No Observed Difference in Inflammatory and Coagulation Markers Following Diets Rich in n-6 Polyunsaturated Fat vs Monounsaturated Fat in Adults With Untreated Hypercholesterolemia: A Randomized Trial.

BACKGROUND: Inflammatory and prothrombotic responses are hallmark to the progression of cardiovascular disease and may be influenced by the type of dietary fat. Cottonseed oil (CSO) is rich in n-6 polyunsaturated fats and improves traditional cardiovascular disease risk factors such as cholesterol profiles. However, some clinicians are still hesitant to promote n-6 polyunsaturated fats consumption despite growing evidence suggesting they may not be independently pro-inflammatory. OBJECTIVE: To investigate the inflammatory and coagulation marker responses to an 8-week diet intervention rich in either CSO or olive oil (OO) (OO is rich in monounsaturated fat) in adults with untreated hypercholesterolemia. DESIGN: This was a secondary analysis of a parallel-arm randomized clinical trial with the main outcome of cholesterol measures. PARTICIPANTS/SETTING: Participants included in this analysis were 42 sedentary adults aged 30 to 75 years (62% women) in the Athens, GA, area, between May 2018 and June 2021, with untreated hypercholesterolemia or elevated blood lipids and body mass index >18.5. Hypercholesterolemia was defined as at least two blood lipid levels in a borderline undesirable/at risk range (total cholesterol level ≥180 mg/dL, low-density lipoprotein cholesterol level ≥110 mg/dL, high-density lipoprotein cholesterol level <50 mg/dL, or triglyceride level ≥130 mg/dL), or at least one in an undesirable range (total cholesterol level ≥240 mg/dL, low-density lipoprotein cholesterol level ≥160 mg/dL, high-density lipoprotein cholesterol level <40 mg/dL, or triglyceride level ≥200 mg/dL). INTERVENTION: Participants were randomly assigned to either the CSO or OO group in a partial outpatient feeding trial. Meals from the study provided approximately 60% of their energy needs with 30% of energy needs from either CSO or OO for 8 weeks. Participants fulfilled their remaining energy needs with meals of their choosing. MAIN OUTCOME MEASURES: Fasting plasma concentrations of inflammatory markers, including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1ß were measured at baseline and 8 weeks. Markers of coagulation potential, including plasminogen activator inhibitor-1, and tissue factor were measured at the same time points. STATISTICAL ANALYSES PERFORMED: Repeated measures linear mixed models were used with treatment and visit in the model for analyses of all biochemical markers. RESULTS: There were no significant differences in fasting C-reactive protein (P = 0.70), tumor necrosis factor-α (P = 0.98), interleukin-6 (P = 0.21), interleukin-1ß (P = 0.13), plasminogen activator inhibitor-1 (P = 0.29), or tissue factor (P = 0.29) between groups across the intervention. CONCLUSIONS: Inflammation and coagulation marker responses to diets rich in CSO vs OO were not significantly different between groups, and neither group showed changes in these markers in adults with untreated hypercholesterolemia. This provides additional evidence suggesting that dietary n-6 polyunsaturated fats may not promote inflammation compared with monounsaturated fatty acids, even in adults at increased risk for cardiovascular disease.

The Role of Plasminogen Activator Inhibitor Type-1 in Fibrosis.

Extracellular matrix (ECM) deposition during wound healing is a physiological response to an insult. Wound healing becomes deregulated in the setting of chronic injury or long-standing metabolic disease, leading to the accumulation of ECM components and fibrosis. Matrix protein turnover is determined by the rate of synthesis as well as the rate of proteolytic degradation and clearance by matrix metalloproteinases (MMPs). The persistent activation of interstitial myofibroblasts, coupled with defects in matrix proteolysis, ultimately disrupts tissue architecture and leads to biochemical and mechanical organ dysfunction with eventual organ failure. Plasminogen activator inhibitor type-1 (PAI-1) regulates tissue homeostasis and wound healing by inhibiting plasmin-mediated MMP activation. Multiple reports using models of liver, lung, and kidney fibrosis suggest that PAI-1 deficiency or inhibition of PAI-1 activity attenuates fibrosis. The disinhibition of plasmin-mediated MMP activation leads to collagen degradation and its diminished accumulation, resulting in the reduction of fibrotic matrix deposition in these organs. Paradoxically, homozygous deficiency of PAI-1 promotes age-dependent spontaneous cardiac fibrosis, suggesting a protective role for PAI-1 in the heart. It remains unclear whether PAI-1-deficient cardiac fibroblasts have increased proliferative, migratory, or differentiation capabilities, that allow them to overcome increased plasmin and MMP activity and matrix clearance. In this review, we examine the specific roles of PAI-1 in fibrosis of different organs including the lung, liver, kidney, and cardiovascular system.

Therapeutic potential of an orally effective small molecule inhibitor of plasminogen activator inhibitor for asthma.

Asthma is one of the most common respiratory diseases. Although progress has been made in our understanding of airway pathology and many drugs are available to relieve asthma symptoms, there is no cure for chronic asthma. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators, has pleiotropic functions besides suppression of fibrinolysis. In this study, we show that administration of TM5275, an orally effective small-molecule PAI-1 inhibitor, 25 days after ovalbumin (OVA) sensitization-challenge, significantly ameliorated airway hyperresponsiveness in an OVA-induced chronic asthma model. Furthermore, we show that TM5275 administration significantly attenuated OVA-induced infiltration of inflammatory cells (neutrophils, eosinophils, and monocytes), the increase in the levels of OVA-specific IgE and Th2 cytokines (IL-4 and IL-5), the production of mucin in the airways, and airway subepithelial fibrosis. Together, the results suggest that the PAI-1 inhibitor TM5275 may have therapeutic potential for asthma through suppressing eosinophilic allergic response and ameliorating airway remodeling.

Impact of transfer status on hospitalization cost and discharge disposition for acute ischemic stroke across the US.

OBJECT In this study, the authors used information provided in the Nationwide Inpatient Sample (NIS) to study the impact of transferring stroke patients from one facility to a center where they received some form of active stroke intervention (intravenous tissue plasminogen activator, thrombectomy, or a combination of both therapies). METHODS Patient demographic characteristics and hospital factors obtained from the 2008-2010 acute stroke NIS data were analyzed. Discharge disposition, hospitalization cost, and mortality were the dependent variables studied. Univariate analysis and multivariate binary logistic regression analysis were performed. Data analysis focused on the cohort of acute stroke patients who received some form of active intervention (55,913 of 1,311,511 patients in the NIS). RESULTS When overall outcome was considered, transferred patients had a significantly higher number of other-than-routine (OTR, i.e., other than discharge to home without home health care) discharge dispositions (p < 0.0001). In multivariate regression analysis including pertinent patient and hospital factors, transfer-in patients had significantly worse OTR discharge disposition (p < 0.0001, odds ratio [OR] 2.575, 95% CI 2.341-2.832). Mean hospitalization cost including an intervention was $70,325.11 for direct admissions and $97,546.92 for transferred patients. Transfer from another facility (p < 0.001, OR 1.677, 95% CI 1.548-1.817) was associated with higher hospitalization cost. CONCLUSIONS The study showed that hospital cost for acute stroke intervention is significantly higher for a transferred patient than for a direct admission. Moreover, the frequency of OTR discharge was significantly higher among transferred patients than direct admissions. Future strategies should focus on ways and means of transporting patients appropriately and directly to stroke centers.

Taming neonatal hypoxic-ischemic brain injury by intranasal delivery of plasminogen activator inhibitor-1.

BACKGROUND AND PURPOSE: Plasminogen activator inhibitor-I (PAI-1), a ≈50-kDa serine protease inhibitor, markedly reduces the extravascular toxicity of tissue-type plasminogen activator in experimental hypoxic-ischemic (HI) brain injury of newborns. However, the current treatment with PAI-1 requires intracerebroventricle injection to cross the blood-brain barrier, which is an invasive procedure of limited clinical potential. Thus, we tested whether intranasal administration of PAI-1 can bypass blood-brain barrier and mitigate neonatal HI brain injury. METHODS: Rat pups were subjected to HI, with or without lipopolysaccharide pre-exposure, followed by intranasal delivery of a stable-mutant form of PAI-1 (CPAI). RESULTS: Immunoblotting showed that CPAI sequentially entered the olfactory bulbs and cerebral cortex after intranasal delivery and reduced ≈75% of brain atrophy in HI or lipopolysaccharide-sensitized HI injury. Mechanistically, CPAI attenuated HI-induced plasminogen activators and lipopolysaccharide/HI-induced nuclear factor-κB signaling, neuroinflammation, and blood-brain barrier permeability. CONCLUSIONS: Intranasal delivery of CPAI is an effective treatment of experimental HI brain injury of newborns. Clinical application of this experimental therapy merits further investigation.

Tranexamic acid: a potential adjunct to resectoscopic endometrial ablation.

Abnormal uterine bleeding (AUB) is a substantial cause of ill health in women worldwide. In this study, our aim was to evaluate the effectiveness of endometrial ablation using a modified urologic resectoscope along with tranexamic acid in AUB. Sixty patients were enrolled in this study. All patients underwent resectoscopic surgery. Patients were randomly divided into two groups. Group 1 (n = 30) received 500 mg of tranexamic acid. Group 2 (n = 30) served as the control group and underwent surgery without the administration of tranexamic acid. Total pictorial blood loss assessment chart (PBAC) scores were significantly lower postoperatively (152.14 ± 9.65 versus 6.6 ± 0.90; P < 0.001). When stratified by the administration of tranexamic acid, the number of patients with a postoperative day 1 PBAC score ≤15 was higher in the tranexamic group (19 versus 13), whereas the number of patients with a post operative day 1 PBAC score >15 was lower in the tranexamic group (11 versus 17), but the differences were not statistically significant (P > 0.05). AUB is a complex disease that may need repeated treatments. In expert hands, the treatment rate of resectoscopic surgery seems acceptable. However, some patients may require additional interventions, like repeated surgery, hysterectomy, or a drug therapy in the long run. Introduction of tranexamic acid as a potential adjunct to rollerball endometrial ablation may present an interesting option that requires additional well-designed studies before firm conclusions can be made.

Effects of additional treatment of sarpogrelate to aspirin therapy on platelet aggregation and plasma plasminogen activator inhibitor activity in patients with stable effort angina.

INTRODUCTION: Serotonin is secreted from platelets at sites of endothelial injury, where it promotes thrombogenic reactions. Serotonin is reported to be associated with not only coronary artery disease but also cardiac events. MATERIALS AND METHODS: We studied 33 patients with stable effort angina (SEA) (11 patients with multivessel disease (MVD) and 22 patients with single vessel disease (SVD)) and 25 patients with chest pain syndrome (CPS). Sarpogrelate was administered to 22 of 33 patients with SEA in addition to aspirin therapy, and platelet aggregation, plasma serotonin concentration, and plasma plasminogen activator inhibitor (PAI) activity were measured before and 1 week after administration. RESULTS AND CONCLUSIONS: Serotonin level was higher in patients with MVD than in those with SVD (p<0.05) and in those with CPS (p<0.001). The formation of small-sized platelet aggregates was significantly higher in the high serotonin group than in the low serotonin group of SEA patients. The formation of large-sized platelet aggregates was significantly decreased by administration of sarpogrelate (P<0.05). The formation of small- or medium-sized aggregates was not significantly decreased. Plasma PAI activity decreased significantly (P<0.05) although the plasma serotonin concentration did not show significant change by administration of sarpogrelate. Plasma serotonin level is increased in relation to severity of coronary artery disease and plasma serotonin level is associated with increased platelet aggregation. Administration of sarpogrelate in addition to aspirin therapy reduces the increased platelet aggregation and PAI activity, and it may indicate that additional administration of sarpogrelate is useful for patients with SEA.

Accelerated thrombus lysis in the blood of plasminogen activator inhibitor deficient mice is inhibited by PAI-1 with a very long half-life.

Patients with defective plasminogen activator inhibitor protein (PAI-1) or with PAI-1 deficiency can experience hemorrhage as a result of a hyperfibrinolysis. In these patients, a normal thrombus forms, but endogenous lysis is unchecked as tissue plasminogen activator is unopposed. Treatment includes anti-fibrinolytic agents, including oral tranexamic acid. Another treatment option is the administration of PAI-1, but this serpin rapidly inactivates itself. We have developed a mutant plasminogen activator inhibitor with a very long half life (VLHL PAI-1, t1/2>700 h). Here we investigate VLHL PAI-1 effects in the blood of PAI-1 deficient mice, as a model of human disease. Using a thrombelastograph, we found that blood clots of PAI-1 knockout mice were lysed much more quickly than wild type mice. Additionally, blood clots had less shear elastic modulus strength than clots of normal animals. VLHL PAI-1 treatment of PAI-1 deficient mice extended or prevented thrombus lysis and increased clot strength in a concentration dependent fashion. These two parameters determine the extent of thrombus growth and regression; thus, further testing is anticipated to confirm the effectiveness of plasminogen activator inhibitor with a very long half life in an in vivo model and we hope that this protein can be effective in human PAI-1 deficiency disorder.

The pathophysiological relevance of PAI-1 in cardiovascular diseases and the development of monoclonal antibodies as PAI-1 inhibitors.

Plasminogen activator inhibitor- (PAI-1) is an important component of the plasminogen/plasmin system as it is the main inhibitor of tissue-type (t-PA) and urokinase-type plasminogen activator (u-PA). Consequently, PAI-1 plays an important role in cardiovascular diseases (mainly through inhibition of t-PA) and in cell migration and tumor development (mainly through inhibition of u-PA and interaction with vitronectin). As a member of the serpin superfamily, PAI-1 shares important structural properties with other serpins. However, PAI-1 also exhibits unique conformational and functional properties. The current review provides an overview of the knowledge on PAI-1 gathered since its discovery two decades ago. We are discussing (a) its structural properties of the protein and their subsequent relation to functional activities, (b) its role in a wide variety of (patho)physiological processes and (c) the development of monoclonal antibodies aiming to modulate pharmacologically this risk factor.

Aerosolized tissue plasminogen inhibitor improves pulmonary function in sheep with burn and smoke inhalation.

Acute respiratory distress syndrome is a major complication in patients with thermal injury. The obstruction of the airway by cast material, composed in part of fibrin, contributes to deterioration of pulmonary gas exchange. We tested the effect of aerosol administration of tissue plasminogen activator, which lyses fibrin clots, on acute lung injury in sheep that had undergone combined burn/smoke inhalation injury. Anesthetized sheep were given a 40% total body surface, third degree burn and were insufflated with cotton smoke. Tissue plasminogen activator (TPA) was nebulized every 4 h at 1 or 2 mg for each nebulization, beginning 4 h after injury. Injured but untreated control sheep developed multiple symptoms of acute respiratory distress syndrome: decreased pulmonary gas exchange, increased pulmonary edema, and extensive airway obstruction. These control animals also showed increased pulmonary transvascular fluid flux and increased airway pressures. These variables were all stable in sham animals. Nebulization of saline or 1 mg of TPA only slightly improved measures of pulmonary function. Treatment of injured sheep with 2 mg of TPA attenuated all the pulmonary abnormalities noted above. The results provide evidence that clearance of airway obstructive cast material is crucial in managing acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

The structural basis for the pathophysiological relevance of PAI-I in cardiovascular diseases and the development of potential PAI-I inhibitors.

Plasminogen activator inhibitor-I (PAI-I) is an important component of the plasminogen/plasmin system as it is the main inhibitor of tissue-type and urokinase-type plasminogen activator. Consequently, PAI-I plays an important role in cardiovascular diseases (mainly through inhibition of t-PA), and in cell migration and tumor development (mainly through inhibition of u-PA and interaction with vitronectin). As a member of the serpin superfamily, PAI-I shares important structural properties with other serpins. However, PAI-I also exhibits unique conformational and functional properties. The current review provides an overview of the knowledge on PAI-I gathered since its discovery two decades ago. We discuss (a) its structural properties of the protein and their subsequent relation to functional activities, (b) its role in a wide variety of (patho)physiological processes and (c) a number of strategies to interfere with its functional properties eventually aiming at pharmacological modulation of this risk factor.

The role of the plasminogen activation system in angiogenesis and metastasis.

The urokinase plasminogen activator system (uPA) has been demonstrated to be required for the movement of cells through a matrix. These observations have been extended to the migration of endothelial cells during the process of angiogenesis, and recent data suggest that the uPA system is central to this process. uPA is a serine protease that is capable of initiating an extracellular cascade of proteolysis that involves the activation of plasminogen and matrix metalloproteases. These proteolytic cascades remodel extracellular matrix (ECM) and basement membrane (BM), allowing for the movement of cells across and through these barriers. In addition, these proteolytic cascades process and release various growth and differentiation factors that are sequestered on the cell surface or within the ECM, which contribute to the evolution of a migratory or invasive cell phenotype. uPA is also able to modulate signaling and cell adhesion through its specific cell surface receptor, uPAR. Recent data suggest that the nonproteolytic activities of the uPA system are coupled to adhesion, migration and signaling through various integrins. This article reviews the evidence for the role of this system in tumor angiogenesis and metastasis, which suggests that the uPA system initiates multiple cascades that contribute to these processes.

Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.

Histopathological findings in experimental aneurysms embolized with conventional and thrombogenic/antithrombolytic Guglielmi coils.

We studied the short- and long-term histological responses induced by conventional and modified electronically detachable coils (GDCs) in experimental aneurysms. Eighteen carotid bifurcation aneurysms were produced microsurgically in rabbits. Six animals each were treated either with conventional or with GDCs coated with a mixture of tissue-thromboplastin to enhance intra-aneurysmal thrombus formation and of plasminogen activator inhibitor type-1 (PAI-1) in inhibit intra-aneurysmal clot fibrinolysis. Six served as untreated controls. Follow-up angiograms were obtained immediately and at 3, 6, 9, 12, 17, and 24 weeks after embolization prior to sacrifice of the animals. All aneurysms were studied macroscopically and histopathologically with the coils in situ. Five of six control aneurysms remained patent. Endovascular occlusion rates between > 90% and 100% were achieved in nine of twelve coiled aneurysms. Follow-up angiography demonstrated recanalization and coil compaction in 5 of them. Gross and microscopic histopathological examination revealed a membrane covering the orifice, intra-aneurysmal scar formation, and development of a neo-intima in both treatment groups at 17 and 24 weeks postembolization. The granulation tissue response appeared to be equally distributed in aneurysms treated with either uncoated or coated coils. Further quantitative morphometric studies are needed to prove if a thrombogenic/antithrombolytic coil-coating might be of value in providing a more enduring anatomic result after GDC-treatment of human brain aneurysms.

Evaluación retrospectiva del uso de activador tisular del plasminógeno (rt-PA) en el manejo del infarto agudo de miocardio en el servicio de urgencias de la Clínica Shaio

Objetivo: Evaluar el uso de activador tisular del plasminógeno recombinante (rt-PA) en los pacientes con IAM que ingresaron por el servicio de urgencias. Materiales y métodos: Estudio descriptivo retrospectivo de corte transversal en donde se tomaron todos los pacientes con diagnóstico de IAM al ingreso en urgencias durante el período comprendido entre enero de 1996 hasta julio de 1997 en los cuales se utilizó la terapia trombolítica con rt-PA. Se administró el esquema acelerado de rt-PA seguido por infusión de heparina para mantener PTT entre 50 y 70 segundos por 24 a 48 horas. Las indicaciones para administrar rt-PA fueron: edad menor de 75 años, infarto de localización anterior y tiempo de evolución menor de 6 horas. La recolección de la información se realizó a partir de la historia clínica. Las variables estudiadas fueron edad, sexo, tipo de infarto, localización, clasificación de killip, tiempo de evolución al momento de la consulta, uso, tipo y causa de exclusión de trombosis con rt-AP. permeabilidad de la arteria relacionada con el infarto, realización de angioplastia, requerimiento de cirugía (electiva o de urgencia), complicaciones y mortalidad antes de la intervención con angioplastia electiva o cirugía. Resultados: De un total de 458 pacientes con diagnóstico de IAM se realizó terapia de recanalización en 206 pacientes (44.5 por ciento), 12 con angioplastia primaria (6 por ciento), 146 (70.5 por ciento) con STK y 48 (23.5 por ciento) con rt-PA. De estos pacientes 42 (87.5 por ciento) fueron hombres y 6 (12.5 por ciento) mujeres. Las edades estuvieron entre 42 años el más joven y 75 años el de mayor edad, con un promedio de 60-17 años. El tiempo promedio de consulta a urgencias después del inicio de los síntomas fue de 4.9 horas. Ningún paciente entró con Killip IV, 3 (6.5 por ciento) Killip I, 14 (29 por ciento) en Killip II yb 31 (64.5 por ciento) en Killip III. La principal causa de exclusión de trombólisis con rt-PA fue la consulta fuera de tiempo > 6 horas. Se presentó un caso de hemorragia de vías digestivas clasificada como menor ya que no requirió transfusión. De las complicaciones secundarias al IAM se presentó choque en 4 (8.3 por ciento), arritmia ventricular en 3 (6.2 por ciento); pericarditis en 2 (4.15 por ciento); angina post IAM en 1 (2.5 por ciento); insuficiencia mitral en 1 (2.5 por ciento); trombo intracavitario 1 (2.5 por ciento). La mortalidad entre los pacientes trombolizados...

Clot lysis: role of plasminogen activator inhibitors in haemostasis and therapy.

An unimpeded circulation of blood depends on the concerted activation of coagulation and fibrinolytic factors. The latter entails the controlled, localised conversion of plasma zymogen plasminogen to the active enzyme plasmin mediated by tissue-type plasminogen activator (tPA). Bulk of tPA activity is in the proximity of the endogenous plasminogen activator inhibitor (PAI) as an active complex. The advent of molecular biology techniques has enabled isolation of cDNA for the inhibitors PAI-1, PAI-2 and PAI-3 and data indicate that these belong to the serine protease inhibitor (Serpine) family with arginine as its active site but immunologically distinct from each other. Enhanced tPA or PAI-1 forms one of the risk factors related to cardiac diseases and thrombotic disorders. A line of therapy entails lowering of PAIs with concomitant increase in tPA levels leading to net enhancement in fibrinolytic activity. In as much as plasminogen activators exert their action extracellularly, they are accessible to inhibitors and therefore PAIs could have a therapeutic potential and serve as prognostic indicators in cancer. Documented findings related to the biochemical characteristics and therapeutic potential of PAIs are presented and discussed in the review.

[Activators and inhibitors of fibrinolysis in chronic glomerulonephritis and amyloidosis]. / Aktivatory i ingibitory fibrinoliza pri khonicheskom glomerulonefrite i amiloidoze.

Functional activities of plasminogen activators (FPAA) and their inhibitors and plasminogen activators's (PA), antigen level were determined in 31 patients with chronic glomerulonephritis, 23 patients with amyloidosis and 15 healthy persons. High FPAA correlated with favourable prognosis of diseases, elevated PA antigen level and diminished alpha 1-antitrypsin, alpha 2-macroglobulin and antiactivator activities. There were decreased PA antigen level and increased inhibitor's activities in group with zero FPAA. Protein loaded functional probe demonstrated the presence of PA reserves in high FPAA patients and "pathological proteolysis" in zero FPAA patients. The last phenomenon was likely connected to nonspecific proteases differed from PA.