Plasminogen Activator Inhibitor Type 1 Levels Research Articles

DYNAMICS OF THE LEVELS OF ASYMMETRIC DIMETHYLARGININE AND PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1 IN PATIENTS WITH ACUTE ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION AND TYPE 2 DIABETES MELLITUS DEPENDING ON THE REPERFUSION STRATEGY

Introduction. Despite the major successes achieved in the treatment of acute coronary syndromes (ACS), acute myocardial infarction (AMI) remains the main cause of death among the working-age population of Ukraine. The means of treatment of interventional cardiology can actually reduce the mortality of patients with ACS, improve the course of the acute period of the disease and ensure less reduction in the functional capabilities of the heart in the future. Among the many pathogenetic mechanisms of vascular inflammation in coronary heart disease and type 2 diabetes, endothelial dysfunction is the determining factor.
 The aim of the study. To evaluate the levels of plasminogen activator inhibitor type 1, asymmetric dimethylarginine and endothelial nitric oxide synthase on the 10-14th day in patients depending on the presence or absence of concomitant diabetes type 2 and the type of reperfusion therapy.
 Materials and methods. 130 patients with acute myocardial infarction were examined, who were divided into 2 groups: 1 group consisted of patients with acute myocardial infarction with accompanying type 2 diabetes (n=73), 2 group – patients with acute myocardial infarction without type 2 diabetes (n =57). The quantitative content of the plasminogen activator inhibitor type 1 (PAI-1) was determined by the immunoenzymatic method using a commercial test system manufactured by Technoclone PAI-1 ELISA Kit (Austria), endothelial nitric oxide synthase (NOS) – Enzyme-Linked Immunosorbent Assay (ELISA) Kit For Nitric Oxide Synthase Endothelial, asymmetric dimethylarginine (ADMA) – Immunodiagnostik ADMA ELISA Kit (Austria).
 Results. Percutaneous coronary intervention (PCI) contributes to a more significant decrease in the content of the marker of endothelial dysfunction – ADMA and an increase in NOS on the 10-14th day of acute myocardial infarction in comparison with standard therapy. During PCI, the level of PAI-1 did not reliably change during treatment due to post-inflammatory and post-traumatic activation of platelets in the vascular wall.
 Conclusions. In patients with acute myocardial infarction with type 2 diabetes mellitus, percutaneous coronary intervention contributes to a significant decrease in the content of asymmetric dimethylarginine and an increase in NOS on the 10-14th day of acute myocardial infarction, but was not accompanied by a significant decrease in the level of PAI-1, which in general indicates positive effect of performed myocardial revascularization.

P421 The faecal biomarker LDN-051 is a novel tool for monitoring disease activity and therapeutic response in Inflammatory Bowel Diseases

Abstract Background Crohn’s disease and ulcerative colitis, two forms of inflammatory bowel disease (IBD) require lifelong treatment and patient monitoring. Current predictors of relapse and therapeutic success have limitations, therefore there is high unmet need to identify novel biomarkers in IBD. Monitoring approaches for IBD are mostly invasive, time-consuming, and expensive. Therefore, a simple, rapid, and non-invasive test, with ability to differentiate IBD from other gastrointestinal conditions and to monitor disease activity, will have important clinical implications. Our previous mucosal cytokine profiling identified that Plasminogen activator inhibitor type 1 (PAI-1) is expressed in IBD patients with active disease, but not in control. Therefore, our aim was to assess the utility of PAI-1 in monitoring disease activity and therapeutic response of IBD patients in different biological samples. Methods Serum, biopsy and faecal samples were collected from 132 IBD patients and 30 controls without IBD. ELISA method was used to define the level of PAI-1 in the mucosa, serum, and faecal samples and the serum CRP levels were also determined. For the mucosal gene expression analysis qRT-PCR was used. The correlation and ROC analyses were applied to observe the relationship between the disease activity and PAI-1 level. Results The applied screening approach detected significant higher expression of PAI-1 in active IBD. We demonstrated that the serum, mucosal and faecal PAI-1 concentration was significantly elevated in IBD patients showing clinical and endoscopic activity. Additionally, in responder patients the initial PAI-1 level decreased significantly upon successful therapy, whereas it remained unchanged in non-responders. We also showed that faecal PAI-1 selectively increases in active IBD patients, but not in other organic gastrointestinal diseases. In addition, the stability analysis of faecal PAI-1 showed that the protein was detectable up to one week at room temperature and 4ºC. The serum, mucosal and faecal PAI-1 level showed positive correlation to the endoscopic activity. ROC curves demonstrated that faecal PAI-1 showed a relatively high power to distinguish between active and control patients. However, the serum CRP level no reflected to the therapeutic response. Conclusion Our results suggest that serum, mucosal and faecal PAI-1 expression reflects to the disease activity in IBD, which could be used to disease monitoring and possibly therapeutic response. The correlation between the faecal PAI-1 level and the endoscopic activity promotes that it could be used as a novel non-invasive disease specific faecal biomarker in the IBD diagnosis.

PAI-1 as a critical factor in the resolution of sepsis and acute kidney injury in old age.

Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our prior work demonstrated that PAI-1 in plasma is positively associated with acute kidney injury (AKI) in septic patients and mice. The objective of this study was to determine if PAI-1 is causally related to AKI and worse sepsis outcomes using a clinically-relevant and age-appropriate murine model of sepsis. Sepsis was induced by cecal slurry (CS)-injection to wild-type (WT, C57BL/6) and PAI-1 knockout (KO) mice at young (5-9months) and old (18-22months) age. Survival was monitored for at least 10 days or mice were euthanized for tissue collection at 24 or 48h post-insult. Contrary to our expectation, PAI-1 KO mice at old age were significantly more sensitive to CS-induced sepsis compared to WT mice (24% vs. 65% survival, p = 0.0037). In comparison, loss of PAI-1 at young age had negligible effects on sepsis survival (86% vs. 88% survival, p = 0.8106) highlighting the importance of age as a biological variable. Injury to the kidney was the most apparent pathological consequence and occurred earlier in aged PAI-1 KO mice. Coagulation markers were unaffected by loss of PAI-1, suggesting thrombosis-independent mechanisms for PAI-1-mediated protection. In summary, although high PAI-1 levels are clinically associated with worse sepsis outcomes, loss of PAI-1 rendered mice more susceptible to kidney injury and death in a CS-induced model of sepsis using aged mice. These results implicate PAI-1 as a critical factor in the resolution of sepsis in old age.

Clinical and diagnostic significance of plasminogen activator inhibitor type 1 in the early development of coronary heart disease

Aim to determine the quantitative content of the tissue plasminogen activator inhibitor type 1 (PAI-1) and to determine its relationship with risk factors for coronary artery disease.
 Material and methods. The study included 67 male and female patients (36 men and 31 women) with coronary artery disease (CAD) and stable angina classes II-IV with the presence of hypertension. The mean age of the patients was 60.20.76 years. In all patients, clinical and anamnestic data were collected during the examination. For pain assessment, we used a verbal scale. We registered the anthropometric data and body mass index. Biochemical and instrumental methods of research were used according to the standards for diagnosing CAD. We assessed the occurrence of risk factors in patients included in the study. A complex of general clinical laboratory and instrumental tests was used, as well as the method of enzyme immunoassay ELISA, which determined the level of PAI-1, platelet aggregation activity, renin, aldosterone, cortisol and endothelin.
 Results. The group of patients demonstrated a reliable elevation of PAI-1 plasma level. Compared with practically healthy people, the level of this biomarker was 1.6 times higher in patients with coronary artery disease. A significant elevation of PAI-1 level indicates an increased risk of endothelial and hemostasiological disorders in patients, which, in turn, increases the risk of thrombogenic complications. The study revealed the correlation of PAI-1 protein in CAD patients with such risk factors as mixed anxiety-depressive disorder, smoking, hypertension, obesity, and hypercholesterolemia.

Diurnal Oscillations of Fibrinolytic Parameters in Patients with Acute Myocardial Infarction and Their Relation to Platelet Reactivity: Preliminary Insights

There is limited information about diurnal changes in fibrinolysis parameters after acute myocardial infarction (AMI) and their relationship with on-treatment platelet reactivity. The aim of this study was to assess tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2-AP) activity, and plasmin-antiplasmin (PAP) complexes in 30 AMI patients taking dual antiplatelet therapy (DAPT), i.e., acetylsalicylic acid and clopidogrel. Fibrinolytic parameters were assessed at four time points (6 a.m., 10 a.m., 2 p.m., and 7 p.m.) on the third day after AMI using immunoenzymatic methods. Moreover, platelet reactivity was measured using multiple-electrode aggregometry, to assess potential differences in fibrinolytic parameters in low/high on-aspirin platelet reactivity and low/high on-clopidogrel platelet reactivity subgroups of patients. We detected significant diurnal oscillations in t-PA and PAI-1 levels in the whole study group. However, PAP complexes and α2-AP activity were similar at the analyzed time points. Our study reveals a potential impact of DAPT on the time course of fibrinolytic parameters, especially regarding clopidogrel. We suggest the presence of diurnal variations in t-PA and PAI-1 concentrations in AMI patients, with the highest levels midmorning, regardless of platelet reactivity. Significantly elevated levels of PAI-1 during the evening hours in clopidogrel-resistant patients may increase the risk of thrombosis.

The Role of Plasminogen Activator Inhibitor Type 1 (PAI-1) in Placenta-Mediated Pregnancy Complications: A Systematic Review.

Plasminogen activator inhibitor type 1 (PAI-1) is a main inhibitor of fibrinolysis. The PAI-1 gene (SERPINE1) harbors genetic variants with the potential of modifying plasma levels of PAI-1. A delicate balance exists between the coagulation and fibrinolytic system, and changes in PAI-1 have been suggested to compromise establishment of a successful pregnancy. Therefore, this systematic review investigated the association between genetic variants and/or plasma levels of PAI-1 and placenta-mediated pregnancy complications. An extensive literature search was conducted in PubMed, Embase, and Web of Science on the 29th of April 2021. All studies underwent quality rating according to The Study Quality Assessment Tools checklist provided by National Heart, Lung and Blood Institute. A total of 71 studies were included, among which 60 studies investigated PAI-1 genotypes and 11 studies measured PAI-1 plasma levels. In 32 out of 59 studies, no association was found between the PAI-1 4G/5G polymorphism (rs1799768) and placenta-mediated pregnancy complications, which was stated as no significant difference in the genotype distribution comparing women with and without placenta-mediated pregnancy complications or no significantly increased odds of placenta-mediated pregnancy complications carrying the 4G/4G or 4G/5G genotype. Eight out of 11 studies reported significantly higher PAI-1 plasma levels in preeclamptic women than in women without preeclampsia. In conclusion, no clear evidence indicates that PAI-1 polymorphisms are associated with placenta-mediated pregnancy complications, and the possible association between high PAI-1 plasma levels and preeclampsia needs further investigations. Thus, investigation of PAI-1 genotypes and PAI-1 plasma levels does not currently seem to have a place in daily clinical practice managing placenta-mediated pregnancy complications.

Фібринолітична активність крові у хворих на цукровий діабет 2-го типу в поєднанні з гіпотиреозом

Метою роботи було дослідження рівня інгібітору активатора плазміногену 1-го типу (ІАП-1) в сироватці крові у хворих на цукровий діабет (ЦД) у поєднанні з гіпотиреозом. Під спостереженням перебували 62 хворі на ЦД 2-го типу, з цього числа у 32 був первинний гіпотиреоз. Контрольну групу сформували 20 осіб без порушень вуглеводного обміну й патології щитоподібної залози. У хворих на ЦД 2-го типу виявлені порушення в системі фібринолізу у вигляді підвищення показника ІАП-1, рівень якого має залежність від індексу маси тіла, окружності талії, рівня глікованого гемоглобіну, показників інсулінорезистентності, ліпідного спектра крові, а також наявності мікроальбумінурії. Наявність гіпотиреозу чинить додатковий негативний вплив на показники вуглеводного, ліпідного метаболізму й рівень ІАП-1 у хворих на ЦД 2-го типу.

Endothelial dysfunction biomarkers in sickle cell disease: is there a role for ADMA and PAI-1?

Within the spectrum of sickle cell disease (SCD) are sickle cell anemia (SCA), presence of hemoglobin SS (HbSS), hemoglobin SC disease (HbSC), and sickle cell β-thalassemia (Sβ-thal). Asymmetric dimethylarginine (ADMA) competitively inhibits the binding of arginine to NOS, reducing NO production. In patients with HbSS, increased levels of ADMA have been reported, as well as changes in many hemostatic biomarkers, including the plasminogen activator inhibitor type 1 (PAI-1). We hypothesized that high levels of ADMA and PAI-1 may be associated with more severe SCD. Thus, ADMA and PAI-1 levels were determined in 78 individuals including 38 adult patients with SCD and 40 control subjects. Higher levels of ADMA were shown in HbSS and Sβ-thal patients compared to controls. Concerning PAI-1, all patients showed high levels of PAI-1 compared to controls. As a role of NO in the pathogenesis of SCD has already been established, we concluded that high levels of ADMA should compromise, at least in part, NO synthesis, resulting in endothelial dysfunction. Elevated plasma levels of PAI-1 in all patients may indicate not only endothelial dysfunction but also a hypofibrinolytic state favoring thrombotic complications. Finally, high levels of ADMA and PAI-1 may be associated with more severe SCD.

Plasminogen Activator Inhibitor Type 1 (PAI-1) and Thrombophilia: A 10 Year Retrospective Review of Clinical Data at a Large Children's Hospital

Introduction: Plasminogen activator inhibitor type 1 (PAI-1) is the most important regulator of fibrinolysis. Elevated PAI-1 levels are reported to be prothrombotic and have been associated with cardiovascular disease, obesity and cancer. PAI-1 synthesis is regulated by insulin, glucocorticoids and cytokines like tumor necrosis factor-α. The single base pair guanine deletion 4G PAI-1 genetic polymorphism has been linked to elevation of PAI-1 antigen and/or activity levels. Genotype frequencies in Caucasian populations have been estimated at 0.25 (5G/5G), 0.49 (4G/5G) and 0.26 (4G/4G). Increased thrombosis risk has been reported in patients with the combination of PAI-1 4G and factor V Leiden (FVL) genetic polymorphisms. Our pediatric specialty laboratory offers PAI-1 genotyping, PAI-1 antigen and PAI-1 activity assays as part of thrombophilia testing. The laboratory at the children's hospital is also a reference lab for the community. We retrospectively reviewed the results of PAI-1 testing over the last 10 years.We hypothesized that the PAI-1 4G polymorphism would be more prevalent in young patients with thrombosis. We also hypothesized that there would be an additive thrombophilia risk from the combination of PAI-1 4G and FVL in young patients with thrombosis.Methods: After IRB approval, using information from Cerner and EPIC, we created a deidentified thrombophilia database of 11,459 unique patients who had thrombophilia testing between March 8, 2007 and June 6, 2017. We identified 1,896 who had PAI-1 genotyping and 2,573 who had antigen and activity testing. Removing those <3 months of age for whom normal ranges for PAI-1 have not been established, we identified 1,418 subjects who had genotype, antigen and activity levels. We also evaluated a subset of 510 pediatric patients with thrombosis, of whom 338 had all three PAI-1 tests and were 3 months or older, and 292 who had both PAI-1 and FVL genotyping. Local genotype frequency was established by the clinical laboratory on 100 controls and was in agreement with published estimates. All comparisons were made using two-sided Fisher's Exact tests. Significance was assessed at the 0.05 level.Results: Ages for subjects tested for PAI-1 ranged from 0.1 - 89.7 years with a mean of 14.3 years, and 41% were male. Compared to the local genotype frequency, PAI-1 4G was not significantly altered in either the thrombophilia cohort or in the subset with pediatric thrombosis (Table 1). This was true even when we re-evaluated by gender or by selecting for those with thrombophilia testing <22 years of age. Among 53 pediatric thrombosis patients with cancer, genotype frequencies for PAI-1 4G did not differ strongly from control group (p=0.14), but numbers were very small. Of the 1,418 thrombophilia testing subjects who had PAI-1 genotype, antigen and activity, correlation between abnormal antigen (p=0.07) or activity (p=0.28) levels and the 4G polymorphism did not reach statistical significance, though it did for those with both abnormal antigen and activity (p=0.05). Among 292 pediatric thrombosis patients with testing (Table 2), there was a suggestion of an effect from the combination of FVL and PAI-1 4G polymorphisms and thrombosis (p=0.06).Conclusions: Abnormal PAI-1 antigen and activity levels are not solely dependent upon the 4G genotype and are likely influenced by other congenital and acquired factors. Among pediatric patients with thrombosis and particularly those with cancer and thrombosis, a possible effect from the PAI-1 4G polymorphism alone or in combination of FVL should be validated in a larger cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The 4G/5G Polymorphism of Plasminogen Activator Inhibitor Type 1 is a Predictor of Moderate-to-Severe Thyroid Eye Disease.

IntroductionThyroid eye disease (TED) is an autoimmune disease of the orbits. Once developed, complete cure is rare. Plasminogen activator inhibitor type 1 (PAI-1) contributes to remodeling of connective tissue and has a central role in the pathogenesis of TED. We aimed to test if the 4G/5G polymorphism of PAI-1 is a predictor of the development of moderate-to-severe TED.MethodsA total of 185 patients with Graves’ disease, 87 of them with TED, 98 without TED, as well as 201 healthy controls, were studied. Genomic DNA was isolated from peripheral blood samples. The 4G/5G polymorphism of the PAI-1 gene was analyzed by allele-specific PCR, and the distribution of genotypes was calculated in each group. Plasma PAI-1 and thyroid hormone levels were measured by ELISA and ECLIA, respectively.ResultsThe 4G/4G genotype was associated with the development of moderate-to-severe TED (OR = 2.54; 95% CI: 1.26–5.14; p < 0.01). The 4G/5G polymorphism of PAI-1 was not a predictor of plasma PAI-1 levels.ConclusionThe 4G/4G genotype of PAI-1 is a risk factor for the development of moderate-to-severe TED. Patients with Graves’ disease who harbor this genotype may be candidates for special attention towards the development of TED.

Impact of Polytrauma and Acute Respiratory Distress Syndrome on Markers of Fibrinolysis: A Prospective Pilot Study.

Acute respiratory distress syndrome (ARDS), which is associated with major morbidity and high mortality, is commonly developed by polytraumatized patients. Its pathogenesis is complex, and its development is difficult to anticipate, as candidate biomarkers for the prediction of ARDS were found not to be reliable for clinical use. In this prospective study, we assessed the serum antigen levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) of 28 survivors of blunt polytrauma (age ≥18 years; injury severity score ≥16) at admission and on days 1, 3, 5, 7, 10, 14, and 21 of hospitalization. Our results show that these patients presented high mean tPA and PAI-1 antigen levels at admission; despite their decline, these parameters remained elevated for 3 weeks. Over this period, the mean tPA antigen level was higher in polytrauma victims suffering from ARDS than in those without ARDS, whereas the mean PAI-1 level was higher in polytrauma victims sustaining pneumonia than in those without pneumonia. Moreover, in each individual developing ARDS, the polytrauma-related elevated tPA antigen level either continued to rise after admission or suffered a second increase up to the onset of ARDS, declining immediately thereafter. Therefore, our findings support the assessment of serum tPA antigen levels after the initial treatment of polytraumatized patients, as this parameter shows potential as a biomarker for the development of ARDS and for the consequent identification of high-risk individuals.

Prognostic significance of VEGF and components of the plasminogen activator system in endometrial cancer

ObjectiveThe plasminogen activator system (PAS) and vascular endothelial growth factor (VEGF) are important in the carcinogenesis and play a key role in cancer invasion and mediating metastasis of carcinomas. The aim of the study was to evaluate the correlation of serum levels of VEGF and components of the PAS with clinicopathological risk factors and outcome in patients with endometrial cancer (EC).MethodsPreoperative blood was collected from 173 patients treated for EC between 1999 and 2009. Serum concentrations of VEGF, urokinase plasminogen activator (uPA) tissue plasminogen activator (tPA), plasminogen activator inhibitor type-1 (PAI-1) and -2 (PAI-2) were assessed by enzyme-linked immunosorbent assays (ELISA).ResultsSerum levels of VEGF and components of the PAS were significantly associated with stage of the disease, tumor histology, tumor grade, myometrial invasion (MI), presence of lymphovascular space invasion (LVSI) and lymph node metastases (LNM). Preoperative serum levels of PAI-1 and -2 and tPA were higher in patients who experienced a recurrence than in patients who remained disease free (p < 0.01). PAI-1 and -2 and tPA were significantly independent prognostic factors for DFS with a HR of 3.85 (95% CI 1.84–8.07), 3.90 (95% CI 1.75–8.66) and 2.53 (95% CI 1.16–5.55), respectively. PAI-1 and tPA turned out to be independent prognostic factors for OS, with a HR of 2.09 (95% CI 1.08–4.05) and 2.16 (95% CI 1.06–4.44), respectively.ConclusionSerum levels of VEGF and components of the PAS at primary diagnosis were associated with well-known clinicopathological risk factors such as; FIGO stage, tumor histology, tumor grade, MI, LVSI and LNM. High concentrations of PAI-1 and-2 and tPA are independent factors for poor prognosis in patients with endometrial cancer.

Recognition of Plasminogen Activator Inhibitor Type 1 as the Primary Regulator of Fibrinolysis.

The fibrinolytic system consists of a balance between rates of plasminogen activation and fibrin degradation, both of which are finely regulated by spatio-temporal mechanisms. Three distinct inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). In this review, we focus on the mechanisms by which PAI-1 governs total fibrinolytic activity to provide its essential role in many hemostatic disorders, including fibrinolytic shutdown after trauma. PAI-1 is a member of the serine protease inhibitor (SERPIN) superfamily and inhibits the protease activities of plasminogen activators (PAs) by forming complexes with PAs, thereby regulating fibrinolysis. The major PA in the vasculature is tissue-type PA (tPA) which is secreted from vascular endothelial cells (VECs) as an active enzyme and is retained on the surface of VECs. PAI-1, existing in molar excess to tPA in plasma, regulates the amount of free active tPA in plasma and on the surface of VECs by forming a tPA-PAI-1 complex. Thus, high plasma levels of PAI-1 are directly related to attenuated fibrinolysis and increased risk for thrombosis. Since plasma PAI-1 levels are highly elevated under a variety of pathological conditions, including infection and inflammation, the fibrinolytic potential in plasma and on VECs is readily suppressed to induce fibrinolytic shutdown. A congenital deficiency of PAI-1 in humans, in turn, leads to life-threatening bleeding. These considerations support the contention that PAI-1 is the primary regulator of the initial step of fibrinolysis and governs total fibrinolytic activity.

Circulating levels of plasminogen activator inhibitor-1 are associated with metabolic syndrome rather than with menopause

The plasminogen activator inhibitor type 1 (PAI-1) is the major determinant of fibrinolytic activity. PAI-1 concentrations are elevated in obesity, type 2 diabetes and metabolic syndrome (MetS). On the other hand, during menopause, fibrinolytic activity decreases and, consequently, PAI-1 concentration increases; however, it is debated whether menopause is an independent determinant factor of PAI-1 levels. The objective of this study was to evaluate the effect of hormonal and metabolic status on the concentration of PAI-1 in pre-and post-menopausal women. A case-control study was conducted in ninety pre-and post-menopausal women aged 45 to 55 years, matched by body mass index (BMI). Anthropometric measurements and biochemical determinations were performed on all participants. The fibrinolytic activity was determined by measuring PAI-1 by ELISA. Of all the women, 30% presented MetS. Women with MetS had higher values of PAI-1 (36.0 ± 19.1 vs 19.3 ± 14.8 ng/mL, p < .001); in contrast, no differences were observed when compared by hormonal status (20.7 ± 18.10 vs 20.2 ± 17.0 ng/mL, NS). The results of this study suggest that in women, MetS plays a more important role in the deterioration of the fibrinolytic mechanisms rather than their hormonal status. Therefore, the identification of cardio-metabolic factors is relevant to reduce the presence of thrombosis in post-menopausal women.

Changes in the plasma level of plasminogen activator inhibitor-1 in patients with cranio-cerebral trauma depending on body weight and PAI-1 -675 4G/5G gene polymorphism

Purpose. To study the association between the plasma level of plasminogen activator inhibitor type-1 (PAI-1) and both body weight and PAI-1 -675 4G/5G gene polymorphism in patients with cranio-cerebral trauma (CCT) over the treatment course. Materials and methods. The hemostasis system state was analyzed in 200 patients with CCT by studying the association between the plasma level of PAI-1 and both body weight and -675 4G/5G polymorphism of the PAI-1 gene. For statistical processing of the obtained study results, a licensed version of the SPSS STATISTICA 17 program was used. K-means cluster analysis was also performed; the Euclidean distance was used as the distance measure. Results. Clustering of patients was performed depending on the plasma PAI-1 content on days 1, 7 and 14 after trauma. All patients were distributed into 3 clusters. Thus, the first cluster included patients with the average PAI-1 concentration within the normal range during the study. The second cluster included patients who presented significantly increased PAI-1 concentration at the time of an injury, which tended to decrease rapidly and almost normalized by day 14. The third cluster consisted of patients with significantly increased plasma concentration of PAI-1 following an injury with the tendency to remain at a high level for 14 days. Due to statistical processing of the study results, an association between an increase in PAI-1 level and both the 4G/4G, 4G/5G genotypes and overweight or obesity in patients was found. Increased levels of PAI-1 were observed in overweight or obese patients with the 4G/4G and 4G/5G genotypes over the course of treatment. Conclusions. The association between both overweight and -675 4G/5G polymorphism of the PAI-1 gene and plasma level of plasminogen activator inhibitor type-1 in patients with traumatic brain injury has been proven.

Prothrombotic state assessment in asthma and its relation to asthma severity and effect of inhaled corticosteroids

Background Coagulation and fibrinolysis have been previously considered as processes that occurred only in blood vessels. Recently, there is increasing evidence that asthma has increased coagulation activation within airways that in turn may lead to an increase in venous thromboembolism. Aim To assess the prothrombotic state in asthmatic patients with different disease severity, correlate to inflammatory markers, in addition to the effect of inhaled corticosteroids (ICS). Patients and methods Ninety patients (30 in the healthy group, 30 in the mild asthma group, 30 in the moderate to severe asthma group) were enrolled in this case–control study. Hemostatic parameters [plasminogen activator inhibitor type 1 (PAI-1) and d-dimers] and inflammatory markers (neutrophil, eosinophils, C-reactive protein) in the peripheral blood were measured. The extent of the effect of different doses of ICS on both hemostatic and inflammatory parameters was assessed. Results Serum PAI-1 was significantly increased among moderate to severe asthmatics [6.0 (5.0–13.0) ng/ml] as compared with the mild asthmatic [3.6 (3.0–5.0) ng/ml] and the control group [4.5 (2.0–5.0) ng/ml]. Moderate to severe asthmatics had higher levels of d-dimer in comparison to mild asthmatic patients and the control group [310.0 (260–1280), 187.5 (160–220), 40.0 (30–70) µg/ml, respectively]. Both PAI-1 and d-dimer levels significantly correlated with ICS doses (r=0.309, P=0.016; r=0.303, P=0.019, respectively). Moreover, both PAI-1 and d-dimer levels increased significantly among asthmatics using medium to high doses of ICS. Conclusion Asthma as a chronic inflammatory disease may have a prothrombotic state, especially those with severe asthma and using high doses of ICS.

Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array

BackgroundConventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX®, a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction.The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test.MethodsThe results of Ki67, uPA/PAI-1 and OncotypeDX® were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed.ResultsWith a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student’s t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student’s t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values.ConclusionA combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised).

Circulating Levels of Bone and Inflammatory Markers in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) can cause short- and long-term complications to the mother and fetus. While the precise mechanisms in preserving glucose balance in a healthy pregnancy are unknown, various growth factors and hormones have been implicated or associated with GDM risk in humans or rodents, including prolactin, tumor necrosis factor alpha (TNFα), osteoprotegerin (OPG), hepatocyte growth factor (HGF), and receptor activator of nuclear factor-kappa B ligand (RANKL). We aimed to evaluate the relationship of these and other protein markers in women with GDM. In this cross-sectional study, blood samples were collected from pregnant women with GDM and with normal glucose tolerance (NGT) at the 24- to 32-week obstetrical visit, during the 1-h oral glucose challenge test or 3-h oral glucose tolerance test. Blood plasma was analyzed for RANKL, OPG, prolactin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), HGF, plasminogen activator inhibitor type 1 (PAI-1), and TNFα. Forty-six women with NGT and 47 women with GDM were included (mean ± standard deviation maternal age 31.6 ± 5.7, mean ± standard deviation gestational age 28.1 ± 2.2 weeks). Groups were similar in terms of age, body mass index, gestational age, and race/ethnicity. Serum levels of OPG, prolactin, TRAIL, HGF, PAI-1, and TNFα were similar in both groups. RANKL was lower in GDM subjects (p = 0.019). Contrary to previous reports in the literature, we found a lower serum RANKL level in women with GDM. Further investigation is needed to determine whether there are suitable serum markers for diagnosing GDM or determining prognosis or severity.

Cell adhesion molecules and plasminogen activator inhibitor type-1 (PAI-1) in patients with rheumatoid arthritis: influence of metabolic syndrome.

Rheumatoid arthritis (RA) is a chronic inflammatory and systemic disease characterized by endothelial activation. The main objective of this study was to verify the profile of cell adhesion molecules (CAM) in RA patients, and the influence of metabolic syndrome (MetS) and drugs used in the treatment of RA in this profile. A second objective was to propose models of prediction of activity in RA using these biomarkers. A total of 115 healthy individuals and 144 RA patients were enrolled. Disease activity was determined by DAS28 (disease activity score 28) based on erythrocyte sedimentation rate (DAS28-ESR) or C-reactive protein (DAS28-CRP). Serum CAM and plasminogen activator inhibitor type-1 (PAI-1), anthropometric and immunological parameters were measured. Vascular cell adhesion molecule-1 (VCAM-1) was significantly decreased, and PAI-1 was significantly higher in RA patients as compared to controls. Binary logistic regression analysis showed that VCAM-1, CRP, and tumor necrosis factor-α (TNF-α) predicted RA with a sensitivity of 95.9% and a specificity of 89.5%. 42.9% of the variance in DAS28-ESR and 49.2% of the variance in DAS28-CRP are explained by increased PAI-1, TNF-α, body mass index (BMI) and decreased platelet endothelial cell adhesion molecule 1 (PECAM-1). Our data show that lower levels of VCAM-1 are associated with RA independently of MetS, while increased PAI-1 levels were associated with both RA and MetS and increased selectins (E-selectin and P-selectin) were exclusively associated with MetS and not with RA. A model to predict disease activity based on PECAM-1, PAI-1, TNF-α, age and BMI is proposed.

Observational study of coagulation activation in early breast cancer: development of a prognostic model based on data from the real world setting

BackgroundCancer and coagulation activation are tightly related. The extent to which factors related to both these pathologic conditions concur to patient prognosis intensely animates the inherent research areas. The study herein presented aimed to the development of a tool for the assessment and stratification of risk of death and disease recurrence in early breast cancer.MethodsBetween 2008 and 2010, two hundreds thirty-five (N: 235) patients diagnosed with stage I–IIA breast cancer were included. Data on patient demographics and clinic-pathologic features were collected in course of face-to-face interviews or actively retrieved from clinical charts. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1), fragment 1 + 2 (F1 + 2), thrombin antithrombin complex (TAT), factor VIII (FVIII), and D-dimer (DD) were measured at breast cancer diagnosis and prior to any therapeutic procedure, including breast surgery. The risk of death was computed in terms of overall survival (OS), which was the primary outcome. For a subset of patients (N = 62), disease free survival (DFS) was also assessed as a measure of risk of disease recurrence.ResultsMedian follow up was 95 months (range 6–112 months). Mean age at diagnosis was 60.3 ± 13.4 years. Cancer cases were more commonly intraductal carcinomas (N: 204; 86.8%), pT1 (131; 55.7%), pN0 (141; 60%) and G2 (126; 53.6%). Elevated levels of PAI-1 (113; 48.1%) represented the most frequent coagulation abnormality, followed by higher levels of F1 + 2 (97; 41.3%), DD (63; 27.0%), TAT (34; 40%), and FVIII (29; 12.3%). In univariate models of OS, age, pT, DD, FVIII were prognostically relevant. In multivariate models of OS, age (p = 0.043), pT (p = 0.001), levels of DD (p = 0.029) and FVIII (p = 0.087) were confirmed. In the smaller subgroup of 62 patients, lymph node involvement, percent expression of estrogen receptors and levels of FVIII impacted DFS significantly.ConclusionsWe developed a risk assessment tool for OS including patient- and cancer-related features along with biomarkers of coagulation activation in a cohort of early BC patients. Further studies are warranted to validate our prognostic model in the early setting and eventually extend its application to risk evaluation in the advanced setting for breast and other cancers.