Plasma Concentrations Of Plasminogen Activator Inhibitor-1 Research Articles

Plasma levels of fibrinolytic and coagulation biomarkers in HIV-infected individuals on highly active antiretroviral therapy: A case-control study in a Northern Ghanaian population.

Impaired coagulation and fibrinolysis have been implicated in thromboembolism in human immunodeficiency virus (HIV)-infected individuals. This study evaluated the plasma levels of plasminogen activator inhibitor-1 (PAI-1) and coagulation biomarkers in HIV-infected individuals on highly active antiretroviral therapy (HAART). This matched case-control study from March to December, 2020 comprised 76 participants: 38 HIV-positive individuals on HAART and 38 apparently healthy HIV-negative individuals as controls. Blood samples were collected for prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimers, PAI-1, and soluble fibrin monomer complex (SFMC) estimations. The data were analysed using SPSS version 22.0 and statistical significance was set at p < 0.05. Activated partial thromboplastin time was significantly lower in HIV seropositive individuals on HAART compared with HIV seronegative controls (25.90 s vs. 29.0 s, p = 0.030); however, PT, SFMC, D-dimers, and PAI-1 were significantly higher among the HIV-seropositive individuals compared with the controls: PT: (16.29 s ± 2.16 vs. 15.15 s ± 2.60, p = 0.010), SFMC: [8.53 ng/mL (8.03-9.12) vs. 7.84 ng/mL (7.32-8.58), p = 0.005]), D-Dimer: [463.37 ng/mL (402.70-526.33) vs. 421.11 ng/mL (341.11-462.52), p = 0.015], and PAI-1: [12.77 ng/mL (10.63-14.65) vs. 11.27 ng/mL (10.08-12.95), p = 0.039]. PAI-1 showed a moderate positive correlation with D-Dimer (r = 0.659, p < 0.001) and SFMC (r = 0.463, p = 0.003) among HIV-positive individuals on HAART. There was a strong positive correlation between the plasma PAI-1 concentration and the HIV viral load (r = 0.955, p < 0.001). HIV-seropositive individuals on HAART have deranged coagulation and fibrinolytic markers. Higher HIV viral load correlates strongly with elevated plasma levels of PAI-1 antigens. Periodic assessment of markers of coagulation and fibrinolysis be included in the management of HIV/AIDS in Ghana.

Features of plasminogen activator inhibitor-1 synthesis by local fat depots of different localization in cardiovascular diseases

Aim. To determine the features of expression and secretion of plasminogen activator inhibitor-1 (PAI-1) by subcutaneous, epicardial and perivascular adipocytes depending on the complexity of coronary artery disease (CAD).Material and methods. The study included 86 patients with CAD, including 35 with moderate atherosclerotic lesions of the coronary arteries (CA) (SYNTAX Score ≤22), 22 with severe (SYNTAX Score of 23-31 pints), 29 with extremely severe (SYNTAX Score ≥32). As a comparison group, 52 patients with heart defects were examined. During an elective surgical intervention, adipose tissue (AT) samples were obtained for subsequent cultivation and determination of PAI-1 gene expression and PAI-1 secretion in AT supernatants of various localizations. Statistical analysis was performed using Statistica 10.0.Results. In CAD, PAI-1 production in all three types of AT and plasma PAI-1 concentration were increased compared with patients with heart defects. Epicardial AT (EAT) in CAD was characterized by the maximum levels of expression and secretion of PAI-1 relative to patients with heart defects and subcutaneous and perivascular (PVAT) fat depots. Moderate coronary involvement (adipose tissue &lt;22) is characterized by the lowest expression and secretion of PAI-1 in all types of AT and plasma concentration of PAI-1. Direct correlations of PAI-1 expression and secretion in EAT and PVAT and plasma PAI-1 level with its secretion in EAT in patients with CAD and heart defects were revealed. A direct correlation between the plasma level of PAI-1 and its secretion in PVAT was found only in CAD.Conclusion. In CAD, there is not only an increase in the plasma PAI-1 level, but also an increase in the expression of PAI-1 gene and the secretion of PAI-1 in all three types of AT compared with patients with heart defects. PAI-1 expression and secretion in EAT, PAI-1 plasma level, and age are predictors of severe/extremely severe coronary involvement in CAD.

Features of plasminogen activator inhibitor-1 synthesis by local fat depots of different localization in cardiovascular diseases

Aim. To determine the features of expression and secretion of plasminogen activator inhibitor-1 (PAI-1) by subcutaneous, epicardial and perivascular adipocytes depending on the complexity of coronary artery disease (CAD).Material and methods. The study included 86 patients with CAD, including 35 with moderate atherosclerotic lesions of the coronary arteries (CA) (SYNTAX Score ≤22), 22 with severe (SYNTAX Score of 23-31 pints), 29 with extremely severe (SYNTAX Score ≥32). As a comparison group, 52 patients with heart defects were examined. During an elective surgical intervention, adipose tissue (AT) samples were obtained for subsequent cultivation and determination of PAI-1 gene expression and PAI-1 secretion in AT supernatants of various localizations. Statistical analysis was performed using Statistica 10.0.Results. In CAD, PAI-1 production in all three types of AT and plasma PAI-1 concentration were increased compared with patients with heart defects. Epicardial AT (EAT) in CAD was characterized by the maximum levels of expression and secretion of PAI-1 relative to patients with heart defects and subcutaneous and perivascular (PVAT) fat depots. Moderate coronary involvement (adipose tissue &lt;22) is characterized by the lowest expression and secretion of PAI-1 in all types of AT and plasma concentration of PAI-1. Direct correlations of PAI-1 expression and secretion in EAT and PVAT and plasma PAI-1 level with its secretion in EAT in patients with CAD and heart defects were revealed. A direct correlation between the plasma level of PAI-1 and its secretion in PVAT was found only in CAD.Conclusion. In CAD, there is not only an increase in the plasma PAI-1 level, but also an increase in the expression of PAI-1 gene and the secretion of PAI-1 in all three types of AT compared with patients with heart defects. PAI-1 expression and secretion in EAT, PAI-1 plasma level, and age are predictors of severe/extremely severe coronary involvement in CAD.

Association between plasminogen activator inhibitor-1 gene polymorphisms and susceptibility to Parkinson's disease in Chinese patients.

Parkinson's disease (PD) is a neurodegenerative disease that usually leads to memory impairment, cognitive decline and dementia. Previous studies have reported that plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms play important roles in cardiovascular diseases, obesity, inflammation and other diseases. However, the role of PAI-1 in the diagnosis of Parkinson's disease has not been reported so far. This study was a case-control study. This study included 131 PD patients and 97 healthy volunteers. polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze the polymorphic loci of five different regions in PAI-1 gene (rs2227631, rs1799889, rs6092, rs2227694 and rs7242). 60 PD patients and 60 healthy volunteers were selected to detect the plasma PAI-1 concentration. The allele and genotype frequencies of SNPs were assessed using the SHEsis program. We found that GG genotype frequency and G allele frequency of rs2227631 was significantly higher in the PD patients. Statistically significant difference for rs1799889 could be observed in overdominant model. In subgroup analysis, a significant difference in genotype frequency distribution and allele frequency was found for rs2227631 and rs1799889 between early-onset PD group and the control group. For cognitive dysfunction, the subcomponent showed that GG genotype frequency and G allele frequency of rs2227631 was significantly higher in normal cognition group. The codominant model of rs1799889 was significantly different between the cognitive impairment group and the control group. In addition, the expression of PAI-1 in plasma of PD patients was significantly higher than that of controls, and further analysis showed that the expression of PAI-1 in patients with cognitive impairment was significantly higher than that in patients with cognitive normal. Our results indicate that the PAI-1 gene rs2227631 and rs1799889 polymorphisms were significantly associated with PD susceptibility in the Chinese Han population. PAI-1 has the potential to become a new therapeutic target and diagnostic marker.

Comparison of the in-vivo effect of two tranexamic acid doses on fibrinolysis parameters in adults undergoing valvular cardiac surgery with cardiopulmonary bypass - a pilot investigation

BackgroundThe blood saving efficacy of TXA in cardiac surgery has been proved in several studies, but TXA dosing regimens were varied in those studies. Therefore, we performed this study to investigate if there is a dose dependent in-vivo effect of TXA on fibrinolysis parameters by measurement of fibrinolysis markers in adults undergoing cardiac surgery with CPB.MethodsA double-blind, randomized, controlled prospective trial was conducted from February 11, 2017 to May 05, 2017. Thirty patients undergoing cardiac valve surgery were identified and randomly divided into a placebo group, low-dose group and high-dose group by 1: 1: 1. Fibrinolysis parameters were measured by plasma levels of D-Dimers, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-antiplasmin complex (PAP), tissue plasminogen activator (tPA) and thrombomodulin (TM). Those proteins were measured at five different sample times: preoperatively before the TXA injection (T1), 5 min after the TXA bolus (T2), 5 min after the initiation of CPB (T3), 5 min before the end of CPB (T4) and 5 min after the protamine administration (T5). A Thrombelastography (TEG) and standard coagulation test were also performed.ResultsCompared with the control group, the level of the D-Dimers decreased in the low-dose and high-dose groups when the patients arrived at the ICU and on the first postoperative morning. Over time, the concentrations of PAI-1, TAFI, and TM, but not PAP and tPA, showed significant differences between the three groups (P < 0.05). Compared with the placebo group, the plasma concentrations of PAI-1 and TAFI decreased significantly at the T3 and T4 (P < 0.05); TAFI concentrations also decreased at the T5 in low-dose group (P < 0.05). Compared with the low-dose group, the concentration of TM increased significantly at the T4 in high-dose group.ConclusionsThe in-vivo effect of low dose TXA is equivalent to high dose TXA on fibrinolysis parameters in adults with a low bleeding risk undergoing valvular cardiac surgery with cardiopulmonary bypass, and a low dose TXA regimen might be equivalent to high dose TXA for those patients.Trial registrationChiCTR-IPR-17010303, Principal investigator: Zhen-feng ZHOU, Date of registration: January 1, 2017.

Effect of Differently Fed Farmed Gilthead Sea Bream Consumption on Platelet Aggregation and Circulating Haemostatic Markers among Apparently Healthy Adults: A Double-Blind Randomized Crossover Trial.

Fish consumption beneficially affects coagulation markers. Few dietary intervention studies have investigated differently fed farmed fish against these cardio-metabolic risk factors in humans. This double-blind randomized crossover trial evaluated differently fed farmed gilthead sea bream consumption against platelet aggregation and circulating haemostatic markers among apparently healthy adults. Subjects aged 30–65 years, with a body mass index 24.0–31.0 kg/m2, consuming less than 150 g cooked fish per week, were recruited in Attica, Greece. Participants were randomized (n = 38, 1:1) to one of two sequences; consumption of fish fed with fish oil diet (conventional fish, CF)/fish fed with olive pomace-enriched diet (enriched fish, EF) versus EF/CF. The primary outcomes were ex vivo human platelet aggregation and circulating plasminogen activator inhibitor-1 (PAI-1) and P-selectin (sP-selectin) concentrations. EF consumption had no significant effect on platelet sensitivity or haemostatic markers compared to CF. Platelet sensitivity to platelet-activating factor (PAF) decreased after CF consumption during the second period (p < 0.01). Plasma PAI-1 and sP-selectin concentrations increased after CF consumption during both periods (p < 0.01 for both). Based on current findings, consumption of enriched farmed gilthead sea bream had no greater effect on coagulation markers in adults compared to the conventionally fed fish.

Empagliflozin decreases the plasma concentration of plasminogen activator inhibitor-1 (PAI-1) in patients with type 2 diabetes: Association with improvement of fibrinolysis

AimsElevation of the plasma concentration of plasminogen activator inhibitor-1 (PAI-1), a rapid-acting inhibitor of fibrinolysis, is associated with development of vascular thrombotic diseases, including coronary artery disease and stroke. We investigated the effects of empagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on the plasma concentration of PAI-1 and fibrinolytic activity in patients with type 2 diabetes. MethodsIn a randomized, active-controlled, open-label trial, 51 patients with type 2 diabetes were randomly allocated at a 2:1 ratio to receive empagliflozin (10 mg/day, n = 31) or standard therapy (n = 18) for 12 weeks. We measured the plasma concentrations of PAI-1 and plasmin-α2-antiplasmin complex (PAP) as indicators of fibrinolytic activity. Serum leptin and high-molecular weight (HMW) adiponectin were also measured. ResultsIn 49 patients who completed the trial, baseline plasma PAI-1 showed a positive correlation with body weight, visceral fat area (VFA), γ-glutamyltranspeptidase (GGT), leptin, and the platelet count, while it showed a negative correlation with HDL cholesterol and PAP. Body weight and VFA decreased significantly in the empagliflozin group, but not in the control group. The serum level of GGT showed a significant decrease at 12 weeks in the empagliflozin group, while it was unchanged in the control group. Serum HMW adiponectin increased significantly in the empagliflozin group. Plasma PAI-1 decreased significantly by 25% in the empagliflozin group, but not in the control group. In the empagliflozin group, the change of plasma PAI-1 was positively correlated with the changes of body weight and leptin, but was negatively correlated with the change of PAP. ConclusionsEmpagliflozin reduced the plasma PAI-1 concentration through its synergistic actions of a glucose-lowering effect, VFA loss, and restoring the adipokine balance. (Clinical trial registry: UMIN000025418).

1150-P: Empagliflozin Decreases the Plasma Concentration of Plasminogen Activator Inhibitor-1 (PAI-1) in Patients with Type 2 Diabetes: Association with Improvement of Fibrinolysis

Objectives: Elevation of the plasma concentration of plasminogen activator inhibitor-1 (PAI-1), a rapid-acting inhibitor of fibrinolysis, is associated with development of cardiovascular diseases. We investigate the effects of empagliflozin, an SGLT2 inhibitor, on the plasma concentration of PAI-1 and fibrinolytic activity in patients with type 2 diabetes. Methods: In a randomized, active-controlled, open-label trial, 51 patients with type 2 diabetes were randomly allocated at a 2:1 ratio to receive empagliflozin (10 mg/day, n=31) or standard therapy (n=18) for 12 weeks. We measured the plasma concentrations of PAI-1 and plasmin-α2-antiplasmin complex (PAP) as indicators of fibrinolytic activity. Serum leptin and HMW adiponectin were also measured. Results: Body weight and visceral fat decreased in the empagliflozin group, but not in the control group. The serum level of γ-GTP showed a significant decrease at 12 weeks in the empagliflozin group, while it was unchanged in the control group. Serum HMW adiponectin increased significantly in the empagliflozin group. Plasma PAI-1 decreased significantly by 25% in the empagliflozin group, but not in the control group. In the empagliflozin group, the change of plasma PAI-1 was positively correlated with the changes of body weight and leptin, but was negatively correlated with the change of PAP. Conclusions: Empagliflozin reduced the plasma PAI-1 concentration through its synergistic actions of a glucose-lowering effect, weight loss, and restoring the adipokine balance. The beneficial effects of empagliflozin on fibrinolysis by decreasing circulating PAI-1 may be associated with improvement of vascular thrombotic outcomes in patients with type 2 diabetes. (Clinical trial registry: UMIN000025418). Disclosure T. Niitani: None. S. Sakurai: None. T. Jojima: None. T. Iijima: None. T. Tomaru: Research Support; Self; Merck &amp; Co., Inc., Teijin Pharma Limited. I. Usui: None. Y. Aso: None.

THE CLINICAL SIGNIFICANCE OF MARKERS OF ENDOTHELIAL DYSFUNCTION IN PROGRESSION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS (IIP)

TYPE: Abstract Publication TOPIC: Pulmonary Vascular Disease PURPOSE: The aim of our study was to define some mediators of ED and angiogenesis (endothelin1 (ET-1), vascular endothelial growth factor (VEGF), Plasminogen Activator Inhibitor-1 (PAI1) in patients with different clinical forms of IIP. METHODS: PATIENTS AND METHODS: 39 patients (22 – usual interstitial pneumonia, 17 – nonspecific interstitial pneumonia) with morphologically proved IIP were examined. Standard clinical examination, pulmonary function tests, echocardiography, high-resolution computed tomography (HRCT), measurement of diffusion capacity of the lung for carbon monoxide (DLCO) were evaluated. Plasma concentrations of ET-1, VEGF and PAI1 (ELISA) and morphometrics of lung biopsy for estimation of intensity of neoangiogenesis were performed. RESULTS: RESULTS: Markers of ED correlated positively with HRCT patterns of lung fibrosis (VEGF r=0,31, p=0,004; ET-1 r=0,37 p=0,003, PAI-1 r=0,38, р=0,006), the level of VEGF in the blood correlated with parameters of neoangiogenesis in the lung tissue (r=0,37, p=0,001). Patients with PH in comparison with patients without PH demonstrated higher concentrations of ЕТ-1 и PAI-1 (r=0,34, p=0,005 and r=0,37, р=0,002 respectively). Inverse correlation was established between PAI-1 and DLCO (r = -0,71, p<0,05), PAI-1 and FVC (r = -0,72, p<0,05). CONCLUSIONS: CONCLUSION: these data demonstrate the important role of the studied markers of ED and neoangiogenesis in the mechanisms of IIP progression and may be used as predictors of survival. CLINICAL IMPLICATIONS: Angiogenesis and endothelial dysfunction(ED) in idiopathic interstitial pneumonias(IIP) are considered as key mechanisms of lung tissue remodeling and pulmonary hypertension (PH). DISCLOSURE: No significant relationships. KEYWORDS: endothelial dysfunction, interstitial pneumonias

Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation.

Objective:Although vascular endothelial growth factor inhibition (VEGFi) represents a major therapeutic advance in oncology, it is associated with hypertension and adverse vascular thrombotic events. Our objective was to determine whether VEGFi caused direct vascular dysfunction through increased endothelin-1 (ET-1) activity or impaired endothelial vasomotor or fibrinolytic function.Methods:Using forearm venous occlusion plethysmography, we measured forearm blood flow during intra-arterial infusions of bevacizumab (36–144 μg/dl forearm volume per minute) administered for 15–60 min in healthy volunteers (n = 6–8). On two separate occasions in 10 healthy volunteers, we further measured forearm blood flow and tissue plasminogen activator (t-PA) release during intra-arterial bradykinin infusion (100 and 1000 pmol/min) in the presence and absence of bevacizumab (144 μg/dl forearm volume per minute), and the presence and absence of endothelin A receptor antagonism with BQ-123 (10 nmol/min). Plasma t-PA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured at baseline and with each dose of bradykinin.Results:Baseline blood flow and plasma ET-1, t-PA and PAI-1 concentrations were unaffected by bevacizumab. Bradykinin caused dose-dependent vasodilatation (P < 0.0001) and t-PA release (P < 0.01) but had no effect on plasma PAI-1 concentrations. Neither bevacizumab nor BQ-123 affected bradykinin-induced vasodilatation and t-PA release.Conclusion:Acute exposure to bevacizumab does not directly cause endothelial vasomotor or fibrinolytic dysfunction in healthy young volunteers.

Fibrinolytic System Changes in Liver Surgery: A Pilot Observational Study.

Introduction: Bleeding occurs frequently in liver surgery. Unbalance between tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) concentrations might increase bleeding. Our aim was to analyze perioperative fibrinolytic changes during liver surgery.Materials and Methods: We evaluated 15 patients for inclusion into a prospective pilot study of liver surgery. We assessed fibrinolysis by plasma PAI-1 and t-PA: before surgery (T1), before Pringle maneuver (PM;T2), at the end of surgery (T3) and 24 h postoperatively (T4), and registered demographic and laboratory data, extent and duration of surgery, hemodynamic parameters, blood loss, and transfused volumes of blood products. Data presented as mean ± SD. Significance at P < 0.05.Results: After exclusion of six patients only undergoing biopsies, we included six women and three men aged 49.1 ± 19.6 years; two patients with liver metastases of colorectal cancer and hepatocellular carcinoma, respectively, two with focal nodular hyperplasia, two with hepatic hemangioma, and one with angiomyolipoma. Six patients underwent PM. PAI-1 plasma concentration (n = 9) rose from 6.25 ± 2.25 at T1 through 17.30 ± 14.59 ng/ml at T2 and 28.74 ± 20.4 (p = 0.007) and 22.5 ± 16.0 ng/ml (p = 0.04), respectively, at T3 and T4. Correspondingly, t-PA plasma concentration (n = 9) increased from 4.76 ± 3.08 ng/ml at T1 through 8.00 ± 5.10 ng/ml (p = 0.012) at T2 and decreased to 4.25 ± 2.29 ng/ml and 3.04 ± 3.09 at T3 and T4, respectively. Plasma t-PA level at T2 was significantly different from those at T1, T3, and T4 (p < 0.004). In PM patients, t-PA levels increased from T1, peaked at T2 (p = 0.001), and subsequently decreased at T3 and T4 (p = 0.011 and p = 0.037), respectively. Mean blood loss was 1,377.7 ± 1,062.8 ml; seven patients received blood products. Patients with higher PAI-1 levels at T3 received more fresh frozen plasma (r = 0.79; p = 0.01) and red blood cells (r = 0.88; p = 0.002).Conclusions: During liver surgery, fibrinolysis increased, as evidenced by rises in plasma PAI-1and t-PA, especially after start of surgery and following PM. Transfused volumes of blood products correlated with higher plasma concentrations of PAI-1. Confirming this tendency requires a larger cohort of patients.

Plasminogen Activator Inhibitor-1 Level Correlates with Lipoprotein Subfractions in Obese Nondiabetic Subjects.

Background The elevated level of plasminogen activator inhibitor-1 (PAI-1) in obese subjects with metabolic syndrome and in patients with type 2 diabetes is well established. The association of plasma PAI-1 and lipid metabolism is still unclear. The aim of the present study was to determine the relationship between plasma PAI-1 levels and the distribution of lipoprotein subfractions in obese and lean nondiabetic individuals. Subjects and Methods We enrolled fifty nondiabetic obese patients and thirty-two healthy volunteers. Lipoprotein subfractions were detected with Lipoprint System. Plasma PAI-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and myeloperoxidase (MPO) concentrations were determined with enzyme-linked immunosorbent assay (ELISA), while serum paraoxonase-1 (PON1) activities were measured by spectrophotometry. Results The TNF-α, IL-6, oxidized low-density lipoprotein (oxLDL), and MPO levels were found to be significantly higher, while PON1 paraoxonase and arylesterase activities were nonsignificantly lower in the obese patients. Strong significant negative correlations were found between plasma PAI-1 concentration and mean LDL size, as well as between PAI-1 concentrations and the levels of the large and intermediate high-density lipoprotein (HDL) subfractions. In multiple regression analysis, PAI-1 was predicted by waist circumference and intermediate HDL subfraction. Conclusion The significant correlations between PAI-1 levels and lipoprotein subfractions indicate the link between PAI-1 and lipid metabolism in obesity.

Evaluation of thrombosis-related biomarkers before and after therapy in patients with multiple myeloma.

BackgroundThrombosis is one of the complications in the clinical course of multiple myeloma (MM). Vascular endothelial cells and/or the hemostatic-coagulatory system are thought to play an important role in thrombosis of MM. In addition to melphalan-prednisone (Mel-P) therapy, several new therapeutic drugs such as lenalidomide or bortezomib have been developed and show effectiveness against MM. However, these new drugs also have risk of therapy-related thrombosis.MethodsWe assessed 103 MM patients and 30 healthy controls, using enzyme-linked immunosorbent assays to evaluate five biomarkers: platelet-derived microparticles (PDMP), plasminogen activator inhibitor-1 (PAI-1), high mobility group box protein-1 (HMGB1), endothelial protein C receptor (EPCR), and soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of Mel-P, bortezomib, and lenalidomide on the plasma concentrations of these biomarkers were investigated.ResultsThe plasma concentrations of PDMP, PAI-1, HMGB1, EPCR, and sVCAM-1 were higher in MM patients than in healthy controls. Mel-P, bortezomib, and lenalidomide therapies all reduced biomarker levels after treatment. However, when only patients with higher levels of EPCR were compared, differences were seen between the three therapies in the elevation of PDMP, HMGB1, and PAI-1.ConclusionThese results suggest that both MM and therapies for MM can induce a hypercoagulable state. The elevated risk of thrombosis conferred by hypercoagulability increases patient morbidity and mortality. Attention should be paid to therapy-related thrombosis when new therapeutic regimens are selected for MM patients.

Vitamin D supplementation lowers thrombospondin-1 levels and blood pressure in healthy adults.

IntroductionVitamin D insufficiency, defined as 25-hydroxyvitamin D (25(OH)D) levels < 75nmol/L is associated with cardio-metabolic dysfunction. Vitamin D insufficiency is associated with inflammation and fibrosis, but it remains uncertain whether these anomalies are readily reversible. Therefore, we aimed to determine the effects of vitamin D supplementation on markers of: 1) nitric oxide (NO) signaling, 2) inflammation, and 3) fibrosis, in healthy volunteers with mild hypovitaminosis.MethodsHealthy volunteers (n = 35) (mean age: 45 ± 11 years) with 25(OH)D levels <75nmol/L, received vitamin D supplementation (Ostelin ® capsules 2000IU) for 12 weeks. Resting systolic and diastolic blood pressures (BP) were assessed. Routine biochemistry was examined. Plasma concentrations of asymmetric dimethylarginine (ADMA), thrombospondin-1 (TSP-1), plasminogen activator inhibitor-1 (PAI-1), hs-CRP, activin-A, and follistatin-like 3 (FSTL3) were quantitated.ResultsVitamin D administration for 12 weeks significantly increased 25-(OH)D levels (48.8 ± 16 nmol/L to 100.8 ± 23.7 nmol/L, p<0.001). There was significant lowering of systolic and diastolic BP, while there was no significant change in lipid profiles, or fasting insulin. Plasma concentrations of ADMA, hs-CRP, PAI-1, activin A, and FSTL-3 did not change with vitamin D supplementation. However, there was a marked reduction of TSP-1 (522.7 ± 379.8 ng/mL vs 206.7 ± 204.5 ng/mL, p<0.001).ConclusionsVitamin D supplementation in vitamin D insufficient, but otherwise healthy individuals markedly decreased TSP-1 levels and blood pressure. Since TSP-1 suppresses signaling of NO, it is possible that the fall in BP is engendered by restoration of NO effect.

Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study.

Coagulation and fibrinolysis remain sparsely addressed with regards to acute respiratory distress syndrome (ARDS). We hypothesized that ARDS development might be associated with changes in plasma coagulation and fibrinolysis. Our aim was to investigate the relationships between ARDS diagnosis and plasma concentrations of tissue factor (TF), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in mechanically ventilated patients at increased risk of developing ARDS. We performed an ethically approved prospective observational pilot study. Inclusion criteria were patients with PaO2/FiO2 < 300 mmHg admitted to the intensive care unit (ICU) for mechanical ventilation for 24 h, or more, because of one or more disease conditions associated with increased risk of developing ARDS. Exclusion criteria were age below 18 years; cardiac disease. We sampled plasma prospectively and compared patients who developed ARDS with those who did not using descriptive statistics and chi-square analysis of baseline demographical and clinical data. We also analyzed plasma concentrations of TF, t-PA, and PAI-1 at inclusion (T0) and on third (T3) and seventh day (T7) of the ICU stay with non-parametric statistics inclusive their sensitivity and specificity associated with the development of ARDS using receiver operating characteristic curve analysis. Statistical significance: p < 0.05. Of 24 patients at risk, 6 developed mild ARDS and 4 of each moderate or severe ARDS, respectively, 3 ± 2 (mean ± SD) days after inclusion. Median plasma concentrations of TF and PAI-1 were significantly higher at T7 in patients with ARDS, as compared to non-ARDS. Simultaneously, we found moderate correlations between plasma concentrations of TF and PAI-1, TF and PaO2/FiO2, and positive end-expiratory pressure and TF. TF plasma concentration was associated with ARDS with 71% sensitivity and 100% specificity, a cut off level of 145 pg/ml and AUC 0.78, p = 0.02. PAI-1 displayed 64% sensitivity and 100% specificity with a cut off concentration of 117.5 pg/ml and AUC 0.77, p = 0.02. t-PA did not change significantly during the observation time. This pilot study showed that increased plasma concentrations of TF and PAI-1 might support ARDS diagnoses in mechanically ventilated patients after 7 days in ICU.

Impact of statin therapy on plasma levels of plasminogen activator inhibitor-1. A systematic review and meta-analysis of randomised controlled trials.

Elevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic cardiovascular disease. Beyond their lipid-lowering effect, statins have been shown to modulate plasma PAI-1 levels but evidence from individual randomised controlled trials (RCTs) is controversial. Therefore, we aimed to assess the potential effects of statin therapy on plasma PAI-1 concentration through a meta-analysis of RCTs. We searched Medline and SCOPUS databases (up to October 3, 2014) to identify RCTs investigating the effect of statin therapy on plasma PAI-1 concentrations. We performed random-effects meta-analysis and assessed heterogeneity (I² test, subgroup and sensitivity analyses) and publication bias (funnel plot, Egger and "trim and fill" tests). Sixteen RCTs (comprising 19 treatment arms) were included and pooled analyses showed a significant effect of statins in reducing plasma PAI-1 concentrations (weighted mean difference WMD: -15.72 ng/ml, 95 % confidence interval [CI]: -25.01, -6.43,). In subgroup analysis, this effect remained significant in with lipophilic statins (atorvastatin and simvastatin) (WMD: -21.32 ng/ml, 95 % CI: -32.73, -9.91, I²=99 %) and particularly atorvastatin (WMD: -20.88 ng/mL, 95 % CI: -28.79, -12.97, I2=97 %). In the meta-regression analysis, the impact of statins on PAI-1 did not correlate with the administered dose, duration of treatment and changes in plasma LDL-cholesterol concentrations. Finally, evidence of publication bias was observed. In conclusion, taking into account the limit of heterogeneity between studies, the present meta-analysis suggests that statin therapy (mainly atorvastatin) significantly lowers plasma PAI-1 concentrations.

Ultrasmall superparamagnetic iron oxide nanoparticles acutely promote thrombosis and cardiac oxidative stress and DNA damage in mice.

BackgroundUltrasmall superparamagnetic iron oxide nanoparticles (USPIO) are being developed for several biomedical applications including drug delivery and imaging. However, little is known about their possible adverse effects on thrombosis and cardiac oxidative and DNA damage.MethodsPresently, we investigated the acute (1 h) effect of intravenously (i.v.) administered USPIO in mice (0.4, 2 and 10 μg/kg). Diesel exhaust particles (DEP; 400 μg/kg) were used as positive control.ResultsUSPIO induced a prothrombotic effect in pial arterioles and venules in vivo and increased the plasma plasminogen activator inhibitor-1 (PAI-1). Both thrombogenicity and PAI-1 concentration were increased by DEP. The direct addition of USPIO (0.008, 0.04 and 0.2 μg/ml) to untreated mouse blood dose-dependently induced in vitro platelet aggregation. USPIO caused a shortening of activated partial thromboplastin time (aPTT) and prothrombin time (PT). Similarly, DEP administration (1 μg/ml) triggered platelet aggregation in vitro in whole blood. DEP also reduced PT and aPTT. The plasma levels of creatine phosphokinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH) and troponin-I were increased by USPIO. DEP induced a significant increase of CK-MB, LDH and troponin I levels in plasma. The cardiac levels of markers of oxidative stress including lipid peroxidation, reactive oxygen species and superoxide dismutase activity were increased by USPIO. Moreover, USPIO caused DNA damage in the heart. Likewise, DEP increased the markers of oxidative stress and induced DNA damage in the heart.ConclusionWe conclude that acute i.v. administration of USPIO caused thrombosis and cardiac oxidative stress and DNA damage. These findings provide novel insight into the pathophysiological effects of USPIO on cardiovascular homeostasis, and highlight the need for a thorough evaluation of their toxicity.

The 4G/4G Genotype of PAI-1 Polymorphism Is Associated with Higher Plasma PAI-1 Concentrations and Mortality in Patients with Severe Sepsis.

ObjectiveTwo studies have reported that patients with the 4G/4G genotype of the plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism had higher plasma PAI-1 concentrations and higher risk of death than those with the 4G/5G or 5G/5G genotypes; one study involved 175 children with meningococcal disease, and the other included 88 adult patients with septic shock. Thus, the objective of this study was to determine whether there is an association between carriage of the 4G/4G genotype, plasma PAI-1 concentrations and mortality in a large series of adult septic patients.MethodsAn observational, prospective, multicenter study was carried out in six Spanish Intensive Care Units including severe septic patients. We determined the PAI-1 4G/5G polymorphism and plasma PAI-1 concentrations in all patients. The end-points of the study were 30-day and 6-month mortality.ResultsWe included a total of 260 patients, 82 (31.5%) with 4G/4G, 126 (48.5%) with 4G/5G and 52 (20.0%) with 5G/5G genotype. Multivariate logistic regression analysis showed that the 4G/4G genotype was associated with higher mortality at 30 days (Odds Ratio = 1.95; 95% CI = 1.063–3.561; p = 0.03) and at 6 months (Odds Ratio = 2.19; 95% CI = 1.221–3.934; p = 0.01), and that higher plasma PAI-1 concentrations were associated with higher mortality at 30 days (Odds Ratio = 1.01; 95% CI = 1.002–1.022; p = 0.02) at 6 months (Odds Ratio = 1.01; 95% CI = 1.003–1.023; p = 0.01). Multivariate linear regression analysis showed that increased plasma PAI-1 concentrations were associated with the PAI-1 4G/4G genotype (regression coefficient = 4.82; 95% CI = 3.227 to 6.406; p<0.001).ConclusionsThe major findings of our study, to our knowledge the largest series reporting data about 4G/5G polymorphism of the PAI-1 gene, plasma PAI-1 concentrations and mortality in septic patients, were that septic patients with the 4G/4G genotype had higher plasma PAI-1 concentrations and higher risk of death than those with 4G/5G or 5G/5G genotypes.

The prevalence of 4G/5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene in central serous chorioretinopathy and its association with plasma PAI-1 levels

Context: Central serous chorioretinopathy (CSCR) is a poorly understood disease and the choroidal circulation abnormality induced by the plasminogen activator inhibitor type 1 (PAI-1) seems to be associated with the pathogenesis. There are many reports indicating that 4G/5G polymorphism of the PAI-1 gene is a risk factor for several diseases related to the elevated serum levels of PAI-1.Objective: To evaluate the 4G/5G polymorphism of the PAI-1 gene and its association with serum levels of PAI-1 in acute CSCR patients.Materials and methods: Sixty CSCR patients and 50 healthy control patients were included. The PAI-1 4G/5G was genotyped using the polymerase chain reaction–restriction technique. Serum PAI-1 level was measured using enzyme-linked immunosorbent assay. Demographic data consisting of age, sex, body mass index (BMI) as well as genotype disturbances and serum PAI-1 levels were compared between the groups. Statistical significance for differences in the serum PAI-1 levels of each group with different genotypes was also analyzed.Results: The CSCR group consisted of 40 male (66.7%) and 20 female (33.3%) patients with a mean age of 46.7 ± 8.39 years. The control group consisted of 32 male (64%) and 18 female (36%) healthy subjects with a mean age of 45.8 ± 8.39 years. There was no statistically significant difference between the groups in terms of age, sex and BMI. In the CSCR group the genotype frequencies were 4G/4G: 30% (n = 18), 4G/5G: 50% (n = 30), 5G/5G: 20% (n = 12) and in the control group genotype frequencies were 34% (n = 17), 42% (n = 21) and 24% (n = 12), respectively. There was no statistically significant difference in the distribution of genotypes among the groups (chi-squared, p = 0.70). The CSCR group had a significantly higher serum PAI-1 concentration than the control group (p = 0.001). In both groups the mean plasma PAI-1 concentration did not vary significantly among the different genotypes (p > 0.05).Discussion and conclusion: Although our results demonstrated that the patients with acute CSCR have higher serum PAI-1 concentrations than the controls, no significant difference was found in the genotype disturbances of the PAI-1 gene between the groups. The current study indicates that 4G/5G polymorphism in the promoter of the PAI-1 gene cannot be considered a risk factor for the elevated serum PAI-1 levels and consequent development of CSCR.

Validation of an immunoassay to measure plasminogen-activator inhibitor-1 concentrations in human saliva.

Introduction:We have previously shown that the concentrations of D-dimer are significantly elevated in saliva compared with plasma. Saliva offers several advantages compared with blood analysis. We hypothesised that human saliva contains plasminogen activator inhibitor-1 (PAI-1) and that the concentrations are not affected by the time of saliva collection. The aim was to adopt and validate an immunoassay to quantify PAI-1 concentrations in saliva and to determine whether saliva collection time has an influence in the measurement.Materials and methods:Two saliva samples (morning and afternoon) from the same day were collected from healthy subjects (N = 40) who have had no underlying heart conditions. A customized AlphaLISA® immunoassay (PerkinElmer®, MA, USA) was adopted and used to quantify PAI-1 concentrations. We validated the analytical performance of the customized immunoassay by calculating recovery of known amount of analyte spiked in saliva.Results:The recovery (95.03%), intra- (8.59%) and inter-assay (7.52%) variations were within the acceptable ranges. The median salivary PAI-1 concentrations were 394 pg/mL (interquartile ranges (IQR) 243.4–833.1 pg/mL) in the morning and 376 (129.1–615.4) pg/mL in the afternoon and the plasma concentration was 59,000 (24,000–110,000) pg/mL. Salivary PAI-1 did not correlate with plasma (P = 0.812).Conclusions:The adopted immunoassay produced acceptable assay sensitivity and specificity. The data demonstrated that saliva contains PAI-1 and that its concentration is not affected by the time of saliva collection. There is no correlation between salivary and plasma PAI-1 concentrations. Further studies are required to demonstrate the utility of salivary PAI-1 in CVD risk factor studies.