Plasminogen Activator Inhibitor-1 Values Research Articles

Abstract 1103: The Relationship Between PAI-1, Corticosterone, And Splenic Activity: Data From The Washington, D.C. Cardiovascular Health And Needs Assessment

Background: Chronic psychosocial stress (CS) has been associated with cardiovascular disease (CVD) which disproportionally affects African Americans (AA) at least partially via activation of the neuro-hematopoietic axis. Prior studies suggest plasminogen activator inhibitor 1 (PAI-1) is associated with hypertension, obesity, atherosclerosis, and major adverse cardiac events. Yet, little is known about the connection between CS and PAI-1 and its potential association with the neuro-hematopoietic axis in AA. Research Question: We examined associations between measures of CS and PAI-1 in a community-based cohort of AA residing in resource-limited Washington, D.C. neighborhoods, at risk for CVD. Methods: Participants were enrolled in the Washington, D.C. CV Health and Needs Assessment (DC-CHNA). CS was evaluated using the Cohen Stress Scale questionnaire. Fasting blood samples were taken to measure circulating levels of PAI-1 as well as cortisol and corticosterone, known biomarkers of stress. Participants underwent 18 FDG PET/CT to measure metabolic activity of the amygdala, bone marrow, and spleen, indicators of the neuro-hematopoietic axis. Multivariable linear regression analyses were adjusted for BMI and ASCVD 10-year risk score. Results: The DC-CHNA consisted of AA, the majority of whom were women, (N=60, mean age: 61±10.52, mean BMI: 33±7.85) at intermediate risk for CVD. Higher CS scores associated with higher PAI-1 levels (β=0.32, p=0.02). Higher PAI-1 associated with higher corticosterone (β=0.35, p=0.01) but not cortisol. Additionally, higher corticosterone associated with splenic activity (β=0.46, p=0.03) but not amygdala or bone marrow activity. Subsequently, higher PAI-1 also associated with higher splenic activity (β=0.22, p=0.01), while bone marrow activity was shown to be trending (β=0.14, p=0.06). Conclusions: We found that chronic psychosocial stress is associated with higher PAI-1 levels, which are associated with corticosterone and splenic activity, thus providing a potential link to how CS contributes to disparate CVD risk and health outcomes. Larger longitudinal studies are needed to investigate the predictive and potential therapeutic value of PAI-1 in individuals at risk for CVD.

ФУНКЦИОНАЛЬНАЯ АКТИВНОСТЬ ЭНДОТЕЛИЯ В СИСТЕМНОМ И МЕСТНОМ КРОВОТОКЕ У ПАЦИЕНТОВ ОБЛИТЕРИРУЮЩИМ АТЕРОСКЛЕРОЗОМ И РАЗВИТИЕ РЕСТЕНОЗА ПОСЛЕ ОПЕРАЦИИ БЕДРЕННО-ПОДКОЛЕННОГО ШУНТИРОВАНИЯ

Objective: To analyze the role of markers of the endothelial dysfunction in the vessels of the systemic and local blood flow before and after femoropopliteal bypass surgery (FPBS) in the development of restenosis at obliterating lesions of the femoropopliteal arterial segment (FPAS). Methods: The results of the examination and treatment of 82 patients with obliterating atherosclerosis who underwent FPBS were analyzed. Before and after surgery they underwent testing for serum homocysteine, oxidized low-density lipoprotein, soluble vascular cell adhesion molecule-1 (sVCAM-1), plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), and annexin V in the systemic and local blood flow. Based on the condition of the reconstruction zone after 12 months, all patients were divided into two groups. Group 1 included patients without restenosis (n=21), and Group 2 – with restenosis (n=61). Results: Before surgery Group 2 patients showed significant differences in the severity of adhesive and hemostatic forms of endothelial dysfunction, as well as apoptosis in comparison with Group 1. It was found that before surgery, Group 2 patients had a significantly higher level of sVCAM-1 in the local bloodstream (by 37.5%, p=0.014), PAI-1 in the systemic and local bloodstream (by 15.6%, p=0.010, and by 16.4%, p=0.008 respectively) and annexin V in the systemic and local bloodstream (by 48.9%, p=0.012 and by 60.2%, p=0.002 respectively). After surgery Group 2 patients had significantly higher levels of PAI-1 in the systemic (by 18.9%, p=0.004) and local (by 11.1%, p=0.049) blood flow, and annexin V in the systemic circulation (by 28.4%, p=0.011) compared with Group 1. Thus increased levels of sVCAM-1 in the local bloodstream, PAI-1, and annexin V – in the systemic and local bloodstream before surgery were associated with postoperative development of restenosis, while higher values of PAI-1 in the systemic and local bloodstream and annexin V in the systemic circulation after surgery were related to subsequent restenosis development. Conclusion: The results of the study indicate impairment of the adhesive and hemostatic function of the endothelium, and increased level of apoptosis in the blood vessels of systemic and local blood flow in patients with restenosis, which can be used to develop personalized approach to management of this disorder and improve the results of revascularization interventions on FPAS. Keywords: Obliterating atherosclerosis of the lower extremities, femoropopliteal bypass surgery, functional activity of the endothelium, restenosis.

Plasminogen Activator Inhibitor-1 Potentiates Neutrophil Infiltration and Tissue Injury in Colitis.

The mechanism underlying inflammatory bowel disease (IBD) remains unclear. We aimed to identify early diagnostic biomarkers and understand their roles in the pathogenesis of IBD. Methods: We identified plasminogen activator inhibitor-1 (PAI-1) as a potential key gene that is upregulated in IBD based on published transcriptomic datasets. To further determine the role of PAI-1 in disease pathogenesis, we induced colitis in wild-type (WT) and PAI-1 knockout (KO) mice by administering dextran sulfate sodium (DSS). We used an RNA array of genes and 16S rRNA sequencing of the microbiome to analyze PAI-1 function. The colon and serum PAI-1 levels in humans were further evaluated for their diagnostic value. Results: PAI-1 expression was significantly increased in patients and DSS-induced WT mice but reduced in PAI-1 KO mice. These changes were associated with significantly decreased neutrophil infiltration in colonic tissues. The RNA array revealed that the CXC chemokines CXCL1 and CXCL5 and their common receptor CXCR2 were among the most significantly different genes between the PAI-1 KO mice with DSS-induced colitis and the WT mice. Mechanistically, PAI-1 deficiency led to blunted activation of the NF-κB pathway in the colon epithelium. The gut microbiome was altered in the PAI-1 KO mice, which showed enriched abundances of short-chain fatty acid-producing genera and diminished abundances of pathogenic genera. Receiver operating characteristic (ROC) curve analysis revealed the diagnostic value of PAI-1. Conclusions: Our data suggest a previously unknown function of PAI-1 inducing neutrophil-mediated chemokine expression by activating the NF-κB pathway and affecting the function of the gut microbiome. PAI-1 could be a potential diagnostic biomarker and a therapeutic target in IBD.

Plasminogen activator inhibitor-1, thrombin-antithrombin, and prothrombin fragment F1+2 have higher diagnostic values than D-dimer for venous thromboembolism after TKA.

ObjectiveTo investigate the diagnostic values of D-dimer, plasminogen activator inhibitor-1 (PAI-1), thrombin–antithrombin (TAT), and prothrombin fragment F1 + 2 (F1 + 2) for predicting venous thromboembolism (VTE) after total knee arthroplasty (TKA).MethodsUltrasonography and CTPA were performed to diagnose VTE in 252 patients who underwent TKAs. Plasma D-dimer, PAI-1, TAT, and F1 + 2 levels were assessed 1–3 days prior to operation (T1), second hour (T2), first (T3), and third day (T4) after the operation. Receiver–operating characteristic curves (ROC) analysis was conducted and pairwise compared to evaluate the diagnostic value of those biomarkers.ResultsPlasma D-dimer levels differed between patients with and without VTE significantly on T4, PAI-1, TAT, and F1 + 2 levels differed on T3 and T4. The areas under ROC of D-dimer, PAI-1, TAT and F1 + 2 levels were 0.645, 0.773, 0.771 and 0.797, respectively. The most feasible cutoff values of D-dimer, PAI-1, TAT and F1 + 2 in predicting VTE after TKA were 2.24 ug/ml, 35.96 ng/ml, 13.36 ng/mg and 11.1 ng/ml, respectively. Pairwise comparison of ROC curves revealed that D-dimer level had the lowest diagnostic accuracy, whereas PAI-1, TAT and F1 + 2 level had similar diagnostic accuracy. There were significant differences in duration of tourniquet time and duration of anesthesia between patients with and without VTE.ConclusionAfter TKA, using 2.24ug/mL as the threshold value of D-dimer is more accurate than using 0.5ug/mL in the monitoring of VTE, PAI-1, TAT and F1 + 2 are more valuable than D-dimer in predicting VTE. Duration of tourniquet and duration of anesthesia are risk factors for the development of VTE.

The predictive value of plasminogen activator inhibitor-1, fibrinogen, and D-dimer for deep venous thrombosis following surgery for traumatic lower limb fracture.

Deep venous thrombosis (DVT) is a common postoperative complication in patients with lower limb fractures. This study aims to investigate the predictive value of plasminogen activator inhibitor-1 (PAI-1), fibrinogen (FIB), and D-dimer (D-D) for DVT following lower limb traumatic fracture surgery and to investigate risk factors for DVT. Clinical data of 63 patients who underwent lower limb traumatic fracture surgery in our hospital from September 2018 to March 2019 were retrospectively analyzed. Patients were divided into a DVT group and a non-DVT group. The differences in the levels of plasminogen activator inhibitor-1 (PAI-1), fibrinogen (FIB), and D-dimer (D-D) were compared, and a receiver operating characteristic (ROC) curve was used to analyze their predictive value for DVT following surgery for lower limb traumatic fracture. Multiple logistic regression analysis was used to analyze the risk factors of DVT. The levels of PAI-1, FIB, and D-D in the DVT group were higher on the third day after surgery compared to the pre-surgical levels, and were also higher than those in the non-DVT group (P<0.05). The area under the ROC curve indicated that the predictive values of PAI-1, FIB, D-D, and the combination of these three indicators for DVT were 0.792, 0.429, 0.966, and 0.992, respectively. Patients with preexisting factors including a BMI ≥24 kg/m2 , a history of diabetes, postoperative infection, an abnormal white blood cell count, an abnormal average thrombocytocrit, and abnormal levels of PAI-1, FIB, and D-D had a higher incidence of DVT following surgery compared to patients without these factors (P<0.05). The results of the multivariate logistic regression model analysis showed that the presence of postoperative infection, abnormal white blood cell count, abnormal mean platelet volume, and abnormal levels of PAI-1, FIB, and D-D were independent risk factors affecting postoperative DVT in patients with lower limb fractures (P<0.05). The levels of PAI-1, FIB, and D-D were significantly increased in patients with DVT following surgery for lower limb fractures. Therefore, early monitoring of PAI-1, FIB, and D-D levels, and coagulation function is a good predictive indicator of postoperative thrombosis.

The urokinase-type plasminogen activator and inhibitors in resectable lung adenocarcinoma

BackgroundThe urokinase-type plasminogen activator (uPA) system is closely related to the occurrence and progression of cancer in many aspects. Previous studies demonstrated that the conclusions about the prognosis value of uPA, plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) in lung cancer are controversial, so this study was performed for the exploration of the predictive effect of uPA, PAI-1 and PAI-2 on the overall survival (OS) of resectable pulmonary adenocarcinoma patients. MethodsUPA, PAI-1 and PAI-2 expression levels were assayed by immunohistochemical staining based on tissue microarray (TMA) that is composed of formalin-fixed paraffin-embedded specimens from 84 resectable lung adenocarcinoma patients from July 2004 to June 2009. The relationship of IHC, mRNA expression levels of three molecules were investigated respectively. The three molecules’ relationship with clinicopathologic parameters and OS was explored by Chi-square, Kaplan-Meier, and Cox regression analyses. The Cancer Genome Atlas (TCGA) database was used to analyze differential gene expressions of RNA-sequencing data of pulmonary adenocarcinoma and normal tissues, and Kaplan-Meier methods were adopted to confirm the prognostic value of uPA, PAI-1 and PAI-2 in resectable lung adenocarcinoma in TCGA database and the R package MethylMix was used to conduct an analysis integrating methylation data and gene expression of RNA-sequencing data based on TCGA. ResultsUPA, PAI-1 and PAI-2 had much higher IHC expression levels in tumor than those in the normal tissues (uPA, Z = -10.511; PAI-1, Z = -4.836; PAI-2, Z = -6.794; all P < 0.0001). High DNA methylation level of gene uPA resulted in the decrease of its expression. In addition, expression level of PAI-2 was positively associated with tumor size (χ2 = 8.372, P = 0.004). Multivariate analyses showed TNM stage III was an independent adverse prognostic factor (hazard ratio = 3.736, 95 % confidence interval = 1.097–12.72, P = 0.035). Kaplan-Meier method revealed that uPA, PAI-1 and PAI-2 expression levels were not related to the OS for 84 resectable lung adenocarcinoma patients. According to TCGA data, PAI-1 expression level was identified as a potential adverse predictor for prognosis of resectable lung adenocarcinoma (Gehan-Breslow-Wilcoxon test, P = 0.025). ConclusionsOur data show that, the expression levels of uPA, PAI-1 and PAI-2 are significantly up-regulated in resectable lung adenocarcinoma. Besides, this study highlights PAI-1 as a latent adverse prognostic factor in resectable adenocarcinoma of lung.

Cardiovascular Risk Indices and Their Impact on Outcome in Patients with Hyperglycaemic Emergencies in a Nigerian Hospital

BackgroundHigh sensitivity C-reactive protein (hsCRP) and Plasminogen Activator Inhibitor-1 (PAI-1) are recognised independent novel risk factors for cardiovascular disease. Few studies have assessed cardiovascular risk factors in patients with hyperglycaemic emergencies (HE), despite it being a major cause of death in diabetics. ObjectiveThe objective of this study was to determine cardiovascular risk indices in patients with hyperglycaemic emergencies and related these with outcome. MethodsThis cross sectional study involved 45 patients that presented with HE and 45 age and sex matched diabetics without HE who served as controls. Historical features, physical findings and laboratory parameters including hsCRP and PAI-1 were compared between subjects and controls. ResultsThe mean values of serum hsCRP and PAI-1 were significantly higher in patients with HE compared to diabetic control. (49.52 ± 13.6 vs. 2.4 ± 1.35, 51.2 ± 28.7 vs. 33.2 ± 10.7 respectively). Traditional cardiovascular risk factors such as HbA1c, Atherogenic Index and microalbuminuria were also significantly higher in them. Mortality was associated with increasing age, higher values of waist circumference, pulse rate, respiratory rate, hsCRP, Atherogenic index and lower blood pressure and HDL values. ConclusionCardiovascular risk indices are higher in patients with HE.

Validating plasminogen activator inhibitor-1 as a poor prognostic factor in sepsis.

Our previous report indicated that plasminogen activator inhibitor-1 (PAI-1) levels of ≥83ng/mL in patients with sepsis tended to be associated with disseminated intravascular coagulation (DIC), suppressed fibrinolysis, multiple organ dysfunction, and mortality. Therefore, the present study aimed to validate whether 83ng/mL was a useful cut-off value for using PAI-1 levels to predict a poor prognosis in sepsis. Patients with sepsis were included in this single-center retrospective study. The patients were classified as having high or low PAI-1 values (<83ng/mL versus ≥83ng/mL), and were compared in terms of their pre-DIC state, intensive care unit-free days, continuous renal replacement therapy-free days, ventilator-free days, catecholamine-free days, and 28-day survival rate. The high PAI-1 group included 61 patients (54%) and the low PAI-1 group included 52 patients (46%). The high PAI-1 group had significantly higher frequencies of a pre-DIC state within 1week (P=0.009). There was no significant difference in ventilator-free days. However, the high PAI-1 group had significantly lower values for intensive care unit-free days (P=0.01), continuous renal replacement therapy-free days (P=0.02), and catecholamine-free days (P=0.02). The high PAI-1 group also had a significantly lower 28-day survival rate based on the Kaplan-Meier analysis (log-rank, P=0.03). Patients with sepsis and PAI-1 levels of ≥83ng/mL had elevated risks of coagulopathy, organ failure, and mortality. Thus, these results suggest that 83ng/mL could be a useful cut-off value for prognostication based on PAI-1 levels in this setting.

To Study the Coagulation Profile Derangements in Metabolic Syndrome

Introduction: The metabolic syndrome is a complex disorder characterized by the presence of a clustering of metabolic risk factors usually in a single individual associated with the presence of central obesity and a strong association with diabetes and cardiovascular disease morbidity and mortality. It is a fast spreading global pandemic &amp; emerging as a public health problem with poor outcome and Quality of life thus more predilection is towards preventive than curative treatment. According to WHO Clinical Criteria, Metabolic syndrome is defined as insulin resistance, identified by 1 of the following, Type 2 diabetes, fasting blood glucose more than 110 mg/dl plus any 2 of the following: antihypertensive medication and /or high blood pressure &gt; 140 mm systolic or &gt;90 mm diastolic, plasma triglyceride (TG) level more than 150 mg/dl (1.7 mmol/L), high-density lipoprotein (HDL) cholesterol level less than 35 mg/dl (0.9 mmol/L) in men or less than 39 (1.0 mmol/L)in women , BMI &gt;30 kg/m2 and/or waist:hip ratio &gt;0.9 in men, &gt; 0.85 in women, Urinary albumen excretion rate &gt; 20 mcg/min or albumin:creatinine ratio&gt;30mg/g Aims &amp; Objectives: To investigate the coagulation profile derangements in metabolic syndrome. To study the relationship of various components of metabolic syndrome with coagulation parameters. Material &amp; Methods: This was a prospective cross-sectional study carried out in Haematology &amp; Medicine Deptt of SafdarJang Hospital, New Delhi. After taking consent from the Hospital Ethics Committee, a total of 50 cases of metabolic syndrome presenting as outpatient or inpatient were included in the study. 50 age &amp; sex matched controls were selected which did not satisfy the criteria for metabolic syndrome. Observation &amp; Results: In our study we found that the cases with metabolic syndrome have significantly increased levels of Fibrinogen, Factor VIII and Plasminogen Activator Inhibitor1 (PAI1). PT &amp; APTT were shorter in cases with metabolic syndrome. The mean value of fibrinogen in cases was 402.24 ± 66.92 mg/dl while that in control was 261.5 ± 41.95 mg/dl with a P value of &lt;.0001 which was statistically significant. The mean value of Factor VIII in cases was 152.66 ± 7.54 IU/dl while that in control was 131.44 ± 6.24 IU/dl with a P value of &lt;.0001 which was statistically significant. The mean value of Plasminogen Activator Inhibitor1 (PAI1) in cases was 49.99 ± 5.34 ng/ml while that in control was 36.75 ± 3.35 ng/ml with a P value of &lt;.0001 which was statistically significant. Prothrombin Time (PT) values in cases were 9.79 ± 0.74 seconds and in controls were 12.04 ± 0.7 seconds &amp; this difference was statistically significant (p&lt;.0001). Activated partial Thromboplastin Time (APTT) values in cases were 28.96 ± 0.92 seconds and in controls were 32.6 ± 1.34 seconds &amp; this difference was statistically significant (p&lt;.0001). Conclusions: The coagulation parameters studied correlated significantly with the components of metabolic syndrome. The values varied significantly with increased number of features of metabolic syndrome. Thus we can conclude that metabolic syndrome is a hypercoagulable state and further studies are required for further evaluation of the consequences of this hypercoagulable state.. Disclosures No relevant conflicts of interest to declare.

Tissue inhibitor metalloproteinase-1, Plasminogen activator inhibitor 1, and neutrophil/lymphocyte ratio as potential early biomarkers for diabetic nephropathy

Background: Albuminuria is used to screen early stages of diabetic nephropathy (DN) but it is limited by the fact that structural damage may precede albumin excretion. This necessitates identifying better biomarkers that diagnose or predict diabetic nephropathy. The study aimed to evaluate tissue inhibitor metalloproteinase-1 (TIMP-1), plasminogen activator inhibitor 1 (PAI-1), and neutrophil/lymphocyte ratio (NLR) as potential biomarkers for early detection of diabetic nephropathy and its progression in patients with type 2 diabetes. Materials and Methods: A total of 88 subjects were included in this cross-sectional hospital-based study, healthy individuals (N=10) and diabetic patients (n= 78). Diabetic patients were classified according to an albumin creatinine ratio (ACR) into normoalbuminuria (A1=30), microalbuminuria (A2=14), and macroalbuminuria (A3 =34). TIMP-1, PAI-1 levels, NLR were measured in all subjects. Multivariate discriminant analysis (MDA) was used to develop a novel index. The diagnostic value of TIMP-1, PAI-1, and NLR was assessed by the area under the receiver operating characteristic (ROC). Results: The mean ± SD of NLR, PAI-1 (ng/ml) and TIMP-1 (ng/ml) in healthy were (1.9±0.30; 6.8 ±2.4 and 76.8±15.7) and in A1 were (3.0 ± 2.5;7.7±1.8 and 91.4±19.8) and in A2 were ( 2.2±1.5; 7.6±1.9 and 104.5±20.9) and in A3 were (5.2±3.9; 8.7±1.2 and 120.6±18.2). The differences between the mean of NLR, PA1-1 and, TIMP in A2 and that of A3 were significant (p <0.007, p =0.03 and, p < 0.011; respectively). TIMP-1 was the most efficient marker with an AUC of 0.72 for discriminant diabetics with A1 from A2; 0.88 for A1 vs A3 and 0.82 for A2 vs A3. A novel index was developed for differentiated between stages of DN based on three blood markers (TIMP-1, PAI-1, and NLR) named TPN. The mean ± SD of TPN index in healthy was (1.1±0.4) and in A1 was (1.2 ±0.3) and in A2 was (1.3 ±0.2) and in A3 were (1.8±0.3) with a highly significant difference between A2 and A3. The AUC of the TPN index was 0.61, 0.88, and 0.88 for discriminant diabetics with A1 from A2, A1 vs A3, and A2 vs A3. Conclusions: A novel index named TPN based on three blood markers (TIMP-1, PAI-1, and NLR) may be potentially useful for early detection and to discriminate macro-albuminuria from micro-albuminuria stages.

Plasminogen Activator Inhibitor 1 for Predicting Sepsis Severity and Mortality Outcomes: A Systematic Review and Meta-Analysis.

Plasminogen activator inhibitor-1 (PAI-1), a crucial regulator of fibrinolysis, is increased in sepsis, but its values in predicting disease severity or mortality outcomes have been controversial. Therefore, we conducted a systematic review and meta-analysis of its predictive values in sepsis. PubMed and Embase were searched until August 18, 2017 for studies that evaluated the relationships between PAI-1 levels and disease severity or mortality in sepsis. A total of 112 and 251 entries were retrieved from the databases, of which 18 studies were included in the final meta-analysis. A total of 4,467 patients (36% male, mean age: 62 years, mean follow-up duration: 36 days) were analyzed. PAI-1 levels were significantly higher in non-survivors than survivors [odds ratios (OR): 3.93, 95% confidence interval (CI): 2.31-6.67, P < 0.0001] and in patients with severe sepsis than in those less severe sepsis (OR: 3.26, 95% CI: 1.37-7.75, P = 0.008). PAI-1 is a significant predictor of disease severity and all-cause mortality in sepsis. Although the predictive values of PAI-1 reached statistical significance, the clinical utility of PAI-1 in predicting outcomes will require carefully designed prospective trials.

PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma.

In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC. Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed. Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035). Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients.

The Role of Pai-1 Gene 4g/5g Polymorphism and Diagnostic Value of Biomarkers in Allergic and Non-Allergic Asthma Phenotype.

SUMMARY – Asthma is a chronic inflammatory disease that is characterized by reversible obstruction of airways, bronchial hyper-reactivity and airway remodeling. The etiology of asthma is multifactorial, with inheritance playing an important role. The aim of our study was to investigate the importance of biomarkers of asthma and the role of plasminogen activator inhibitor-1 (PAI-1) gene as a genetic factor that could be involved in the pathogenesis of asthma. The research was conducted at Jordanovac University Department for Lung Diseases and Croatian Institute of Transfusion Medicine. The research included 149 patients with asthma and 89 healthy individuals. We collected demographic data of both study groups, determined asthma severity using GINA guidelines, and the values of biomarkers and PAI-1 by using laboratory techniques. Based on the results, we concluded that patients with allergic phenotype of asthma were younger, had better lung function and higher levels of IgE. By observing FeNO values, we were not able to distinguish asthmatic patients that had been diagnosed with obstruction of airways from asthmatic patients with normal lung function because FeNO indicates the inflammatory component of disease. The 4G/5G polymorphism of PAI-1 gene did not show any statistically significant difference in the distribution of 4G/4G, 4G/5G and 5G/5G between the group of asthmatic patients and control group.

Early pregnancy plasminogen activator inhibitor-1 levels in Nigerian women and its relationship with preeclampsia.

This study compared early plasma levels of plasminogen activator inhibitor-1 (PAI-1) in normal pregnancy and preeclampsia and determined its relationship with disease severity. This was a prospective cohort study of 195 normotensive, aproteinuric pregnant women without prior history of gestational hypertension. The women were attending the Antenatal Clinic at The Lagos University Teaching Hospital and were within 24 weeks gestation at recruitment. The outcome measures were PAI-1, systolic blood pressure (SBP), diastolic blood pressure (DBP), and significant proteinuria. The endpoint of the study was the development of preeclampsia. The diagnosis of preeclampsia was made by the attending Obstetrician. The data were analyzed using the IBM SPSS statistical software. Statistical significance was set at P < 0.05. First trimester PAI-1 levels were significantly higher in the women who later developed preeclampsia compared to those who had a normal pregnancy (P < 0.0001). In these group of women who later developed preeclampsia, PAI-1 had an inverse relationship with gestational age (r = 0.878) whereas in normal pregnancy, PAI-1 and gestational age had a direct relationship (r = 0.017). Second trimester systolic and DBP values were also significantly higher in the women who later developed preeclampsia compared to normal pregnancy, P = 0.007 and 0.004, respectively. There was, however, no correlation between PAI-1 values and SBP, DBP and proteinuria in the women who developed preeclampsia. Plasma levels of PAI-1 are increased early in pregnancies complicated by preeclampsia, but the lack of correlation of this marker with disease severity may limit its clinical utility.

Evaluation of Fibrinolytic Inhibitors: Alpha-2-Antiplasmin and Plasminogen Activator Inhibitor 1 in Patients with Obstructive Sleep Apnoea.

Obstructive sleep apnoea (OSA) induces thrombophilia and reduces fibrinolysis. Alpha-2-antiplasmin (a-2-AP) and plasminogen activator inhibitor 1 (PAI-1) are major inhibitors of the fibrinolytic system. Increased concentrations of these factors are associated with a higher risk of cardiovascular diseases. The aim of this study was to assess plasma a-2-AP and PAI-1 in patients with OSA and evaluate correlations with the polysomnographic record and selected risk factors of cardiovascular diseases. The study group comprised 45 patients with OSA, and the control group consisted of 19 patients who did not meet the diagnostic criteria of OSA. Plasma a-2-AP and PAI-1 concentrations were assessed by enzyme-linked immunosorbent assay (ELISA). In the study group, the median value of plasma a-2-AP was higher than that of the control group (157.34 vs. 11.89 pg/ml, respectively, P<0.0001). A-2-AP concentration increased proportionally to the severity of OSA. The concentration of a-2-AP was positively correlated with the apnoea-hypopnoea index (AHI), apnoea index (AI), respiratory disturbances time (RDT), and desaturaion index (DI), and negatively correlated with mean and minimal oxygen saturation (SpO2 mean, SpO2 min, respectively). The median value of PAI-1 was higher in the study group than the control group (12.55 vs. 5.40 ng/ml, respectively, P = 0.006) and increased along with OSA severity. PAI-1 concentration was positively correlated with AHI, AI, RDT, DI, and body mass index (BMI) and negatively correlated with SpO2 mean and SpO2 min. Higher plasma concentrations of a-2-AP and PAI-1 in patients with OSA indicated that these patients had increased prothrombotic activity. OSA increases the risk of cardiovascular complications as it enhances prothrombotic activity.

The impact of dietary flavonoid supplementation on smoking-induced inflammatory process and fibrinolytic impairment

Background and aimsSmoking is associated with increased inflammatory process and impairment of fibrinolytic status. Concord grape juice (CGJ), a rich source of flavonoids, can modify cardiovascular risk factors. We aimed to evaluate the impact of CGJ on smoking-induced impairment of inflammatory and fibrinolytic status in healthy smokers. MethodsWe studied the effect of a 2-week oral treatment with CGJ in 26 healthy smokers on three occasions (day 0: baseline, day 7 and day 14) in a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm) and 20 min after (Sm20) cigarette smoking. Serum levels of intercellular adhesion molecule-1 (sICAM-1) and plasminogen activator inhibitor 1 (PAI-1) were measured as markers of inflammatory and fibrinolytic status, respectively. ResultsTreatment with CGJ reduced pSm sICAM-1 levels (p < 0.001), while placebo had no impact on ICAM-1 levels (p = 0.31). Moreover, treatment with CGJ decreased pSm values of PAI-1 (p < 0.001) while placebo had no impact on PAI-1 levels (p = 0.89). Smoking induced an elevation in PAI-1 levels after smoking compared to pro-smoking levels in all study days and in both arms (CGJ and placebo) of the study (p < 0.001 for all). Interestingly, CGJ compared to placebo, attenuated the acute smoking increase in sICAM-1 and PAI-1 levels (p < 0.001 and p = 0.005 respectively). ConclusionsCGJ consumption improved inflammatory and fibrinolytic status in healthy smokers and attenuated acute smoking induced increase in ICAM-1 and PAI-1 levels. These findings shed further light on the favorable effects of flavonoids in cardiovascular health.

Plasminogen activator inhibitor-1 and type 2 diabetes: a systematic review and meta-analysis of observational studies.

An emerging body of evidence has implicated plasminogen activator inhibitor-1 (PAI-1) in the development of type 2 diabetes (T2D), though findings have not always been consistent. We systematically reviewed epidemiological studies examining the association of PAI-1 with T2D. EMBASE, PubMed, Web of Science, and the Cochrane Library were searched to identify studies for inclusion. Fifty-two studies (44 cross-sectional with 47 unique analytical comparisons and 8 prospective) were included. In pooled random-effects analyses of prospective studies, a comparison of the top third vs. bottom third of baseline PAI-1 values generated a RR of T2D of 1.67 (95% CI 1.28–2.18) with moderate heterogeneity (I2 = 38%). Additionally, of 47 cross-sectional comparisons, 34(72%) reported significantly elevated PAI-1 among diabetes cases versus controls, 2(4%) reported significantly elevated PAI-1 among controls, and 11(24%) reported null effects. Results from pooled analyses of prospective studies did not differ substantially by study design, length of follow-up, adjustment for various putative confounding factors, or study quality, and were robust to sensitivity analyses. Findings from this systematic review of the available epidemiological literature support a link between PAI-1 and T2D, independent of established diabetes risk factors. Given the moderate size of the association and heterogeneity across studies, future prospective studies are warranted.

Pleural Effusion and Plasma Levels of Fibrinolytic Parameters in Tuberculosis Pleurisy and Contribution to the Diagnosis

Objective: The presence of a relationship between tuberculosis and hypercoagulability has been reported. In the case of the occurrence of hypercoagulability, the body responds by activating the fibrinolytic system. In this study, we aimed to investigate the values of fibrinolytic parameters and their contribution to the diagnosis in patients with tuberculosis pleurisy (TP). Methods: Forty four patients with tuberculosis pleurisy (30 cases), malignant plural effusion (8 cases), and transudative pleural effusion (6 cases) were involved in the study. Transudative and malignant fluids constituted the control group. The concentrations of pleural fluid and plasma D-Dimer, fibrinogen, tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), t-PA/PAI-1 complexes and serum, and pleural fluid, adenosine deaminase (ADA), glucose, lactate hydrogenase (LDH), total protein and albumin levels of the cases were measured. Results: In the patients with tuberculosis pleurisy, the values of pleural fluid fibrinogen and pleural fluid PAI-1 were found to be significant ly higher according to the results of Mann-Whitney U test (p≤0.05 and p≤0.001, respectively). Conclusion: In tuberculosis pleurisy, fibrinolytic system activates in parallel with the increased hypercoagulation and fibrinolytic parame ters also increase. These parameters can be benefited unless the diagnosis of tuberculosis pleurisy can be established through conventional diagnostic methods.

Saturated Fatty Acid Intake Can Influence Increase in Plasminogen Activator Inhibitor-1 in Obese Adolescents

The aim of this study was to verify if saturated fatty acid intake adjusted by tertiles can influence metabolic, inflammation, and plasminogen activator inhibitor-1 (PAI-1) in obese adolescents. Body mass, height, body mass index, waist circumference, blood pressure, and body composition of 108 obese adolescents were obtained. Fasting glucose, insulin, PAI-1, and CRP were determined. Insulin resistance was assessed by Homeostasis Model Assessment (HOMA-IR) and insulin sensitivity by Quantitative Insulin Sensitivity Check Index (QUICKI). Dietetic intake was estimated by a 3-day dietary record, and volunteers were divided according to consumption of saturated fatty acids: tertile 1 [Low Saturated Fatty Acid Intake (Low-SFA): ≤12.14 g], tertile 2 [Moderate Saturated Fatty Intake (Moderate SFA intake): 12.15-20.48 g], and tertile 3 [High Saturated Fatty Acid Intake (High-SFA Intake); >20.48 g]. Statistical analysis was performed using STATISTICA 7.0 software and the significance level was set at p<0.05. The most important finding in the present study is that Moderate and High-SFA intakes presented significantly higher values of PAI-1 than Low-SFA Intake. PAI-1 was positively associated with saturated fatty intake, waist circumference, mean blood pressure, and HOMA-IR. SFA intake was predictor of PAI-1 independent of body fat, HOMA-IR and total-cholesterol. In addition, PAI-1 was an independent predictor of blood pressure. HOMA-IR and QUICKI presented significantly higher and lower, respectively, in High-SFA compared to Moderate-SFA intake. High-SFA influenced cardiovascular disease risks, since it increased PAI-1 and insulin resistance, and decreased insulin sensibility, leading to vicious cycle among food ingestion, pro-thrombotic state, and cardiovascular risks in obese adolescents.

Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

An independent role of nonalcoholic fatty liver disease (NAFLD) in the development of cardiovascular disease has been suggested, probably mediated through increased levels of prothrombotic factors. Therefore, we examined whether NAFLD is linked to a prothrombotic state, independently of metabolic risk factors in a large single-center cohort of overweight/obese patients. Patients presenting to the obesity clinic underwent a detailed metabolic and liver assessment, including an extensive panel of coagulation factors. If NAFLD was suspected, a liver biopsy was proposed. A series of 273 consecutive patients (65% female) with a liver biopsy were included (age, 44 ± 0.76 years; body mass index: 39.6 ± 0.40 kg/m(2)). Increase in fibrinogen, factor VIII, and von Willebrand factor and decrease in antithrombin III correlated with metabolic features, but not with liver histology. Levels of plasminogen activator inhibitor-1 (PAI-1) increased significantly with increasing severity of steatosis (P < 0.001), lobular inflammation (P < 0.001), ballooning (P = 0.002), and fibrosis (P < 0.001). Patients with nonalcoholic steatohepatitis had significantly higher PAI-1 values than those with normal liver (P < 0.001). In multiple regression, including anthropometric and metabolic parameters, steatosis remained an independent predictor of PAI-1 levels, explaining, together with fasting C-peptide and waist circumference, 21% of the variance in PAI-1. No consistent correlations with histology were found for the other coagulation factors. In obesity, NAFLD severity independently contributes to the increase in PAI-1 levels, whereas other coagulation factors are unaltered. This finding might, in part, explain the increased cardiovascular risk associated with NAFLD.