Concentrations Of Plasminogen Activator Research Articles

Dysregulated Clot Mechanics and Kinetics Impacted by Injury Severity, Predict Mortality After Trauma.

Introduction: Coagulopathy following traumatic injury impairs stable blood clot formation and exacerbates mortality from hemorrhage. Understanding how these alterations impact blood clot stability is critical to improving resuscitation. Furthermore, the incorporation of machine learning algorithms to assess clinical markers, coagulation assays and biochemical assays allows us to define the contributions of these factors to mortality. In this study, we aimed to quantify changes in clot formation and mechanics after traumatic injury and their correlation to mortality.Materials and Methods: Plasma was isolated from injured patients upon arrival to the emergency department prior to blood product administration, or procedural intervention. Coagulation kinetics and mechanics of healthy donors and patient plasma were compared with rheological, turbidity and thrombin generation assays. ELISA's were performed to determine tissue plasminogen activator (tPA) and D-dimer concentration. Recursive elimination with random forest models were used to assess the predictive strength of clinical and laboratory factors.Results: Sixty-three patients were included in the study. Median injury severity score (ISS) was 17, median age was 38 years, and mortality was 30%. Trauma patients exhibited reduced clot stiffness, increased fibrinolysis, and reduced thrombin generation compared to healthy donors. Deceased patients exhibited the greatest deviation from healthy levels. Fibrinogen, clot stiffness, D-dimer and tPA all demonstrated significant correlation to ISS. Machine-learning algorithms identified the importance of coagulation kinetics and clot structure on patient outcomes.Conclusions: Rheological markers of coagulopathy and biochemical factors are associated with injury severity and are highly predictive of mortality after trauma, providing evidence for integrated predictive models and therapeutic strategies.

Age-related characteristics of the content and activity of certain components of the blood fibrinolytic system in cases of uterine cancer

Uterine cancer (UC) is the third most common cancer in women in Russia. Knowledge of age-specific features of the fibrinolytic system in patients with UC can be useful in terms of improving its pathogenetic therapy. Aim of the study was to investigate the peculiarities of the content and activity of some components of the fibrinolytic system in the blood of UC patients of different age groups. Material and methods. 30 healthy women (donors) and 56 patients with uterine cancer T1a-2N0M0, adenocarcinoma G1–G3 were divided into subgroups according to age: reproductive, perimenopause and menopause. ELISA of urokinase (u-PA), its receptor (u-PAR) and its inhibitor (PAI-1), tissue-type plasminogen activator (t-PA) content were performed in blood collected before treatment. Results. In reproductive UC patients, inhibitor u-PA (PAI-1) activity increased 14-fold (hereinafter the difference is statistically significant, p < 0.05) and content increased 2.9-fold, while receptor u-PA (u-PAR) level decreased 1.7-fold compared to reproductive donors. Perimenopausal UC patients showed a 3.3-fold increase in PAI-1 content and a 6.3-fold increase in PAI-1 activity compared to perimenopausal donors, t-PA concentration decreased 1.3-fold relative to donors and was 1.9-fold lower than in reproductive UC patients. In menopausal patients with UC, the activity and content of PAI-1 enhanced 5.5-fold and 4.5-fold, respectively, compared to donors. Additionally, they were 2.1-fold and 1.2-fold lower than in reproductive UC patients. The activity of u-PA increased 2.6-fold, reaching the values of reproductive UC patients. The activity of t-PA was 1.3-fold higher than in donors, but did not differ from the activity in other RTM patients, while the level of t-PA occupied an intermediate position between the corresponding indices in young UC patients (it was 1.4-fold lower) and perimenopausal UC patients (it was 1.4-fold higher). Conclusions. The development of UC is accompanied by an imbalance of components of the fibrinolytic system in the blood, depending on the age of women, with a minimum spectrum of changes in the indicators in reproductive patients and maximum - in menopause patients, which indicates the pathognomonicity of these factors in PTM and requires an individual approach to the management of such patients.

Search for predictors of complications of acute coronary syndrome with ST segment elevation – protocol of a prospective open cohort study PROMETHEUS

During the first year after myocardial infarction, coronary artery restenosis, fatal arrhythmias, hospitalization for heart failure or cardiac death may occur. It is necessary to search for biomarkers to predict complications of myocardial infarction. As such predictors, it seems promising to introduce the ABCDE-SE echocardiographic protocol, as well as study the metabolism of vitamin D and proteins of the fibrinolysis system. Cardiospecific microRNAs-21, -29, -143 can be used as pathogenetic factors in the development of complications; it is proposed to study the ongoing pharmacotherapy and patients’ compliance with it as controllable factors.Aim: To search for predictors of complications of myocardial infarction based on the assessment of echocardiographic parameters, vitamin D metabolism, components of the fibrinolysis system and cardiac-specific microRNAs.Material and Methods. The PROMETHEUS study is designed as a prospective, open-label, non-randomized cohort study. It is planned to include 300 patients newly admitted to the vascular center with a preliminary diagnosis of ST-segment elevation ACS. All patients will have their vitamin D concentrations determined; genetic variants of polymorphisms of the vitamin D receptor gene and vitamin D binding protein; concentrations of urokinase and soluble urokinase receptor; microRNA-21, -29, -143, as well as echocardiography using the ABCDE-SE protocol at 1, 3, 6 and 12 months from inclusion. Pharmacotherapy will be assessed at all stages.Expected results: Based on the results of the study, a comprehensive algorithm for optimizing the prediction and prevention of complications of myocardial infarction will be developed and introduced into practical healthcare.

Age-Related Changes in Clinical and Analytical Variables in Chronic Hemodialyzed Patients.

Worldwide, the number of elderly individuals receiving chronic hemodialysis is rising. The aim of our study was to evaluate several clinical and analytical biomarkers in chronically dialyzed patients and analyze how they change with age. A cross-sectional study was performed by evaluating 289 end-stage renal disease patients undergoing dialysis. We evaluated the hemogram, adipokines, the lipid profile, and several markers related to inflammation, endothelial function/fibrinolysis, nutrition, iron metabolism, and cardiac and renal fibrosis. Clinical data and dialysis efficacy parameters were obtained from all patients. The relationships between studied biomarkers and age were assessed by a statistical comparison between younger (adults with age < 65 years) and older (age ≥ 65 years) patients and by performing regression analysis. Participants presented a mean age of 68.7 years (±13.6), with 66.8% (n = 193) being classified as older. Compared to younger patients, older patients presented the following: (a) significantly lower values of diastolic blood pressure (DBP) and ultrafiltration volume; (b) lower levels of phosphorus, uric acid, creatinine, and albumin; and (c) higher circulating concentrations of tissue-type plasminogen activator (tPA), D-dimer, interleukin-6, leptin, N-terminal pro B-type natriuretic peptide, and tissue inhibitor of metalloproteinase-1. In the multiple linear regression analysis, DBP values, tPA, phosphorus, and D-dimer levels were independently associated with the age of patients (standardized betas: -0.407, 0.272, -0.230, and 0.197, respectively; p < 0.001 for all), demonstrating relevant changes in biomarkers with increasing age at cardiovascular and nutritional levels. These findings seem to result from crosstalk mechanisms between aging and chronic kidney disease.

The role of plasminogen and urokinase activator of plasminogen in the treatment of endogenous uveitis in children

AIM: To determine the content of plasminogen and urokinase activator of plasminogen in tears and blood serum and to identify correlations between the studied parameters and the clinical picture of uveitis.&#x0D; MATERIAL AND METHODS: One hundred thirty-three eyes with uveitis were examined in 74 patients aged 3 to 17 yr (average 10.453.35 yr). The content of the urokinase activator of plasminogen (UPA) was studied in 188 tear samples and 22 blood serum samples. The dynamics of UPA in tears were studied in 28 patients (51 eyes). The plasminogen content of 86 tear samples and 34 blood serum samples was studied. The dynamics of plasminogen in tears were studied in five patients (nine eyes). The concentrations of UPA and plasminogen were measured using the ELISA method and the kits ELISA kit for plasminogen activator, urokinase (UPA)/ELISA Kit for Plasminogen, Cloud-Clone Corp., USA).&#x0D; RESULTS: An increase in the content of UPA in the tears of children with uveitis was associated with higher inflammatory activity (p=0.04). An increase in the content of UPA in tears was associated with an increase in the degree of proliferative changes (p=0.04). An increase in the content of UPA and plasminogen in tears was found 12 months after surgery. There was an increase in the content of UPA (p=0.0001) and plasminogen in tears (p=0.009) and blood serum (p=0.09) with age.&#x0D; CONCLUSION: The content of UPA in tears increased significantly when severe uveitis was compared with inactive uveitis. An increase in the content of UPA in tears was associated with an increase in the degree of proliferative changes, which reflects the severity of the uveitis course. The content of UPA and plasminogen in tears and blood serum increased with age. An increase in UPA and plasminogen was observed within 12 months after surgery, with both returning to preoperative values by the third month of the postoperative period, which reflects the normal course of the wound healing process.

Congruent identification of imbalanced fibrinolysis by 2 distinct clot lysis time assays

BackgroundA plasma-based clot lysis time (CLT) assay is an established research test to assess plasma fibrinolytic potential, with application in hyperfibrinolytic or hypofibrinolytic conditions. Interprotocol variations make comparisons between laboratories challenging. The aim of this study was to compare the results of 2 different CLT assays performed by 2 distinct research laboratories by using their own protocol. MethodsWe evaluated fibrinolysis in the plasma of 60 patients undergoing hepatobiliary surgery and in plasma from a healthy donor that was spiked with commonly used anticoagulant drugs (enoxaparin, dabigatran, and rivaroxaban) in 2 distinct laboratories (Aarhus and Groningen) by using 2 different assays that differ, among others, in tissue plasminogen activator (tPA) concentration. ResultsOverall conclusions on fibrinolytic potential in patients undergoing hepatobiliary surgery were similar between the 2 CLT assays, with hyperfibrinolytic and hypofibrinolytic profiles identified at the same time points during and after surgery. Severe hypofibrinolysis was less commonly reported in the Aarhus assay (36/319 samples; 11%) than in the Groningen assay (55/319 samples; 17%). No clot formation was observed in 31 of 319 samples in the Aarhus assay vs 0 of 319 samples in the Groningen assay. Clotting times increased much more profoundly on the addition of all 3 anticoagulants in the Aarhus assay. ConclusionsDespite the differences in laboratory, protocol, reagents, operator, data processing, and analysis, overall conclusions on fibrinolytic capacity are similar between the 2 laboratories. With a higher concentration of tPA in the Aarhus assay, the test becomes less sensitive for the detection of hypofibrinolysis and is more sensitive to the addition of anticoagulants.

Connexin43 in Post-Surgical Peritoneal Adhesion Formation.

Post-surgical peritoneal adhesions are a serious problem for the quality of life and fertility. Yet there are no effective ways of preventing their occurrence. The gap junction protein Cx43 is known to be involved in fibrosis in several different organs and disease conditions often associated with inflammation. Here we examined the Cx43 dynamic expression in an ischemic button model of surgical adhesions. Using the mouse ischemic button model, Cx43 antisense was delivered in Pluronic gel to attenuate Cx43 expression. The severity of button formation and immunofluorescence analysis of Cx43 and TGF-β1 were performed. The concentration of tissue plasminogen activator via ELISA was also performed. As early as 6 h after button formation, the Cx43 levels were elevated in and around the button and some weak adhesions were formed. By 24 h Cx43 levels had increased further and adhesions were more defined. At 7 days the adhesions were much more robust, opaque, and vascularized, requiring blunt or sharp dissection to break them. Cx43 antisense attenuated its upregulation and, reduced the number and severity of adhesions that formed. Targeting Cx43 after surgical procedures may be a potential therapeutic strategy for preventing adhesion formation or at least reducing their severity.

A Subset of Secreted Proteins in Ascites Can Predict Platinum-Free Interval in Ovarian Cancer.

Simple SummaryIdentifying proteins that correlate with better or worse outcomes may help to identify new treatment approaches for advanced high-grade serous ovarian cancer. Here, we utilize a machine learning technique to correlate the levels of 58 secreted proteins in tumor ascites with the time to disease recurrence after chemotherapy, which is known clinically as the platinum-free interval. We identify several candidate proteins correlated to shorter or longer platinum-free intervals and describe model analysis methods that may be useful for other studies aiming to identify factors impacting patient outcomes. Future validation of these factors in a prospective cohort would confirm their clinical utility, whereas a study of the mechanisms that they impact may identify new therapies.The time between the last cycle of chemotherapy and recurrence, the platinum-free interval (PFI), predicts overall survival in high-grade serous ovarian cancer (HGSOC). To identify secreted proteins associated with a shorter PFI, we utilized machine learning to predict the PFI from ascites composition. Ascites from stage III/IV HGSOC patients treated with neoadjuvant chemotherapy (NACT) or primary debulking surgery (PDS) were screened for secreted proteins and Lasso regression models were built to predict the PFI. Through regularization techniques, the number of analytes used in each model was reduced; to minimize overfitting, we utilized an analysis of model robustness. This resulted in models with 26 analytes and a root-mean-square error (RMSE) of 19 days for the NACT cohort and 16 analytes and an RMSE of 7 days for the PDS cohort. High concentrations of MMP-2 and EMMPRIN correlated with a shorter PFI in the NACT patients, whereas high concentrations of uPA Urokinase and MMP-3 correlated with a shorter PFI in PDS patients. Our results suggest that the analysis of ascites may be useful for outcome prediction and identified factors in the tumor microenvironment that may lead to worse outcomes. Our approach to tuning for model stability, rather than only model accuracy, may be applicable to other biomarker discovery tasks.

Comparative Study on the Chronic Vascular Responses Induced by Regular Versus Occasional Waterpipe Smoke Inhalation in Mice.

Waterpipe smoke (WPS) is the second most prevalent form of smoking in the world. There are ample evidences about the vascular alterations caused by regular WPS (Reg-WPS). Nonetheless, comparison of the chronic vascular response induced by regular versus occasional WPS (Occ-WPS) exposure is very scarce. We investigated, in BALB/c mice, the effects of Occ-WPS (30 minutes/day, 1 day/week) versus Reg-WPS (30 minutes/day, 5 days/week) for 6 months on thrombogenicity and platelet aggregation in vivo and in vitro. Moreover, various markers of endothelial integrity, inflammation and oxidative stress were assessed by enzyme-linked immunosorbent assay and colorimetric assay. Control mice were exposed to air. Our results showed that either Occ-WPS or Reg-WPS exposure shortened the thrombotic time in pial microvessels in vivo. Moreover, in pial venules, this effect was more marked in Reg-WPS group (-47%) compared with Occ-WPS (-34%). Similarly, exposure to either Occ-WPS or Reg-WPS reduced the prothrombin time and activated partial thromboplastin time. Platelet count was increased only in Reg-WPS exposure. Exposure to either Occ-WPS or Reg-WPS induced platelet aggregation in vitro. In addition, there was a statistically significant difference between Occ-WPS and Reg-WPS groups in platelet count and aggregation. Plasma concentration of tissue factor (+98%), P-selectin (+14%) and E-selectin (+16%) were significantly increased in Occ-WPS group compared with air exposed group. Likewise, compared with air group Reg-WPS caused an increase in concentration of tissue factor (+193%), P-selectin (+21%) and E-selectin (+42%). Nevertheless, only Reg-WPS induced a decrease (-38%) in the plasma concentration of tissue plasminogen activator. Notably, our results showed a statistically significant difference between Occ-WPS and Reg-WPS groups in the concentration of tissue factor. Erythrocyte numbers, hemoglobin concentration, hematocrit and lactate dehydrogenase activity were augmented only in Reg-WPS group compared with either control or Occ-WPS groups. Likewise, only Reg-WPS induced an increase in proinflammatory cytokines, tumor necrosis factor-α and interleukin-1β compared with either control or Occ-WPS groups. However, markers of oxidative stress including 8-isoprostane and total antioxidants were enhanced in both Occ-WPS and Reg-WPS compared with control group. Our data confirm the vascular toxicity of the chronic Reg-WPS exposure and shows that even occasional chronic exposure to WPS caused thrombosis, platelet aggregation, endothelial alterations and oxidative stress. The latter findings are an additional cause of concern about the long-term toxicity of occasional waterpipe smoking.

Simulated in vitro hypoxic conditions from psoriatic arthritis cartilage change plasminogen activating system urokinase and serpine functionality. Reversal of antiapoptotic protection suggests common homeostatic buffering.

Rheumatoid and psoriatic arthritis are both characterised by synovial destruction associated with a higher turnover of the extracellular matrix. In both conditions, inflammatory processes create hypoxic environments which destabilise members of the plasminogen activating system. Comparing the effect of bioactive concentrations of urokinase (uPA) and serpine (PAI-1) on cellular survival of human fibroblast-like-synoviocytes (HFLS) in rich and hypoxic growth media. Monocultures of HFLS were exposed to bioactive uPA and PAI-1 concentrations in both media conditions for 24, 48 and 72 h. Cellular survival was evaluated with a cell viability assay by spectrum absorbance of formazan reduced WST-8. PAI-1 at 0.1 and 1 μg/ml was found to stimulate cell viability under hypoxic stress at 48 and 72 h of incubation, with the effect increasing from 48 to 72 h. uPA increased cell viability in rich medium at 48 and 72 h of incubation between 5 and 40 ng/l, but was found to reduce viability at 80 ng/l at 24 and 48 h. PAI-1 increased cell viability in the hypoxic stress model, while high concentrations of uPA decreased cell viability in rich medium. The alternative modes of function at extreme concentrations provide a novel description of PAI-1 and uPA activity based on their colocalization and mutual buffering capacity, helping to place these molecules more accurately in the context of arthritic synovial deterioration.

Quantification of clot spatial heterogeneity and its impact on thrombectomy

BackgroundCompositional and structural features of retrieved clots by thrombectomy can provide insight into improving the endovascular treatment of ischemic stroke. Currently, histological analysis is limited to quantification of compositions and...

Rotational thromboelastometry for diagnosis of fibrinolysis induced by urokinase in an in-vitro model.

Fibrinolysis can be abnormally activated in several critical care settings but it's often misdiagnosed by standard laboratory tests. Although rotational thromboelastometry can assess the whole coagulative process, its ability to detect fibrinolysis has been questioned. Aim of this study was to investigate the ability of thromboelastometry in detecting induced fibrinolysis in an in-vitro model. Whole blood samples were taken from 18 healthy volunteers. Each sample was split and added with increasing urokinase concentrations till to reach 0, 50, 75 and 100 IU/ml. Thromboelastometry tests, extem and aptem, were performed on the obtained samples. If significant lysis at 50 IU/ml was recorded, also 10, 25 and 35 IU/ml drug concentrations were tested. No lytic effects were detected in 10 IU/ml samples. Lysis variables were the most sensitive in detecting fibrinolysis even at 25 IU/ml (P < 0.05). Clot firmness parameters were also affected by urokinase, but only at the two highest drug concentrations (P < 0.05). Extem/aptem ratio enhanced the sensitivity of these parameters only if lysis was more marked. Analysing groups of different lysis severity, the time to achieve maximum clot firmness could anticipate an ongoing fulminant or intermediate lysis with 100% sensitivity and 100% specificity (P < 0.05) when lower than 1341.5 s. Rotational thromboelastometry could detect fibrinolysis when it was induced in vitro by 25 IU/ml urokinase or more. Apart from the parameters specific for lysis, time to achieve maximum clot firmness appeared as the earliest indicator of fibrinolysis with high sensitivity and specificity especially if a more intense lysis was going on.

Гострий тромбоз стента при інфаркті міокарда, ускладненому кардіогенним шоком, за наявності цукрового діабету 2-го типу

Актуальність. Гострий тромбоз стента (ТС) є нечастим, але грізним ускладненням при стентуванні вінцевих артерій. Він виникає під час черезшкірних коронарних втручань або впродовж 24 годин після цієї процедури. Мета дослідження: з’ясувати причини та проаналізувати фактори, що призвели до гострого ТС при гострому коронарному синдромі і цукровому діабеті (ЦД) 2-го типу, для уникнення подібних ускладнень. Матеріали та методи. Обстежено 119 пацієнтів із гострим інфарктом міокарда з елевацією сегмента ST, які лікувалися в інфарктному відділенні комунального некомерційного підприємства «Клінічна лікарня швидкої медичної допомоги м. Львова». Усім пацієнтам проводили коронарографію та стентування вінцевих артерій, ультраструктурні дослідження тромбоцитів венозної крові за допомогою електронної мікроскопії. Результати. Пацієнти із ЦД 2-го типу мають вищий кардіоваскулярний ризик розвитку серцево-судинних ускладнень, що пов’язано з ендотеліальною дисфункцією, схильністю до гіперкоагуляції і, як наслідок, тенденцією до вазоконстрикції, запальних реакцій та порушень гемостазу. У цієї категорії пацієнтів спостерігається підвищена адгезивність тромбоцитів і збільшена концентрація тканинного активатора плазміногену. В експрес-некроптатах і періопераційних біоптатах міокарда пацієнтів із ЦД нами виявлено домінування процесів гіперкоагуляції в мікросудинах міокарда в результаті активності системи згортання крові за відсутності безпосередньої участі тромбоцитів, оскільки частина з них була кальцифікована (осміофільні) і мала знижену функціональну здатність, в результаті чого відмічається резистентність до аспірину. В осіб із ЦД 2-го типу виникає зазвичай тяжкий і більш генералізований коронаросклероз, що призводить до погіршення перебігу гострого коронарного синдрому і частішого виникнення ТС, що робить доцільним додаткове призначення ривароксабану цій категорії пацієнтів. Висновки. Враховуючи виявлені нами ознаки зниженої реактивності тромбоцитів і домінування активації системи згортання крові у хворих на ЦД і з підвищеним ризиком коронаротромбозу, вважаємо, що застосування нових пероральних антикоагулянтів є актуальним і заслуговує подальших досліджень.

UNDERSTANDING THE RELATIONSHIP BETWEEN URINARY SUPAR AND TREATMENT RESPONSE IN PEDIATRIC NEPHROTIC SYNDROME

Objectives: To investigate the relationship between the concentration of urinary soluble urokinase plasminogen activator (suPAR) pretreatment with the treatment responsiveness in children with primary nephrotic syndrome. Methods: Longitudinal follow-up study. Results: A study of 30 children diagnosed with the initial nephrotic syndrome was followed up at Hue Pediatric Center of Hue Central Hospital and Pediatrics Departement of Hue University of Medicine and Pharmacy Hospital. Urinary suPAR/creatinine ratio was 2712 ± 2217 pg/mg (605 - 11443 pg/mg), urinary suPAR/creatinine ratio in children 1-6 years old was significantly higher than that in group 7-15 years old, there was no signifficant difference about urinary suPAR between hematuria and non-hematuria group. Urinary suPAR/creatinine ratio was not significantly associated with serum albumin, glomerular filtration rate and proteinuria. After 2 months of steroid treatment, 100% patients was completely remission. Following- up 28 patients after 6 months of steroid treatment: the rate of completely remission, infrequent relapse and frequent relapse were 67.8%, 25% and 7.2% respectively, there was no signifficant difference about urinary suPAR/creatinine ratio among three groups. Conclusions: Pre-treatment urinary suPAR/creatinine ratio do not help predict the ability of steroid responsiveness in the early period of treatment. More research is needed to understand more the role of urinary suPAR in pediatric nephrotic syndrome. Key words: soluble urokinase plasminogen activator, urinary suPAR, childhood nephrotic syndrome

Local Cerebral Recombinant Tissue Plasminogen Activator Concentrations During Acute Stroke

Local Cerebral Recombinant Tissue Plasminogen Activator Concentrations During Acute Stroke

Aberrant Factors of Fibrinolysis and Coagulation in Pancreatic Cancer.

Aberrant factors associated with fibrinolysis and thrombosis are found in many cancer patients, which can promote metastasis and are associated with poor prognosis. The relationship between tumor-associated fibrinolysis and thrombosis is poorly understood in pancreatic cancer. This review provides a brief highlight of existing studies that the fibrinolysis and coagulation systems were activated in pancreatic cancer patients, along with aberrant high concentrations of tissue plasminogen activator (t-PA), urine plasminogen activator (u-PA), D-dimer, fibrinogen, or platelets. These factors cooperate with each other, propelling tumor cell shedding, localization, adhesion to distant metastasis. The relationship between thrombosis or fibrinolysis and cancer immune escape is also investigated. In addition, the potential prevention and therapy strategies of pancreatic cancer targeting factors in fibrinolysis and coagulation systems are also been discussed, in which we highlight two effective agents aspirin and low-molecular weight heparin (LMWH). Summarily, this review provides new directions for the research and treatment of pancreatic cancer.

Some fibrinolytic parameters in coronary artery disease patients: focus on unstable angina subgroups

Unstable angina is classified into new-onset, progressive, and angina at rest. Though hemostasis plays a crucial role in the pathogenesis of coronary artery disease, including unstable angina, limited data exist regarding peculiarities of fibrinolytic parameters in the above-mentioned types of unstable angina. Our study aims to investigate if there is a difference in the fibrinolytic state between the groups of patients with new-onset, progressive unstable angina in comparison with stable angina patients depending on medical history data, electrocardiographic and hemodynamic features. In our cross-sectional study, we recruited 93 coronary artery disease patients (mean age 62.32 (6.94) years, 41 males (44.1%)). They were divided into 3 groups: stable angina patients (n=22) (control), new-onset unstable angina patients (n=21), and progressive unstable angina patients (n=50). The groups were comparable by baseline characteristics. Blood samples were obtained before treatment onset. The concentrations of tissue plasminogen activator and inhibitor of plasminogen activator (type 1) were measured by the ELISA method. We registered 14 points at the admission department, particularly age, sex, body mass index, smoking, presence of the family history of cardiovascular disorders, ST-segment depression, T-wave variability, arrhythmias, left bundle branch blockage, heart rate, systolic and diastolic blood pressure, Sokolov-Lyon voltage criteria, and unstable angina type (new-onset or progressive). After comparison of fibrinolytic parameters’ concentrations among groups under investigation, we defined the main independent predictors among observed 14 parameters to create optimal regression models for assessment of fibrinolytic parameters concentrations. The groups under investigation differ significantly in concentration of tissue plasminogen activator (P&lt;0.001) and inhibitor of plasminogen activator (type 1) (P&lt;0.001). The tissue plasminogen activator concentration correlated significantly with ST depression (r=0.344, P=0.001), T wave variability (r=-0.233, P=0.02), systolic blood pressure (r=-0.675, P&lt;0.001), diastolic blood pressure (r=-0.655, P&lt;0.001), heart rate (r=-0.568, P&lt;0.001) and clinical unstable angina subgroups (r=-0.706, P&lt;0.001) as well as plasminogen activator inhibitor (type 1) concentration associated with age (r=-0.560, P&lt;0.001), body mass index (r=-0.249, P=0.049), ST-segment depression (r=0.542, P&lt;0.001), arrhythmia (r=0.210, P=0.03), systolic blood pressure (r=0.310, P=0.04), and clinical unstable angina subgroups (r=-0.406, P&lt;0.001). An optimal regression models for tissue plasminogen activator and its inhibitor assessment included systolic blood pressure, heart rate, unstable angina subgroup (R2adj. = 65.0%, P&lt;0.001) and systolic blood pressure, unstable angina subgroup (R2adj. = 42.7%, P&lt;0.001), respectively. Thus, fibrinolytic state among unstable angina clinical types differs significantly independently on observed baseline clinical, electrocardiographic and hemodynamic parameters. This finding confirms the utility of Braunwald unstable angina classification.

Effect of a Recombinant Dimeric Tumor Necrosis Factor Receptor on Inflammatory Responses to Intravenous Endotoxin in Normal Humans

AbstractTo determine the role of tumor necrosis factor (TNF ) in lipopolysaccharide (LPS)-induced inflammation, 12 healthy subjects received an intravenous injection with LPS (2 ng/kg) preceded by infusion of either a recombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6) from −30 minutes to directly before LPS injection. LPS elicited a transient increase in plasma TNF activity, peaking after 1.5 hours (219 ± 42 pg/mL; P < .05). Infusion of TNFR:Fc completely neutralized endogenous TNF activity. LPS administration was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator, plasminogen activator activity, and plasmin-α2 -antiplasmin complexes), followed by inhibition (plasma plasminogen activator inhibitor type I), changes that were completely prevented by TNFR:Fc. By contrast, TNFR:Fc did not influence LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes). TNFR:Fc strongly inhibited endothelial cell activation (plasma levels of soluble E-selectin), modestly reduced neutrophil responses (neutrophilia and plasma concentrations of elastase-α1 -antitrypsin complexes and lactoferrin), but did not affect the release of secretory phospholipase A2 or lipopolysaccharide-binding protein (P < .05). Infusion of TNFR:Fc only (without LPS) in another 6 normal subjects did not induce any inflammatory response. These data indicate that TNF is involved in only some inflammatory responses to intravenous LPS in humans.

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats.

Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.

Tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in patients with symptomatic lower extremity artery disease.

Background Lower extremity artery disease (LEAD) involves progressive arterial narrowing manifested by intermittent claudication (IC). LEAD entails endothelial dysfunction and fibrinolytic disorders. In the current study, we analyze the selected parameters of the fibrinolytic system in the blood of patients with symptomatic LEAD depending on clinical parameters. Methods The test group was comprised of 80 patients with diagnosis of LEAD based on Ankle-Brachial Index (ABI) test (27 female/53 male) with an average age of 63.5±9 years. The control group included 30 healthy, non-smoking volunteers (10 female/20 male), with the median age of 56±6 years. The research material - venous blood - was sampled to determine the concentrations of tissue-type plasminogen activator (t-PA Ag), plasminogen activator inhibitor type 1 (PAI-1 Ag), D-dimer, fibrinogen, and platelet count (PLT). Results We found elevated concentrations of t-PA Ag, PAI-1 Ag, D-dimer, and fibrinogen in the plasma of subjects with symptomatic LEAD. Various stages of the Fontaine classification demonstrated a gradual, statistically significant increase in the concentrations of fibrinogen and PLT count as the disease progressed. More so, in the subgroup of LEAD patients aged ≥65 years, we observed significantly higher levels of D-dimer than in the group of younger subjects. In addition to that, the LEAD group demonstrated negative correlations of IC distance, fibrinogen concentrations, and PLT count, negative correlations of ABI at rest and concentrations of D-dimer and PLT count, as well as positive correlations between age and D-dimer levels. Conclusions High t-PA Ag concentrations in LEAD patients suggest damage to the endothelium which comprises the main source of this factor. With high PAI-1 Ag levels, inactive fibrinolytic t-PA-PAI-1 complexes are formed. Increasing fibrinogen concentrations at the subsequent stages in accordance with the Fontaine classification, indicate increasing inflammation. Moreover, heightened values of D-dimer reflect an increased secondary fibrinolysis activation as patients get older and impaired extremity vascularization, manifested by the decreasing ABI, progresses.