Higher Plasma Plasminogen Activator Inhibitor-1 Levels Research Articles

Plasminogen Activator Inhibitor-1 as a Marker of Thrombosis among Prehypertensive Patients: A Cross-sectional Study

Introduction: Impaired endogenous fibrinolysis has been shown to play a role in the pathogenesis and complications of hypertension. Plasminogen Activator Inhibitor-1 (PAI-1) is said to be a predictor of impaired fibrinolysis and thrombosis. Prehypertension is a common worldwide condition and is known to be an independent risk factor for Cardiovascular Disease (CVD). Aim: Present study aimed to measure plasma PAI-1 levels in prehypertensive patients and normal subjects and to find the correlation between elevated PAI-1 levels with Blood Pressure (BP), triglycerides, total cholesterol, Low-Density Lipoproteins (LDL) cholesterol, High-Density Lipoproteins (HDL) cholesterol, and urine albumin. Materials and Methods: This cross-sectional analytical study included 100 patients, comprising 50 prehypertensive individuals and 50 controls, aged between 35 and 50 years. The study was conducted at Sapthagiri Institute of Medical Sciences and Research Centre in Bangalore, India. Anthropometric measurements, PAI-1 levels, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and urine albumin were measured using standard procedures. The data were statistically analysed using the Statistical Package for Social Sciences (SPSS) version 10.0, applying Student t-test and Chisquare test. Correlation analysis was performed to assess the relationship between PAI-1 and various parameters. Results: A total of 100 patients were included in the study which had 64 men and 36 women with a mean age of 46±7 years. PAI-1 levels were significantly higher in the prehypertensive group compared to the control group (p-value=0.013). Participants with higher plasma PAI-1 levels had significantly elevated BP (p-value=0.001) compared to those with lower PAI-1 levels. Total cholesterol, triglycerides, and LDL cholesterol were significantly increased in prehypertensive individuals (p-value=0.001), whereas HDL cholesterol was significantly lower (p-value=0.001). The study also observed a significant increase in urine albumin in the prehypertensive group with elevated PAI-1 levels compared to the controls (p-value=0.001). The study revealed that elevated plasma PAI-1 levels did not show a significant positive correlation with SBP and DBP (r=0.138 and 0.660, p-value of 0.338 and 0.648, respectively). Plasma PAI-1 levels were weakly correlated with total cholesterol (r=0.145, p-value 0.315), LDL cholesterol (r=-0.068, p-value 0.640), HDL cholesterol (r=0.21, p-value 0.882), and triglycerides (r=0.207, p-value 0.150). There was no significant correlation between increased PAI-1 levels and urine albumin (r=-0.225, p-value of 0.117). Conclusion: Present study demonstrated that plasma PAI-1, total cholesterol, triglycerides, LDL cholesterol, and urine albumin were significantly elevated in prehypertensive individuals, suggesting vascular damage and inflammation. As prehypertension is often asymptomatic, patients with prehypertension should be considered to have an increased risk for CVD.

The Role of PAI-1 4G/5G Promoter Polymorphism and Its Levels in the Development of Ischemic Stroke in Young Indian Population

The plasminogen activator inhibitor-1 (PAI-1) gene has been found to be associated with the pathogenesis and progression of vascular diseases including stroke. A 4G/5G, PAI-1 gene polymorphism has been found to be associated with the plasma PAI-1 levels in different ethnic populations but results are still controversial. The aim of this study was to determine the potential association of 4G/5G polymorphism and plasma PAI-1 levels in the development of ischemic stroke (IS) in young Asian Indians. One hundred patients with IS and an equal number of age- and sex-matched controls were studied. The 4G/5G polymorphism was genotyped in the study population through allele-specific polymerase chain reaction. Plasma PAI-1 levels were evaluated using a commercial kit. The PAI-1 levels were significantly higher in patients when compared to the controls ( P = .03). The variant 4G allele for the PAI-I 4G/5G polymorphism showed both genotypic ( P = .0013, χ2 = 10.303; odds ratio [OR] = 3.75) as well as allelic association ( P = .0004, χ2 = 12.273; OR = 1.99) with IS. The homozygous variant 4G/4G also was found to be associated with the higher PAI-1 levels (0.005). The variant allele 4G of PAI-1 4G/5G polymorphism and higher plasma PAI-1 levels were found to be significantly associated with IS in young Asian Indians.

Abstract MP017: Association of Change in Plasminogen Activator Inhibitor-1 Through Young Adulthood With Metabolic Disease in Middle Age: the Coronary Artery Risk Development in Young Adults (CARDIA) Study

Introduction: Circulating plasminogen activator inhibitor-1 (PAI-1) levels are elevated in obesity and diabetes mellitus (DM) in cross-sectional studies. Preclinical studies support a role for PAI-1 in obesity development and insulin signaling. To date, no studies have investigated the prospective association of PAI-1 in young adults with incident obesity and DM. Hypothesis: Higher PAI-1 concentrations and greater increases in PAI-1 during young adulthood are associated with higher incidence of obesity and diabetes. Methods: We performed an ancillary study in CARDIA measuring PAI-1 in plasma at exam year (Y) 7 and Y20 in a subset of 1200 participants (ppts) free of obesity and DM at Y7. Multivariable logistic regression was used to examine the association between PAI-1 at Y7 and change from Y7 to Y20 with incident obesity and diabetes by Y30. Covariates for adjustment included demographics (age, race, sex, center, education), lifestyle risk factors (physical activity, energy intake, smoking), metabolic traits (BMI, fasting glucose [for DM]), and Y7 PAI-1 level. Results: At Y7, ppts (32±4 years, 54% female, 37% black) had mean BMI 24.5±3 kg/m 2 , fasting glucose 89±8 mg/dL, and median PAI-1 14 (IQR: 8-24) ng/mL. Median change in PAI-1 from Y7 to Y20 was +10.0 ng/mL (IQR: +1.0-28.0 ng/dL). Each 1 standard deviation higher ln(PAI-1) at Y7 was associated with an adjusted hazards ratio for incident DM of 1.35 (95% CI: 1.09-1.67). Each 1 standard deviation greater increase in PAI-1 from Y7 to Y20 was associated with an adjusted odds ratio (OR) for incident obesity and DM of 1.21 (1.02-1.43) and 1.36 (1.10-1.68), respectively. When examined by quartiles, the highest (vs. lowest) quartile of Y7 to Y20 PAI-1 change was associated with an adjusted OR of 2.37 (1.33-4.21) for incident obesity and 3.11 (1.45-6.68) for incident DM by Y30, independent of Y7 BMI and PAI-1 (FIGURE) . Conclusions: Higher plasma PAI-1 levels and greater increases in PAI-1 during young adulthood are positively associated with incident obesity and DM by middle age.

Abstract 52: Early Elevation of Plasma Plasminogen Activator Inhibitor-1 is Associated with Vasospasm following Subarachnoid Hemorrhage

Background: While the mechanism of early brain injury following subarachnoid hemorrhage (SAH) remains unclear, animal studies suggest that SAH is associated with significant changes in the fibrinolytic cascade. Human data shows that SAH-related brain ischemia is associated with the polymorphism in plasminogen activator inhibitor 1 (PAI-1) promotor linked to higher plasma PAI-1 levels. However, human plasma PAI-1 has not been previously studied in SAH. We hypothesize that elevated plasma PAI-1 is associated with VSP and poor outcome in SAH. Methods: In a prospective cohort of 61 SAH subjects, we compared plasma PAI-1 levels by ELISA (R&D Systems) on post-SAH days 1, 5, 7 and 14 with respect to angiographic VSP and to functional outcome at 3- and 6-months. Angiographic VSP was defined as >50% reduction in vessel caliber on post-SAH day 6-8 angiography. Poor functional outcome was defined as a modified Rankin score >2. Biomarker levels were compared using Wilcoxon rank sum test. Bonferroni correction was applied for multiple comparisons. Results: Subjects with (n=25) and without VSP (n=36) were comparable in gender, Fisher and Hunt and Hess (HH) grade distribution, aneurysm treatment modality, and incidence of hydrocephalus. Subjects with VSP had lower mean age (50 vs. 56). Elevated plasma PAI-1 on post-SAH day 1 was strongly association with VSP (3.28 vs. 1.82 ng/mL; p=.0058) and showed a trend towards association with VSP on post-SAH day 5 (2.65 vs 1.83 ng/mL, p=0.05). Plasma PAI-1 levels were not associated with functional outcome at 3 or 6 months. Elevated plasma PAI-1 on post-SAH day 1 remained significantly associated with VSP (p=0.0155) after adjustment for age and HH and Fisher grades by logistic regression. Conclusion: Early elevation of plasma PAI-1 on post-SAH day 1 is strongly and independently associated with angiographic VSP in this small prospective SAH cohort and may be a candidate biomarker for VSP. Future mechanistic studies with simultaneous measurements of tissue plasminogen activator (tPA) and tPA-PAI complex and larger clinical studies are necessary to understand the utility of PAI-1 as potential biomarker in SAH.

Different patterns of fibrinolytic abnormalities and lipid profile in hypothyroid and hyperthyroid patients

Altered fibrinolytic parameters and serum lipid profile are strongly related to thyroid dysfunction. To investigate the patterns of the fibrinolytic abnormalities and serum lipid profile in the hypo- and hyperthyroid patients. We also took an aim at studying the relationships between free T4 levels (FT4) and these parameters. Hyperthyroid (n = 30), hypothyroid (n = 20) patients and euthyroid control subjects (n = 30) were evaluated for several fibrinolytic parameters including plasma plasminogen activator inhibitor-1 (PAI-1) and D-dimer (D-D). Serum lipid profile and lipoprotein(a) (Lp(a)) were also measured. We found different patterns of fibrinolytic abnormalities and lipid profile in hypo- and hyperthyroid patients. The hypothyroid patients had low plasma PAI-1 levels and high D-D values as compared to hyperthyroid patients (p < 0.001) and euthyroid control subjects (p < 0.05 and 0.001, respectively). In sharp contrast, the hyperthyroid patients had high plasma PAI-1 levels (p < 0.001) but without concomitant change in plasma D-D values, as compared to the euthyroid control subjects. Hypothyroidism was associated with high total cholesterol, triglycerides, LDL-C and Lp(a) levels and low HDL-C levels as compared to both hyperthyroid and euthyroid states (p < 0.001). FT4 levels were correlated positively with HDL-C but negatively with total cholesterol, triglycerides, LDL-C and Lp(a) levels in both hypo- and hyperthyroid patients. Also FT4 levels were correlated positively with PAI-1 but negatively with D-D in both hypo- and hyperthyroid patients (p < 0.02, 0.01, 0.001 and 0.03 respectively). We found hyperfibrinolytic, and hypofibrinolytic patterns in hypothyroid, hyperthyroid patients, respectively. The hypothyroid patients had atherogenic lipid profile. These variations indicate possible pathophysiologic roles for thyroid hormones in the regulation of the fibrinolytic system and lipid profile. Mechanisms of these variations are open for future investigations.

Plasminogen activator inhibitor-1 removal using dextran sulphate columns. Evidence of PAI-1 homeostasis

Patients with high plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels are prone to develop thrombosis. Lowering PAI-1 levels may offer a therapeutic option and help to better understand PAI-1 metabolism. We examined the effect on plasma PAI-1 levels of LDL-apheresis using dextran sulphate (DS) columns in 12 patients (9 male, 3 female, 49 +/- 10 years) with heterozygous familial hypercholesterolaemia and coronary artery disease. One plasma volume equivalent (2.3-4.0 l) was treated during each procedure (at flow rates of 23 +/- 2 ml/min). Lipids and PAI-1 antigen levels were measured in plasma before and immediately after 19 aphereses (once in 7 patients, twice in 3 patients and three times in 2 patients) and also at 3 and 7 days post apheresis in five of these patients and in the column eluates from 8 of these patients. DS-apheresis reduced plasma cholesterol (50 +/- 8%), triglyceride (45 +/- 27%), apolipoprotein B (59 +/- 10%) and PAI-1 antigen levels from 10.2 +/- 5.2 to 6.0 +/- 3.1 ng/ml (P = 0.005). The PAI-I changes were independent of circadian variation. PAI-I bound to the DS-columns (3.51 +/- 1.03 ng/ml filtered plasma) and the percent of filtered PAI-1 that was bound correlated inversely (r = -0.81, P < 0.02) with basal PAI-1 levels indicating a high affinity saturable binding process. In four patients, plasma PAI-1 levels post-apheresis were higher than expected based on the amount of PAI-removed by the DS columns. The difference between the expected and actual PAI-1 level post apheresis, reflecting PAI-1 secretion or extracellular redistribution, correlated inversely with basal PAI-1 levels (r = -0.83, P = 0.01). PAI-1 levels returned to baseline pre-apheresis values 7 days post apheresis. PAI-1 antigen may be removed from plasma without adverse effect, resulting temporarily in its extracellular redistribution and restoration to baseline levels over one week. PAI-1 redistribution particularly when baseline pre-apheresis values were low may reflect a homeostatic mechanism to maintain sufficient PAI-1 levels. Procedures that could selectively remove PAI-1 from plasma may offer a treatment option for those with very high plasma PAI-1 levels and thrombosis.

The Relationship of Plasminogen Activator Inhibitor-1 Levels to the ST Deviation Pattern of Acute Myocardial Infarction

Objectives: Myocardial infarction (MI) may be classified as ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI). Procoagulants such as plasminogen activator inhibitor-1 (PAI-1) as well as markers of inflammation such as C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) are elevated in acute coronary syndromes. However, no study has examined whether levels of these markers differ in patients with STEMI as opposed to NSTEMI. We sought to determine whether there are differences in plasma levels of PAI-1, CRP, SAA or IL-6 in patients with STEMI compared to patients with NSTEMI. Methods: Seventy-six consecutive patients presenting with acute MI (37 with STEMI and 39 with NSTEMI) were prospectively enrolled. Blood samples were obtained from patients within 6 h from presentation and plasma PAI-1, CRP, IL-6 and SAA concentrations were measured. Results: Plasma levels of PAI-1 were significantly higher in patients with STEMI compared to NSTEMI: 85.7 ± 5 vs. 61.3 ± 5 ng/ml (p < 0.001), while CRP, SAA and IL-6 levels were not significantly different between STEMI and NSTEMI patients. Conclusions: Higher plasma PAI-1 levels in STEMI patients may contribute to the predilection of these patients to occlusive thrombi and STEMI.

Plasma Adiponectin, T94G Gene Polymorphism and PAI-1 in Patients with and without Hypertension

Background: Reduced adiponectin level has been associated with metabolic syndrome, type 2 diabetes, coronary artery disease and gene polymorphisms, but the interrelationships of T94G genotype, plasma adiponectin and plasminogen activator inhibitor-1 (PAI-1) are less understood. Patients and Methods: The T94G genotypes and plasma levels of adiponectin, and PAI-1 were determined in 568 Chinese patients, 212 with and 356 without hypertension, to study the possible associations of T94G genotype, plasma adiponectin, PAI-1 and blood pressure. Results: Hypertensive patients showed significantly lower plasma adiponectin (9.7 ± 11.1 vs. 11.5 ± 10.0 µg/ml, p = 0.04) and higher PAI-1 (p < 0.001) levels but not significantly greater adiponectin TT genotype percentage (38.7 vs. 33.5%) and T allele frequency (0.620 vs. 0.585) than normotensive subjects. Plasma adiponectin was inversely related to PAI-1 activity (r = –0.09, p = 0.03) and antigen (r = –0.202, p < 0.001). Furthermore, the TT genotypic group showed significantly lower plasma adiponectin level (10.4 ± 10.5 vs. 13.4 ± 10.8 µg/ml, p = 0.03) and higher plasma PAI-1 activity (17.0 ± 9.7 vs. 13.5 ± 7.6 IU/ml, p = 0.003) and antigen (32.3 ± 22.7 vs. 25.9 ± 14.7 ng/ml, p = 0.01) than the GG genotypic group. Multiple linear regression analysis in all study subjects, in men and in normotensives documented an impact of adiponectin T94G genotype on plasma levels of adiponectin (p = 0.007, 0.003 and 0.03) and PAI-1 activity (p = 0.02, 0.03 and 0.04) and antigen (p = 0.03, 0.007 and 0.04) after adjustment for potential confounding factors. Conclusions: The present study demonstrated a significant correlation of the TT genotype with lower plasma adiponectin and higher plasma PAI-1 levels in a Chinese population. The contribution of this genotype seemed greater in men and normotensives. It suggested the adiponectin gene T94G polymorphism might affect the regulation of circulating adiponectin and PAI-1.

Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance.

High plasminogen activator inhibitor 1 (PAI-1) levels are associated with an increased cardiovascular risk of atherothrombosis. Furthermore, increased plasma PAI-1 levels are associated with dyslipidemia, hyperinsulinemia and hypertension. This association between PAI-1 and metabolic components of the Metabolic Syndrome could explain the predisposition of insulin resistant patients to atherothrombosis. Recent studies have suggested that visceral adipose tissue might be the link between elevated plasma PAI-1 and insulin resistance in the Metabolic Syndrome. Indeed, visceral adipose tissue was proposed as a potentially important source of PAI-1 in humans. However, in light of recent studies, visceral adipose tissue appears to be involved in the increase of plasma PAI-1 via the metabolic disorders usually associated with central obesity, rather than directly. High plasma PAI-1 levels are undoubtedly related to insulin resistance, and the mechanisms which could explain such an increase in the Metabolic Syndrome appear to be multi-factorial and remain to be elucidated. These mechanisms may involve several metabolic disorders such as hyperinsulinemia, dyslipidemia, impaired glucose tolerance and hypertension, which would favor PAI-1 synthesis and release from different cell types.

Plasma plasminogen activator inhibitor 1, insulin resistance and android obesity

Plasma plasminogen activator inhibitor 1 (PAI-1) levels are elevated in insulin-resistant subjects and are associated with increased cardiovascular risk of atherothrombosis. Strong association between PAI-1 and the metabolic components of the insulin resistance syndrome is found in clinical studies, suggesting that insulin resistance may regulate circulating PAI-1. However, the mechanisms underlying increased PAI-1 levels in such conditions are still poorly understood. Several studies have been carried out specifically in patients with central or android obesity, a major characteristic of the insulin resistance syndrome, and have suggested that visceral adipose tissue may be the major component of the relationship between android obesity and PAI-1. Accordingly, adipose tissue PAI-1 production was found to be elevated in obese human subjects, particularly in visceral adipose tissue. The genetic background for having high PAI-1 levels in several populations have been looked for and its role appeared to be weaker than that of the metabolic condition. High plasma PAI-1 levels are then clearly related to android obesity and insulin resistance, but the mechanisms whereby PAI-1 increases in plasma in these diseases remain to be determined.

Evidence for a relationship between plasminogen activator inhibitor-1 and gamma glutamyl transferase

Plasma plasminogen activator inhibitor-1 (PAI-1) levels are elevated in insulin-resistant obese subjects (1). However, the mechanisms responsible for such elevation are unknown. It has been shown that insulin increases PAI-1 synthesis by the human hepatoma cell line Hep G2 (2) and by freshly isolated human hepatocytes (3). Moreover, a recent study showed that PAI-1 synthesis in presence of insulin was markedly increased in Hep G2 cells down-regulated for insulin receptor (4); these results agree with those found in vivo in insulin-resistant subjects. On the other hand, it has recently been proposed that mild liver abnormalities and steatosis may be among the factors accounting for high plasma PAI-1 levels in hyperlipidemic subjects (5,6). Steatosis and hepatic abnormalities are also a common feature of obese subjects (7,8). Thus the purpose of this investigation was to determine whether plasma PAI-1 levels were correlated with hepatic enzymes in non-hypertriglyceridemic subjects with a wide range of body mass index (BMI) and levels of insulin resistance.

Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity.

Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tissue-type plasminogen activator, has been shown to be an independent risk factor for recurrent myocardial infarction (MI) at a young age. To investigate whether genetic variation in the PAI-1 gene is affecting plasma PAI-1 levels, a sample of 145 patients with an MI before the age of 45 years was genotyped for two polymorphisms at the PAI-1 locus, together with a sample of 95 healthy individuals of a similar age. All individuals were measured for plasma PAI-1 levels as well as for other fibrinolytic and metabolic risk indicators. A HindIII restriction fragment length polymorphism (RFLP) was used in this study in conjunction with a previously unreported eight-allele dinucleotide repeat polymorphism at the PAI-1 locus. The dinucleotide repeat polymorphism and HindIII RFLP were in strong linkage disequilibrium. There was no difference in the frequency of alleles of either polymorphism between patient and control groups. However, the smaller dinucleotide repeat alleles were significantly associated (p = 0.03) with higher plasma PAI-1 levels in the patient sample. This association was also apparent in the control sample but not at significant levels. Differences in regression coefficients for the effect of triglycerides on plasma PAI-1 levels suggest that triglyceride regulation of PAI-1 is genotype specific. Our data suggest that genetic variation at this locus contributes to between-individual differences in the level of plasma PAI-1, which is important in fibrinolysis and the pathogenesis of MI.