombi, which were not detected in controls or in animals infected with the bacterial mutant. In lungs, ExoU induced an intense inflammatory response with high concentrations of total and polymorphonuclear leukocytes, interleukin-6 and tumor necrosis factor-alfa in mice BALF. Immunohistochemical analysis showed intense fibrin deposition in the alveoli...

Polimorfismo 4G/5G del inhibidor del activador de plasminógeno tipo 1 en síndrome metabólico / Plasminogen activator inhibitor-1 polymorphisms in metabolic syndrome

El inhibidor del activador de plasminógeno tipo 1 (PAl-1, Plasminogen Activator Inhibitor 1) es el inhibidor primario de la fibrinólisis. Se ha descrito que un aumento o disminución puede asociarse a riesgo de trombosis y hemorragia, respectivamente. De los nueve polimorfismos que se han descrito en su gen, el denominado 4G15G ha sido el más estudiado. Se ha visto que personas con el genotipo 4G/4G presentan mayor concentración plasmática do PAl-1. En individuos con Síndrome Metabólico (SM) se ha observado mayor concentración do PAl-1. El propósito de este estudio fue conocer el genotipo 4G/5G en individuos con SM (n: 82) respecto a un grupo control (n: 75). Para ello se utilizo el método PCR alelo especifica. La frecuencia genotípica obtenida en los sujetos con SM fue de 23 por ciento, 43 por ciento y 34 por ciento para los genotipos 4G/4G, 4G/5G y 5G/5G, respectivamente. En los sujetos sin SM so observo una prevalencia de 11 por ciento, 56 por ciento, 33 por ciento para los genotipos 4G/4G, 4G/5G y 5G/5G, respectivamente. Las diferencias entre los distintos genotipos y la condición de ser o no SM no fueron significativas (p= 0,083), posiblemente porque nuestra población en estudio fue pequeña. Por otra parte, no hubo relación entre el genotipo y la concentración plasmática de PAl-1; es posible que esta última este influenciada por distintos factores, además del polimorfismo 4G/5G. La frecuencia genotípica obtenida en este estudio fue similar a la encontrada en sujetos latinos y diferentes a las de afroamericanos e italianos, posiblemente el genotipo pudiera estar influenciado por la raza.

Genetic polymorphisms of plasminogen activator inhibitor-1, vascular endothelial growth factor and angiotensin converting enzyme among pre-eclamptic women

Pre-eclampsia is one of the leading causes of maternal as well perinatal morbidity and mortality. The exact pathogenesis of pre-eclampsia is most likely multifactorial. Polymorphisms of plasminogen-activator inhibitor-1 [PAI-1], vascular endothelial growth factor [VEGF] and angiotensin converting enzyme [ACE] may contribute to the pathogenesis of pre-eclampsia. This study was conducted to evaluate the PAI-1, VEGF and ACE genetic polymorphisms in pregnant women with and without pre-eclampsia. A total of 42 pre-eclamptic women and 20 women with normotensive pregnancy, aged between 20-43 years were enrolled in this study. Genomic DNA was isolated from peripheral blood leucocytes. The 4G/5G polymorphism of the PAI-1 gene and insertion-deletion polymorphism of the ACE gene were detected in DNA samples with the use of the polymerase chain reaction [PCR] and the 936 C/T polymorphism of the VEGF gene was determined by polymerase chain reaction-restriction fragment length polymorphism [PCR-RFLP]. Chi-squared and student t-tests were used for statistical analysis. In pre-eclampsia [n=42 women], the frequencies of 4G4G and 4G5G genotypes of PAI-1 gene were significantly higher [14.3% and 57.1% respectively] than in the normotensive pregnant controls [0% and 15%, respectively], P<0.001. The 4G allele frequency was significantly higher in pre-eclampsia [42.9%] than pregnant controls [7.5%]; P<0.001. Besides, no difference was detected in the ACE [I/D] and VEGF [936C/T] genotypes distribution of pre-eclampsia and normal pregnancy. The 4G allele of the 4G/5G polymorphism in the promoter region of the PAI-1 gene is suggested to be a genetic risk factor for pre-eclampsia

[Evaluation of thrombophilic factors in women with PCOS]

Polycystic ovary syndrome [PCOS] is associated with insulin-induced elevations of plasminogen activator inhibitor [PAI-1], the most potent inhibitor of fibrinolysis. Hypofibrinolysis due to increased PAI-1 levels in PCOS patients bears a high risk for miscarriage and some other pregnancy complications which are probably due to increased thrombophilic states. In this study we compared thrombophilic factors in women with PCOS with those of healthy women. This analytical study was performed on 123 infertile women with PCOS as the case group, and 73 women non-PCOS women with male factor infertility as the control group. All the individuals attended Rouin Tan Arsh Hospital for receiving fertility treatment in Tehran, Iran during 2008. Blood samples were taken from both groups on the third day of menstrual cycle for the evaluation of protein S, activated protein C resistance [APC-R], hemocysteine, FSH, LH, prolactin, testosterone, FBS and 2-hr GTT. The mean protein S and APC-R values were lower in the case group compared to the controls, but the differences were not statistically significant [p=0.752 and p=0.603, respectively]. The mean hemocysteine value was higher in the control than the case groups [13.25 mmol/l vs. 12.49 mmol/l, respectively] but this difference was not significant either [p=0.157]. PCOS and older age tended to elevate hemocysteine [p<0.05]. Comparison of thrombophilic factors in women with PCOS and women without the disease showed no significant statistical differences. PCOS and older age seemed to raise the risk for abnormal changes in hemocysteine levels

The effect of thyroid hormones on the white adipose tissue gene expression of PAI-1 and its serum concentration

Metabolic syndrome is associated with an increased risk of developing cardiovascular diseases and Plasminogen activator inhibitor 1 (PAI-1) overexpression may play a significant role in this process. A positive correlation between adipose tissue gene expression of PAI-1 and its serum concentration has been reported. Furthermore, high serum levels of thyroid hormones (T3 and T4) and PAI-1 have been observed in obese children. The present study evaluates the impact of thyroid hormone treatment on white adipose tissue PAI-1 gene expression and its serum concentration. Male Wistar rats (60 days old) were treated for three weeks with T4 (50 µg/day, Hyper) or with saline (control). Additionally, 3T3-L1 adipocytes were treated for 24 h with T4 (100 nM) or T3 (100 nM). PAI-1 gene expression was determined by real-time PCR, while the serum concentration of PAI-1 was measured by ELISA using a commercial kit (Innovative Research, USA). Both the serum concentration of PAI-1 and mRNA levels were similar between groups in retroperitoneal and epididymal white adipose tissue. Using 3T3-L1 adipocytes, in vitro treatment with T4 and T3 increased the gene expression of PAI-1, suggesting non-genomic and genomic effects, respectively. These results demonstrate that thyroid hormones have different effects in vitro and in vivo on PAI-1 gene expression in adipocytes.

Tissue plasminogen and plasminogen activator inhibitor-1 serum level in osteoarthritis and rheumatoid arthritis patients

The activity of tissue plasminogen activator [t-PA] and plasminogen activator inhibitor-1 [PAI-1] in the plasma of 40 rheumatoid arthritis [RA] patients [Gl] and 10 osteoarthritis [OA] patients [G2] was measured. Group I mean age was 40.95 +/- 3.57 and the duration of disease was 91.65 +/- 37.93 weeks. Group II mean age was 50.87 +/- 5.39 and the duration of disease was 77.43 +/- 12.75 weeks. Ten apparently healthy subjects were examined as a control group [G3]. Their mean age was 25.44 +/- 10.45. The relationship between plasma t-PA and PAI-1 and their correlation with disease activity were studied in patients with rheumatoid arthritis [RA=G1] and [OA=G2], and control group a comparative study group showed that, RA Gl increased t-PA and PAI-1 activity, in comparison with OA patients and control group. In addition, there was an imbalance between plasminogen activator inhibitor-type 1 [PAI-1] and t-PA in RA than OA patient or control. These results show an alteration of the PAI-1/t-PA system in RA, which increases with disease activity. This alteration may play a role in joint destruction in RA

Obesity increases transcription of heme oxygenase-1 gene and synergistically stimulates angiogenesis with vascular endothelial growth factor and plasminogen activator inhibitor-1 in rats

Angiogenesis plays an important role in obesity; heme oxygenase-1 [HO-1] has been implicated in the process of angiogenesis. To investigate the effect of obesity on transcription of HO-1 gene and to study the relation between elevated HO-1 and other angiogenic factors such as vascular endothelial growth factor [VEGF] and plasminogen activator inhibitor -1 [PAI-1] which are though to play an important role in the pathogenesis of obesity. Obesity was induced in 15 albino rats by feeding high fat diet for 3 months to establish diet-induced obesity. Another 15 rats were used as control. Blood samples were collected from tail vein; plasma PAI-1, lipid profile, free fatty acids [FFA], leptin and VEGF were measured. RNA was extracted from liver of obese and normal rats and RT-PCR was done, beta-actin mRNA expression for each sample was used as internal control. In rats fed high fat diets for 3 months, the total body weight were significantly increased [247.0 +/- 14.66g] compared to control group [126.37 +/- 23.26 g]. Obese rats showed a significant increase in serum triacylglycerol [TAC], total cholesterol [TC], low density lipoproteins-cholesterol [LDL-C], leptin and plasma free fatty acids, while serum high-density lipoproteins-cholesterol [HDL-C] was significantly decreased. HO-1-mRNA was increased in liver homogenates of obese rats compared to non-obese rats. These results indicate that the body response to obesity by elevating the expression of the stress gene HO-I. Angiogenic factors VEGF and PAI-I were significantly increased in obese compared to non-obese rats. Our findings suggest that HO-I and angiogenic factors [VEGF and PAI-I] play an important role in pathogenesis of obesity

effect of crude extract of purslane on blood coagulation and fibrinolysis

Purslane is a highly nutritious food. It was considered to have haemostatic properties. Purslane succulent leaves contain the highest concentration of essential omega-3 fatty acids. Humans and other mammals can't make omega-3 fatty acids so, they must be taken directly from food. The aim of the present work was to study the effect of crude extract of purslane on coagulation factors and fibrinolysis in albino rat. This study was conducted on twenty Albino rats weighing 200-250 gm divided into two groups one control and the other take purslane alcohol extract in a dose of 5gm/kg by intragastric tube for three weeks. All animals were scarified and blood samples were collected in 3.8% sodium citrate and analyzed for prothrombin time, activated partial thrombolplastin, coagulation factor II, VII, X and plasminogen activator inhibitor. The results show significant increase in prothrombin time significant decrease in coagulation factor II, VII X while activated partial thromboplastin time show insignificant change. As regard plasminogen activator inhibitor it showed significant increase. In conclusion purslane crude extract with its high content with omega-3 fatty acids can prolong coagulation time but has reverse effect on fibrinolysis

Relationship between adipokines, inflammation, and vascular reactivity in lean controls and obese subjects with metabolic syndrome

PURPOSE: Metabolic syndrome is an important risk factor for cardiovascular disease. Adipokines interfere with insulin action and endothelial cell function. We investigated the relationship among adipokines, metabolic factors, inflammatory markers, and vascular reactivity in obese subjects with metabolic syndrome and lean controls. METHODS: Cross-sectional study of 19 obese subjects with metabolic syndrome and 8 lean volunteers evaluated as controls. Vascular reactivity was assessed by venous occlusion pletysmography measuring braquial forearm blood flow (FBF) and vascular resistance (VR) responses to intra-arterial infusions of endothelium-dependent (acetylcholine-Ach) and independent (sodium nitroprusside-SNP) vasodilators. Blood samples were obtained to evaluate C reactive protein (CRP), plasminogen activator inhibitor 1 (PAI-1), fibrinogen, adiponectin, resistin, and lipid profile. Patients were classified with regard to insulin resistance through the HOMA-IR index. RESULTS: PAI-1, CRP and fibrinogen were higher and adiponectin was lower in metabolic syndrome subjects compared to controls. Metabolic syndrome subjects had impaired vascular reactivity. Adiponectin and PAI-1 were associated with insulin, HOMA-IR, triglycerides, and HDLc; and resistin with CRP. Adiponectin was associated with VR after Ach in the pooled group and resistin with D FBF after Ach in the metabolic syndrome group. CONCLUSION: Metabolic syndrome subjects exhibited low levels of adiponectin and high levels of CRP, fibrinogen, and PAI-1. Adiponectin and PAI-1 correlated with insulin resistance markers. Adiponectin and resistin correlated with vascular reactivity parameters. An adipocyte-endothelium interaction might be an important mechanism of inflammation and vascular dysfunction.

A Síndrome Metabólica é um importante fator de risco para doenças cardiovasculares. As adipocinas interferem com a ação da insulina e com a função endotelial. OBJETIVO: Investigar a relação entre adipocinas, fatores metabólicos, marcadores inflamatórios e reatividade vascular para inferência da função endotelial em pacientes obesos e controles magros. MATERIAL E MÉTODO: Estudo transversal de 19 pacientes obesos com Síndrome Metabólica e 8 controles magros. A reatividade vascular foi avaliada pela pletismografia de oclusão venosa medindo o fluxo sangüíneo da artéria braquial e sua resistência vascular a partir de infusões intra-arteriais de vasodilatadores endotélio-dependente (acetilcolina) e endotélio-independente (nitroprussiato de sódio). Foram também avaliados no sangue a proteína C reativa (PCR), o inibidor do ativador do plasminogênio 1 (PAI-1), fibrinogênio, adiponectina, resistina e o perfil lipídico. Os pacientes foram classificados quanto à resistência insulínica pelo índice HOMA-IR. RESULTADO: PAI-1, PCR e fibrinogênio apresentaram valores mais altos e a adiponectina mais baixos para os pacientes com Síndrome Metabólica do que com os controles. Pacientes com Síndrome Metabólica apresentaram prejuízo da reatividade vascular. A adiponectina e PAI-1 estiveram associadas à insulina, HOMA-IR, triglicerídeos e HDLc; e resistina com o PCR. Adiponectina esteve associada com a resistência vascular e a resistina com o fluxo sangüíneo depois da acetilcolina em pacientes com Síndrome Metabólica. CONCLUSÃO: Pacientes com Síndrome Metabólica exibiram baixas concentrações sangüíneas de adiponectina e altos níveis de PCR, fibrinogênio e PAI-1. Adiponectina e PAI-1 correlacionaram com os marcadores da resistência insulínica. Adiponectina e resistina correlacionaram com a reatividade vascular. A interação adipócito-endotélio vascular pode ser um importante mecanismo de inflamação e disfunção vascular.

Fibrinogen and plasminogen activator inhibitor-1 level in peripheral arterial disease of type 2 diabetes patients.

AIM: To determine association of fibrinogen and plasminogen activator inhibitor-1 with peripheral arterial disease (PAD) in type 2 diabetes patients. METHODS: This is a cross-sectional study with 52 type 2 diabetes patients of 41-74 years old. The subjects were divided into two groups, those who were diagnosed with PAD (16) and without PAD (36). Diagnosis of PAD was based on the ankle brachial index (ABI) measurement. Fibrinogen and plasminogen activator inhibitor-1 (PAI-1) level were evaluated as hemostatic factors. The two groups were compared for age, sex, smoking, plasma fasting glucose, total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglyceride concentrations, diabetes duration, systolic blood pressure and diastolic blood pressure level. Statistical analyse were conducted to check the significance of differences between variables in the two groups as well as interrelationship between hemostatic factors and other parameters. RESULTS: Fibrinogen was similar in both group (402.42 +/- 74.44 mg/dl in PAD group and 322.45 +/- 101.05 mg/dl in non-PAD group) (p= 0.259). PAI-1 was also similar in both group (8.93 +/- 11.02 IU/ml in PAD group and 7.06 +/- 7.32 IU/ml in non-PAD group) (p=0.721). Hyperfibrinogenemia was more prevalent in PAD group (68.8%) than in non-PAD group (25%) (p= 0.005). CONCLUSION: Our data showed that fibrinogen and PAI-1 level were similar in both groups. As a risk factor hyperfibrinogenemia was more prevalent in PAD group.

Plasma Level of IL-6 and Its Relationship to Procoagulant and Fibrinolytic Markers in Acute Ischemic Stroke

Procoagulant or impaired fibrinolytic states as well as inflammatory reactions mediated by cytokines are likely involved in the pathogenesis of acute ischemic stroke. We examined the potential relationship between interleukin 6 (IL-6) and hemostatic markers. The procoagulant and fibrinolytic states were assessed in 46 patients with acute stroke by measuring plasma levels of plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), and plasminogen-antiplasmin complex (PAP). Circulating IL-6 levels were measured using ELISA (Quantikine, R and D systems, MN, USA). Circulating IL-6 (mean, 26.5 pg/mL) and PAI-1 (mean, 19.9 ng/mL) levels were higher in patients with acute stroke than in healthy subjects (mean, 3.0 pg/mL, 10.4 ng/mL, respectively). TAT levels were statistically different according to the etiologic subtypes of stroke (atherogenic, 2.5 ng/mL; lacunar 3.2 ng/mL; cardiogenic 9.9 ng/mL, p = 0.021). Neither procoagulant levels nor fibrinolytic markers significantly correlated with circulating IL-6 levels. Our findings suggest that elevated proinflammatory cytokines during the initial hours of ischemic stroke may be an independent pathogenic factor or a consequence of the thrombotic event with no relationship to the procoagulant or fibrinolytic states.

Extracellular accumulation of bioactive substances; interleukin -1beta [IL-1beta] and plasminogen activator inhibitor-1 [PAI-1] in stored blood units, relation to bacterial contamination

Bacterial contamination of blood and its cellular components remains an unresolved problem in transfusion medicine. Its relation to release of some bioactive substance from cellular blood components is not determined. The present work was designed to explore the levels of two bioactive compounds Interleukin-1 beta and Plasminogen activator inhibitor-1 in stored blood and their relation to bacterial contamination of these units. This study was conducted on 112 blood units obtained from blood bank of Mansoura University Children Hospital. Sequential blood samples were obtained both immediately after donation and 10 days after for measurement of interleukin-1 beta and Plasminogen activator inhibitor-1 and for bacterial culture by BACTEC 9050 system. There was statistically significant increase in both IL-1 beta and PAI-1 [p= 0.0001] after 10 days of blood units storage. Bacteriological culture revealed no growth in 68% and positive growth in 32% of blood units. The commonest isolated organism was Staph. aureus [15%] followed by Staph. epidermedis [13%] then Yersinia sp. and Enterobacter sp. [2%] for each.From the present study we could conclude that; stored blood units contain platelets and WBCs derived bio-active substances PAI-1 and IL-beta which increase with the duration of blood storage. Furthermore, the extended duration of storage carries the danger of blood contamination by bacteria. Automated blood culture system seems to be helpful in identification of bacterial contamination of blood units. We recommend fresh blood transfusion as early as possible and the practice of Leucofilteration to avoid blood transfusion complications

Effects of cardiac rehabilitation on fibrinolysis in patients with coronary artery disease.

The aim of the present study was to demonstrate the influence of exercise component of a cardiac rehabilitation program on fibrinolysis in coronary artery disease (CAD) patients. Cardiac rehabilitation program was claimed to have an important role for improving quality of life and reducing the incidence of recurrent disease. The program used in the present study included aerobic exercise for 8 weeks, 4 days per week, 30 minutes per day at light to moderate intensity. Thirty-three male patients with CAD were recruited in the present study. Subjects from Thammasat University Hospital and King Chulalongkorn Memorial Hospital, whose age ranging from 40 to 70 years, were random assigned into 2 groups: control and experimental groups. The results showed that no significant differences in tissue plasminogen activator levels (t-PA) (both antigen and activity), plasminogen activator inhibitor-1 levels (PAl-1) (both antigen and activity) were observed in control and experimental groups after exercise training for 8 weeks as compared to the baseline. However significant improvement of fibrinolysis via a decrease in PAI-1 activity level from 16.3 (3.7) to 14.8 (6.3) AU/ml (p < 0.024) and an increase in t-PA activity from 2.3 (0.8) to 2.7 (0.5) IU/ml and t-PA antigen from 7.5 (2.9) to 9.2 (2.7) ng/ml (p < 0.01) in experimental group were observed when compared between pre and post acute submaximum exercise (65% VO(2 peak)) at the end of the program. In addition the authors found a significant improvement in VO(2 peak) resting heart rate, and serum triglyceride level in experimental group after 8 weeks of exercise training. This study demonstrated that patients with CAD participating in 8 weeks exercise cardiac rehabilitation program at light--moderate intensity could improve physical fitness and physical health although there was no significant change of fibrinolysis. The CAD patients should be advised to enroll in this cardiac rehabilitation program since it did not have any harmful effect due to the fibrinolytic function but it also augmented the patients' physical health.

Improved procoagulant activity and dyslipidemia in obese patients post bariatric surgery

Obesity is an increasing health problem worldwide. Obesity has characteristics of a prothrombotic state along with other endocrine and metabolic disturbances. We focused on the pathophysiological substrate of hypercoagulability and the potential consequences of weight loss post bariatric surgery on biochemical markers of procoagulant activity and dyslipidemia. A total 24 morbidly obese patients [18 women, 6 men] of mean age 32.96 +/- 5.9 and mean BMI 44.25 +/- 2.8 kg/m2 underwent restrictive gastric surgery [vertical banded gastroplasty,VBG]. Body mass index, blood pressure, lipid profile, plasma fibrinogen and plasminogen activator inhibitor-1 were monitored at baseline, 6 and 12 months post surgery. A significant weight loss was observed in all patients during the one year follow-up period. Mean body mass index was 44.25 +/- 2.8 kg/m2 before surgery, and significantly decreased to 37.79 +/- 2.60 kg/m2 at 6 month [p<0.001] and to 35.62 +/- 2.69 kg/m2 at 12 [P<0.001] months post bariatric surgery. After the dramatic weight reduction, a significant reduction in TC [p<0.01], LDL-C [p<0.01] and TG [p<0.001], plasma fibrinogen [p<0.001] and PAI - l [p<0.001] levels were observed throughout 12-month follow-up, with a significant rise in HDL-C[p<0.001]. Bariatric surgery could optimize cardiovascular risk profile and exert beneficial effects on thrombosis and the hemostasis axis in obesity. Weight loss resulted in improved metabolic parameters, suggesting a lowered atherogenic risk

Immunological markers of liver fibrosis in cirrhotic patients

Liver fibrosis occurs in response to chronic injury of any etiology. Kupffer cell [macrophage] activation accompanies liver injury with altered cytokine metabolism. This study aimed to investigate serum levels of tumour necrosis factor alpha [TNFa] and interleukin-6 [IL -6] as proinflammatory and profibrogenic cytokines in cirrhotic patients and relate them with the degree of liver disease and with the level of type -I plasminogen activator inhibitor [PAI-1] as a marker of fibrinolytic activity. The study included 20 cirrhotic patients and 15 healthy controls. After performing clinical and ultrasonic evaluation, liver function tests and hepatitis viral markers, patients were divided according to Child's Pugh classification of severity of liver disease into 3 groups, [group I] compensated cirrhosis, [group II] cirrhosis with ascites, [group III] decompensated cirrhosis. Serum levels of tumour necrosis factor alpha and interleukin-6 and plasma levels of type -I plasminogen activator inhibitor were measured. All patients showed significant positivity with hepatitis C virus antibodies. The Child-Pugh score of severity of liver disease was significantly increased in groups II and III compared to group I and control subjects. Serum TNFa. was significantly increased in all three groups of cirrhotic patients compared to control group. [P<0.05].Serum IL-6 was significantly increased in groups II and III [class B and C] compared to control group and there was significant difference between groups II and III and I and III So levels of IL-6 increased progressively with evolution of the disease. There was no statistical significant difference in plasma levels of PA1-1 between patients and controls. A positive significant correlation existed between TNFa and IL-6 in group II of patients [r= 0. 784 P=0.065] and between IL-6 and PAI-1 in groups II and III [r=0.78 P=0.067 and r= 0.000 P= 0.999 respectively]. In conclusion, this study revealed that in cirrhotic patients, serum levels of TNFa and IL-6 were significantly higher than control group, and IL-6 increased in advanced stages of the disease compared to early ones. There was positive correlation between TNFa and IL-6 in group II of patients. We suggested that the profibrogenic cytokines TNFa and IL-6 are implicated in fibrogenesis in cirrhotic patients and can be used as indicators for its progression. Further studies are needed to evaluate the use of their inhibitors as novel therapeutic agents to control undesirable fibrosis

Relationship of tissue plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen with coronary artery disease in South Indian male subjects.

AIM: Prevalence rates of coronary artery disease (CAD) are reported to be very high in Asian Indians. Conventional risk factors do not explain the high rates of CAD among Indians. Recently, several newer risk factors have been reported to be associated with CAD. We measured tissue plasminogen activator (tPA) antigen, plasminogen activator inhibitor-1 (PAI-1) and fibrinogen levels in South Indian diabetic and non-diabetic subjects with and without CAD. METHODS: Four groups of subjects were studied (all males); Group 1 comprised of non-diabetic subjects without CAD (n=50). Non-diabetic subjects with CAD formed group 2 (n=50); group 3 comprised of type 2 diabetic patients without CAD (n=50) and group 4 consisted of type 2 diabetic patients with CAD (n=50). CAD was diagnosed based on coronary angiographic evidence of severe double or triple vessel disease. RESULTS: Both diabetic and non-diabetic patients with CAD had significantly higher levels of tPA, PAI-1 and fibrinogen compared to non-diabetic without CAD (p < 0.05). Patients with CAD were distributed more in the upper tertiles of these risk factors compared to those without CAD. A strong association between tPA and PAI-1 was noted in the Pearson's correlation analysis (p < 0.001). Univariate regression analysis showed tPA (Odds ratio--1.12, p = 0.03), PAI-1 (Odds ratio--1.03, p = 0.008), fibrinogen (Odds ratio--1.01, p < 0.0001), serum cholesterol (Odds ratio--1.008, p = 0.04) and hypertension (Odds ratio--3.7, p = 0.0001) to be associated with CAD. Multiple logistic regression analysis revealed hypertension (Odds ratio--4.6, 95% confidence interval--2.113-9.950, p = 0.0001) and fibrinogen (Odds ratio--1.012, 95% confidence interval--1.007-1.018, p = 0.0001) as risk factors for CAD. CONCLUSION: Our study suggests that prothrombogenic risk factors particularly fibrinogen may be associated with CAD in South Indians.

Plasma plasminogen activator inhibitor-1 activity in normoglycemic hypertriglyceridemic north Asian Indian subjects: a preliminary case-control study.

BACKGROUND: Recent evidence suggests that increased activity of plasma plasminogen activator inhibitor-1, an important component of the insulin resistance syndrome, plays a crucial role in the pathogenesis of atherosclerosis. METHODS AND RESULTS: In this case-control study, relationships between plasma plasminogen activator inhibitor-1 activity, serum triglyceride levels and hyperinsulinemia were explored in 40 non-diabetic patients with primary hypertriglyceridemia (Group 1) and 40 non-diabetic normotriglyceridemic controls (Group 2) matched for potential confounders like smoking and physical activity. Mean values of fasting serum insulin levels were increased in Group 1 (p>0.05). Hyperinsulinemia was observed in 14 (17.5%) individuals in Group 1 and 11 (13.8%) individuals in Group 2. Mean plasma plasminogen activator inhibitor-I activity in Group 1 (9.8+/-8.4 IU) was higher than in Group 2 (7.0+/-7.7 IU), though the difference was not significant (p>0.05). However, when only subjects with elevated levels of plasma plasminogen activator inhibitor-1 activity were taken into account, mean values were significantly higher in Group 1 (p<0.05). The plasma plasminogen activator inhibitor-1 activity was higher in subjects with body mass index >25 in both the groups, significantly so in males (p=0.05). Hyperinsulinemic subjects with a body mass index >25 and raised serum triglyceride levels had higher mean values of plasma plasminogen activator inhibitor-1 activity (18.42+/-11.15 IU) than subjects with similar characteristics and normal triglyceride levels (14.22+/-8.20 IU, p<0.05). CONCLUSIONS: Though in the current study a trend for hyperinsulinemia and high plasma plasminogen activator inhibitor-1 activity was observed in hypertriglyceridemic subjects, a larger study is needed to achieve significant differences and correlations. Obese male subjects, irrespective of their lipid profile, are at risk for thrombotic events in view of their significantly higher plasma plasminogen activator inhibitor-1 values. Procoagulant tendency is further enhanced if hypertriglyceridemia and hyperinsulinemia are added on to obesity.