Plasminogen Activator Inhibitor-1 Antigen Concentrations Research Articles

Effects of ultra-low-dose versus standard hormone therapy on fibrinolysis and thrombin generation in postmenopausal women

ObjectiveTo assess the effects of different doses of oral hormone therapy (HT) on thrombin generation and fibrinolysis. Study designOne hundred fifty postmenopausal women were assigned in a randomized controlled study in which the effect of standard dose (1mg 17β-estradiol/5mg dydrogesterone), ultra-low-dose HT (0.5mg 17β-estradiol/2.5mg dydrogesterone) on fibrinolysis and coagulation was compared to controls. Factors measured included plasma clot lysis time (CLT), fibrinolysis activators and inhibitors, thrombin generation (prothrombin fragments 1+2 [F1+2], endogenous thrombin potential [ETP]), normalized activated protein C sensitivity ratio (nAPCsr), and factor (F)VIII activity and were determined before and after 24 weeks of HT. ResultsIn ultra-low-dose group posttreatment CLT tended to be shorter when compared to standard HT (−7%) and control group (−4%) with reduced plasminogen activator inhibitor-1 (PAI-1) antigen (by −16% vs both groups). Higher mean changes from baseline between ultra-low-HT group and standard group in CLT (−7.4 vs 3.05) and PAI-1 antigen concentration (−5.1 vs 0.9) were observed. Standard HT, compared with the ultra-low-dose HT, led to higher F1+2 (+9%) and FVIII activity (+37%). ConclusionsIn contrast to the standard HT, ultra-low-dose HT may enhance fibrinolysis through reduced PAI-1 levels.

The Occurrence of Thrombosis in Inflammatory Bowel Disease Is Reflected in the Clot Lysis Profile.

The occurrence of thromboembolic events (TE) is an important extraintestinal manifestation in patients with inflammatory bowel disease (IBD). The aim of this study was to compare fibrinolysis and clot lysis parameters between (1) patients with IBD and healthy controls and (2) patients with IBD with TE (IBD + TE) and without TE (IBD - TE). One hundred thirteen healthy controls and 202 patients with IBD, of which 84 patients with IBD + TE and 118 patients with IBD - TE, were included in this case-control study. Three clot lysis parameters (area under the curve, 50% clot lysis time, and amplitude) were determined using a clot lysis assay. Plasminogen activator inhibitor 1 (PAI-1) and thrombin activatable fibrinolysis inhibitor concentrations were determined by enzyme-linked immunosorbent assay. PAI-1 antigen, active PAI-1, and intact thrombin activatable fibrinolysis inhibitor concentrations, as well as 50% clot lysis time and area under the curve, were significantly associated with the presence of IBD (all P < 0.05). The median time between TE and plasma collection was 5.0 (1.8-11.0) years. Comparing IBD + TE versus IBD - TE, active to total PAI-1 ratio (0.36 [0.24-0.61] versus 0.24 [0.13-0.40]), area under the curve (31 [24-49] versus 22 [13-31]), 50% clot lysis time (110 [64-132] versus 95 [70-126] minutes), and amplitude (0.295 [0.222-0.436] versus 0.241 [0.168-0.308]) were significantly higher in IBD + TE (all P <0.05) and remained higher after adjustment for age, gender, C-reactive protein, type of disease, presence of comorbidities, and disease activity. Patients with IBD have an altered clot lysis profile compared with healthy controls. Clot lysis parameters differ significantly between patients with IBD with and without a history of TE and should be included in the risk assessment.

The moderating effect of personal mastery and the relations between stress and Plasminogen Activator Inhibitor-1 (PAI-1) antigen.

This study tested whether feelings of personal control over one's life circumstances (i.e., personal mastery) would attenuate the relations between stress (i.e., negative life events and caregiving distress) and Plasminogen Activator Inhibitor (PAI)-1 antigen, an inhibitor of fibrinolysis implicated in the development of cardiovascular disease. Seventy-one spousal dementia caregivers were assessed for plasma levels of PAI-1 antigen, negative life events, caregiver distress, and feelings of personal mastery. Regression analysis was used to determine if personal mastery moderated the relations between stress (i.e., life stress and caregiving distress) and PAI-1 antigen levels. Plasminogen activator inhibitor (PAI)-1 antigen in plasma. After controlling for other factors associated with PAI-1 antigen levels, negative life events were positively associated with plasma PAI-1 antigen concentrations in participants low in personal mastery (beta = .31; p = .050) but not in individuals high in personal mastery (beta = .22; p = .184). The moderating effect of mastery on the relations between caregiving distress and PAI-1 antigen did not reach statistical significance (p = .091). These data suggest that mastery may protect individuals from some of the alterations in hemostatic factors that have been linked to cardiovascular risk.

Epicardial fat thickness: Relationship with plasma visfatin and plasminogen activator inhibitor-1 levels in visceral obesity

Background and aim Epicardial fat (EF), a true visceral adipose tissue (VAT) deposited around the heart, is considered as possible cardiovascular risk indicator, in view of its ability to produce and release several inflammatory adipo-cytokines. It is still not known whether increased cardiac adiposity is related to increased inflammatory adipo-cytokines in obesity. The aim of this study was to evaluate whether echocardiographic EF thickness, an indicator of cardiac adiposity, is related to circulating levels of inflammatory adipo-cytokines such as visfatin and plasminogen activator inhibitor-1 (PAI-1) in visceral obesity. Methods and results EF thickness (measured by echocardiography), visfatin, PAI-1 antigen and some inflammatory markers were studied in 42 women, 27 of them severely obese (OB) (BMI 43.5 ± 4.8 kg/m 2) but with no apparent complications, and 15 normal-weight controls. Abdominal VAT in the OB was assessed by computed tomography. OB had thicker EF and higher visfatin and PAI-1 antigen concentrations than controls ( P < 0.0001). EF thickness, log-visfatin and log-PAI-1 antigen concentrations directly correlated with VAT ( P < 0.0001). Log-visfatin and log-PAI-1 antigen were correlated with EF thickness even after adjusting for indices of fat distribution ( P < 0.01 and P < 0.001 respectively). Moreover, when dividing OB on the basis of median EF thickness, women with greater EF thickness had more VAT and higher adipo-cytokine concentrations and inflammatory markers. Conclusions This study suggests that EF thickness, an indicator of cardiac adiposity, may be significantly related to inflammatory adipo-cytokines in visceral-obese patients. This suggests EF might be used as an easy and reliable marker of visceral adiposity and inflammation and as a cardiovascular risk indicator.

Weight reduction, but not a moderate intake of fish oil, lowers concentrations of inflammatory markers and PAI‐1 antigen in obese men during the fasting and postprandial state

In obese subjects, chronic low-grade inflammation contributes to an increased risk of metabolic abnormalities, which are reversed by weight loss. Sustained weight loss, however, is difficult to achieve and more insight into dietary approaches on anti-inflammatory responses in obese subjects is needed. In this respect, fish oil deserves attention. Eleven obese men (BMI: 30-35 kg m(-2)) received daily fish oil (1.35 g n-3 fatty acids) or placebo capsules in random order for 6 weeks. Eight subjects continued with a weight reduction study that lasted 8 weeks. Mean weight loss was 9.4 kg. At the end of each experimental period a postprandial study was performed. Relative to fasting concentrations, interleukin-6 (IL-6) levels increased by 75% 2 h and by 118% 4 h after the meal (P < 0.001), when subjects consumed the control capsules. In contrast, C-reactive protein (C-RP) concentrations decreased slightly by 0.7% and 6.6% (P = 0.046), and those of plasminogen activator inhibitor-1 (PAI-1) antigen by, respectively, 26% and 53% (P < 0.001). Tumour necrosis factor-alpha (TNF-alpha; P = 0.330) and soluble TNF-receptor concentrations (sTNF-R55 and sTNF-R75; P = 0.451 and P = 0.108, respectively) did not change. Changes relative to fasting concentrations were not significantly affected by either fish oil or weight reduction. Absolute IL-6, C-RP, sTNF-R55, sTNF-R75, and PAI-1 antigen concentrations, however, were consistently lower after weight reduction, but not after fish oil consumption. For slightly obese subjects a moderate intake of fish oil does not have the same favourable effects on markers for a low-grade inflammatory state as weight reduction.

4G/5G PAI-1 promoter polymorphism and acute-phase levels of PAI-1 following coronary bypass surgery: a prospective study.

The 4G/5G plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism has been associated with basal PAI-1 levels, with ischemic heart disease, and with adverse prognosis in critically ill patients. We hypothesized it might also influence the acute-phase levels of PAI-1 following coronary bypass surgery. In 111 consecutive patients undergoing elective coronary bypass surgery, 4G/5G genotyping and serial plasma PAI-1 activity and antigen levels were prospectively measured before surgery, daily up to 72 h, and at discharge. The inflammatory reaction was additionally assessed by white cell count, fibrinogen, interleukin-6, and C-reactive protein levels. PAI-1 activity and antigen concentrations increased approximately two-fold after surgery, peaking at 48 hours. Carriers of the 4G-allele, compared with 5G/5G homozygotes, showed approximately 20% higher PAI-1 activity and antigen both preoperatively ( P = 0.007 and P = 0.035) and after surgery. White cell count, fibrinogen, interleukin-6, and C-reactive protein values did not differ significantly according to genotypic groups. In multivariate analysis, the 4G/5G genotype was the only significant modulator of postoperative PAI-1 activity (P = 0.003) and the main significant modulator of postoperative PAI-1 antigen (P = 0.013). No significant interaction was found between the effects of time and genotype on postoperative PAI-1. This indicates that the association between 4G/5G and acute-phase PAI-1 levels is secondary to the genotype-related difference of baseline PAI-1. Postoperative PAI-1 concentrations of patients undergoing elective coronary bypass surgery are higher in carriers of the 4G-allele than in 5G/5G homozygotes as a result of higher baseline values. Knowledge of 4G/5G status may be useful to predict acute-phase PAI-1 concentrations.

The plasminogen activator inhibitor-1 −675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH Study

Although the potential role of plasminogen activator inhibitor-1 (PAI-1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial. To investigate whether plasma PAI-1 concentrations and the -675 4G/5G polymorphism located in the PAI-1 gene could constitute risk markers for myocardial infarction (MI). We used a European case-control study, the HIFMECH study, comparing 598 men with MI and 653 age-matched controls. Insulin resistance explained a major part of the variation in PAI-1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI-1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase=1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR=1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR=1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI-1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P=0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P=0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI-1 antigen concentrations (P=0.01 and 0.02 after adjustment for PAI-1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C-reactive protein (P=0.01). This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.

Remnant Lipoproteins Induce Endothelial Plasminogen Activator Inhibitor-1

Remnant lipoproteins (RLPs) accumulate in type III hyperlipoproteinemia, a condition associated with significant cardiovascular morbidity. The effect of RLPs on fibrinolysis is unknown. Our aim was to study the effect of RLPs on endothelial expression of plasminogen activator inhibitor-1 (PAI-1). After 24-h culture of human aortic endothelial cells with RLPs at concentrations of 0 (control), 0.038, or 0.076 mg triglyceride/mL, postculture PAI-1 antigen concentrations were: 870 ± 80, 1963 ± 183 (P = 0.005), and 3551 ± 177 ng/mL (P < 0.001), respectively. Furthermore, after 24-h incubation of endothelial cells with RLPs (0 or 0.076 mg triglyceride/mL), PAI-1 activity increased from 0.667 ± 0.144 to 1.268 ± 0.198 U/mL, respectively (P = 0.008) and endothelial PAI-1 mRNA increased to 2.7 ± 0.66 that of control (P = 0.048). In conclusion, RLPs from patients with type III hyperlipoproteinemia induce endothelial cell PAI-1 expression, which may contribute to a prothrombotic state.

Lack of association between the angiotensin-converting enzyme insertion/deletion polymorphism and plasminogen activator inhibitor-1 antigen levels in the National Heart, Lung, and Blood Institute Family Heart Study.

Experimental and clinical research supports a direct link between activation of the renin-angiotensin system and production of plasminogen activator inhibitor-1 (PAI-1), the primary physiologic inhibitor of tissue plasminogen activator. Several studies have reported higher PAI-1 levels in individuals carrying the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene. We investigated the association between ACE genotypes and plasma PAI-1 levels in a family study of 577 women and 428 men from four US communities. Participants were between 25 and 84 years of age without evidence of coronary heart disease (CHD). Mean geometric plasma PAI-1 levels adjusted for ethnicity were 17.4, 17.9, and 18.1 ng/ml in participants with the DD, insertion-deletion (ID), and II genotypes, respectively (P = 0.89 for difference). We found no associations between ACE I/D genotypes and plasma PAI-1 antigen concentrations in a subset of participants without major CHD risk factors (hypertension, hypercholesterolemia, overweight, smoking, diabetes) or in a small sample of African-Americans. Our findings suggest that the ACE insertion/deletion polymorphism has relatively little, if any, influence on circulating PAI-1 levels in the population at large.

Effect of Activation and Inhibition of the Renin-Angiotensin System on Plasma PAI-1

Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 AM through 2 PM) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P=0.048). PAI-1 antigen correlated with aldosterone (r=0.56, P<10(-7)) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6. 7, P=0.04) and morning (F=24, P=0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P=0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.7+/-4.6 versus 16. 1+/-3.3 and 16.3+/-3.7 ng/mL, respectively; P<0.05). This study provides evidence of a direct functional link between the RAS and fibrinolytic system in humans. The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1.

Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI family heart study.

Elevated plasminogen activator inhibitor-1 (PAI-1) and fibrinogen concentrations are risk factors for coronary heart disease. We investigated environmental, familial, and genetic influences on PAI-1 antigen and fibrinogen concentrations in 2029 adults from 512 randomly ascertained families in 4 US communities. We used maximum-likelihood segregation analysis to fit several genetic and nongenetic modes of inheritance to the data to determine whether mendelian inheritance of a major gene could best explain the familial distributions of these 2 hemostatic factors. Age- and gender-adjusted familial correlations for PAI-1 antigen level averaged 0.16 in first-degree relatives (95% CI=0.11 to 0.21); the spouse correlation was positive but not statistically significant (r=0.10, 95% CI=-0.02 to 0.23). Complex segregation analysis indicated a major gene associated with higher PAI-1 concentrations in 65% of individuals from these families. Demographic, anthropometric, lifestyle, and metabolic characteristics together explained 37% to 47% of the variation in PAI-1 antigen levels, and the inferred major gene explained an additional 17% of the variance. Positive and statistically significant age- and gender-adjusted familial correlations in first-degree relatives indicated a possible heritable component influencing plasma fibrinogen concentration (r=0. 17, 95% CI=0.13 to 0.22); however, segregation analysis did not provide statistical evidence of a major gene controlling fibrinogen level. These family data suggest that there are modest familial and genetic effects on the concentration of PAI-1.

Circadian variation in blood thrombogenic characteristics in middle-aged healthy men given isoenergetic carbohydrate or fatty breakfasts

Summary The objectives of the study were to measure diurnal changes in three blood thrombogenic variables of middle-aged men; to determine whether a moderate change in dietary fat intake of equienergetic breakfasts influenced the changes and to determine whether, independent of time, these variables correlated with several risk factors of coronary heart disease and diabetes found in previous studies to be subject to diurnal change. There were two studies, in each of which two dietary treatments were allocated at random to volunteers paired according to risk factors of cardiovascular disease. The studies took place at Pathology Department, Papworth Hospital, Cambridge, UK. Thirty-six healthy males, 35–65 years of age, were selected for normal characteristics of middle-age. Diets were imposed for 17 days in Experiment 1 and 28 days in Experiment 2, with the exclusion of prescription drugs, any drug containing salicylic acid or sodium salicylate, smoking, travel and foods containing fish or their products. Platelet aggregation with two agonists, plasma plasminogen activator inhibitor-1 antigen concentration and plasma tissue-plasminogen activator activity was measured. Platelet aggregability described a diurnal trend from before breakfast. At 1 h after rising, aggregability was 10–25% higher (P There is a diurnal trend in risk of thrombogenesis, unrelated, in terms of both platelet aggregation and plasminogen activator inhibitor-1 antigen, to a moderate change in fat intake of isoenergetic meals at breakfast imposed over a period of 3–4 weeks. The diurnal trend is in accord with our evidence of a similar trend in insulin sensitivity.

PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants.

Plasminogen activator inhibitor-1 (PAI-1) plasma levels have been consistently related to a polymorphism (4G/5G) of the PAI-1 gene. The renin-angiotensin pathway plays a role in the regulation of PAI-1 plasma levels. An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been related to plasma and cellular ACE levels. In 1032 employees (446 men and 586 women; 22 to 66 years old) of a hospital in southern Italy, we investigated the association between PAI-1 4G/5G and the ACE I/D gene variants and plasma PAI-1 antigen levels. None of the individuals enrolled had clinical evidence of atherosclerosis. In univariate analysis, PAI-1 levels were significantly higher in men (P<.001), alcohol drinkers (P<.001), smokers (P=.009), and homozygotes for the PAI-1 gene deletion allele (4G/4G) (P=.012). Multivariate analysis documented the independent effect on PAI-1 plasma levels of body mass index (P<.001), triglycerides (P<.001), sex (P<.001), PAI-1 4G/5G polymorphism (P=.019), smoking habit (P=.041), and ACE I/D genotype (P=.042). Thus, in addition to the markers of insulin resistance and smoking habit, gene variants of PAI-1 and ACE account for a significant portion of the between-individual variability of circulating PAI-1 antigen concentrations in a general population without clinical evidence of atherosclerosis.

Plasma Levels of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 Are Correlated With the Presence of Transplant Coronary Artery Disease in Cardiac Transplant Recipients

Hemostatic factors are involved in the pathogenesis of native coronary artery disease. However, their role in transplant coronary artery disease is less established. To assess the role of hemostatic factors in transplant coronary artery disease we studied 52 consecutive cardiac transplant patients. The presence of transplant coronary artery disease was determined by angiography. Plasma levels of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von Willebrand Factor (vWF), and fibrin D-dimer were determined by enzyme-linked immunosorbent assays. Serum lipids were measured by enzymatic methods. Patients with transplant coronary artery disease had higher circulating t-PA (8.6 ± 0.8 vs. 5.4 ± 0.6 ng/ml, p = 0.021) and PAI-1 antigen concentrations (38.0 ± 3.4 vs 25.8 ± 2.2 ng/ml, p = 0.037). t-PA and PAI-1 antigen concentrations correlated with the severity of angiographic disease (R = 0.34; p = 0.014 for t-PA, and R = 0.45; p = 0.001 for PAI-1). Serum cholesterol levels were higher in patients with transplant coronary artery disease (221 ± 7.6 vs 191 ± 9.2 mg/dl, p = 0.039). Serum triglycerides were also higher in patients with transplant coronary artery disease by angiography (246 ± 38.3 vs 139 ± 20.8 mg/dl, p = 0.050). Multivariate analysis identified t-PA antigen (p = 0.003) and triglyceride levels (p = 0.038) as independent predictors for the presence of transplant coronary artery disease. We conclude that cardiac transplant patients with evidence of transplant coronary artery disease on coronary angiography have altered hemostatic function which is reflected by elevated levels of circulating t-PA and PAI-1 antigens. The interaction of the hemostatic system and serum lipids in the development of transplant coronary artery disease warrants further study.

Increased neutrophil elastase, persistent intravascular coagulation, and decreased fibrinolytic activity in patients with posttraumatic acute respiratory distress syndrome.

To investigate the role of plasma neutrophil elastase (elastase-alpha1-proteinase inhibitor complex), plasminogen activator inhibitor-1 (PAI-1), and disseminated intravascular coagulation (DIC) in patients with posttraumatic acute respiratory distress syndrome (ARDS) and to explore the time course of the changes of these factors after trauma, we performed a prospective case-control study. The study subjects consisted of 41 trauma patients, 5 with ARDS, 7 at risk for but not developing the syndrome, and 29 control patients without or with no risk for ARDS. Plasma neutrophil elastase, PAI-1 activity, and PAI-1 antigen concentration were measured on the day of the injury and on days 1, 3, and 5 after admission. DIC was measured on the basis of the DIC score. The results of these measurements and demographic data were compared among the three groups. Neutrophil elastase, PAI-1 activity, and PAI-1 antigen concentration for the ARDS patients continued to be markedly high until the fifth day of admission, and the values on the fifth day were significantly higher than those of the other two groups. All patients with ARDS developed DIC. A decrease in the DIC score was found for the control patients and also for the patients at risk for ARDS; however, for the patients with ARDS, the DIC score did not improve during the study period (p = 0.5809). We provide precise information on the time course of neutrophil elastase, PAI-1, and DIC in trauma patients with ARDS and those at risk of developing this syndrome. Neutrophil activation and persistent intravascular coagulation as well as impaired fibrinolysis may play a role in the pathogenesis of posttraumatic ARDS.

Massive Fibrin Formation with Consecutive Impairment of Fibrinolysis in Patients with Out-of-Hospital Cardiac Arrest

Hypoxia and ischaemia influence blood coagulation and fibrinolysis. This study has been made to determine whether human cardiopulmonary arrest causes fibrin formation and reduction of fibrinolysis. Serial levels of fibrinopeptide A (FPA), fibrinopeptide B beta 15-42 (FPB beta 15-42), D-dimer, tissue plasminogen activator antigen concentration (t-PA antigen), t-PA activity, plasminogen activator inhibitor-1 antigen concentration (PAI-1 antigen), and PAI-1 activity were determined in 63 patients with out-of-hospital cardiopulmonary arrest. In the resuscitated patients, the markedly elevated FPA (194.8 +/- 54.2 ng/ml) at the beginning of cardiopulmonary resuscitation (CPR) significantly decreased to 32.4 +/- 9.1 ng/ml at 24 h after admission (p < 0.01), however, this was still about 20 times that of the normal controls. FPB beta 15-42 and D-dimer increased from the start of CPR to 60 min (189.3 +/- 97.4 ng/ml; p < 0.01 and 7726 +/- 3556 ng/ml; p < 0.001, respectively), and then decreased at 24 h after arrival at the Emergency Department (40.4 +/- 11.1 ng/ml and 5434 +/- 1049 ng/ml, respectively). At 30 min after arrival, FPA and FPB beta 15-42 significantly differed between the resuscitated patients and the patients who died (p < 0.001 and P < 0.05, respectively). Although t-PA antigen and t-PA activity was elevated at the time of arrival, 24 h thereafter, no-t-PA activity was detected. At 24 h after admission, PAI-1 antigen and PAI-1 activity were significantly increased (472.2 +/- 145.5 ng/ml; p < 0.001 and 103.6 +/- 36.1 IU/ml; p < 0.001, respectively). In conclusion, during and after CPR in patients with out-of-hospital cardiac arrest, massive fibrin generation with consecutive impairment of fibrinolysis were observed. These fibrin-mediated events may have some role in the derangement of vital organ function after cardiac arrest.

Relationship of hepatic and peripheral insulin resistance with plasminogen activator inhibitor-1 in Pima Indians

Plasminogen activator inhibitor-1 (PAI-1) is related to insulin resistance and several components of the insulin resistance syndrome, and PAI-1 levels are elevated in subjects with non—insulin-dependent diabetes mellitus. Many Pima Indians are obese, insulin-resistant, and hyperinsulinemic, and they have high rates of diabetes but a low risk of ischemic heart disease. In contrast to whites and Asians, PAI-1 activity is similar between nondiabetic and diabetic Pima Indians. We therefore examined the association of PAI-1 with hepatic and peripheral insulin action measured using the hyperinsulinemic-euglycemic clamp. To investigate if insulin per se has any effect on PAI-1 in vivo, we also assessed the effects of endogenous (during a 75-g oral glucose load) and exogenous (during hyperinsulinemic clamp) insulin on PAI-1 antigen. Twenty-one (14 men and seven women; mean age, 26.3 ± 4.8 years) Pima Indians underwent a 75-g oral glucose tolerance test (OGTT) and a sequential hyperinsulinemic-euglycemic clamp. Peripheral insulin action was measured as absolute glucose uptake (M value) and normalized to estimated metabolic body size (EMBS). Hepatic insulin action was measured as percent suppression of basal hepatic glucose output during hyperinsulinemia. PAI-1 antigen was determined using a two-site enzyme-linked immunosorbent assay that detects only free PAI-1. PAI-1 antigen concentrations were significantly related to body mass index ([BMI] r s = .54, P = .012), waist ( r s = .52, P = .016) and thigh ( r s = .63, P = .002) circumference, and fasting plasma insulin concentration ( r s = .59, P = .004). PAI-1 antigen concentrations were not significantly associated with peripheral glucose uptake (M value) during either low-dose ( r s = −.01, P = NS) or high-dose ( r s = −.11, P = NS) insulin infusion. PAI-1 antigen was negatively correlated with basal hepatic glucose output ( r s = −.57, P = .013) and percent suppression of hepatic glucose output during hyperinsulinemia ( r s = −.69, P = .005). However, this relationship was largely due to the confounding effects of BMI, waist and thigh girth, fasting insulin, and 2-hour postload glucose concentrations, and was not significant when controlled for these variables (partial r s = −.30, P = NS). There was no significant relationship of PAI-1 antigen concentration with glucose storage or glucose oxidation. Despite a threefold increase in plasma insulin concentrations during the OGTT, there were no significant changes in PAI-1 antigen concentrations (median, 57, 61, 55, and 44 ng/mL at 0, 60, 120, and 180 minutes, respectively; P = NS by ANOVA). During the hyperinsulinemic clamp, mean plasma insulin concentrations at the end of low-dose (240 pmol/m 2/min) and high-dose (2,400 pmol/m 2/min) infusions were 1,005 and 14,230 pmol/L, respectively. However, PAI-1 antigen concentrations at the end of low-dose and high-dose insulin infusions were similar to those at baseline (median, 63, 43, and 58 ng/mL, respectively; P = NS by ANOVA). PAI-1 antigen in Pima Indians is related to several components of the insulin resistance syndrome. However, direct measurement of insulin resistance indicates that hepatic but not peripheral insulin resistance is related to PAI-1 antigen. Neither endogenous nor exogenous hyperinsulinemia for short periods had any significant effect on PAI-1 antigen concentrations. Short-term hyperinsulinemia is unlikely to be an important regulator of PAI-1 in Pima Indians. The relationship of PAI-1 antigen to hepatic insulin resistance is largely dependent on the relationship of PAI-1 to indices of obesity and fasting insulin concentrations.

Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Stroke Patients

Abnormal endogenous fibrinolytic activity may be a risk factor for stroke. Since the possible variation of tissue-type plasminogen activator (TPA) antigen and plasminogen activator inhibitor-1 (PAI-1) antigen concentrations over time after stroke has been rarely studied, it was examined in plasma from stroke patients in the acute and convalescent phases of the disease and in a control group. Plasma concentrations of TPA and PAI-1 were determined in 135 stroke patients and in 77 control subjects. All but 4 patients were examined within 7 days after stroke onset, and 32 patients and 18 control subjects were reexamined 2 to 4 years later. In the acute phase, stroke patients had significantly higher TPA (median, 10 micrograms/L) and PAI-1 (median, 14 micrograms/L) antigen concentrations, compared with control subjects (median values, 6 micrograms/L [P = .0001] and 8 micrograms/L [P < .01], respectively); TPA levels were higher in both the cerebral infarction (n = 122) and cerebral hemorrhage (n = 12) subgroups, whereas PAI-1 levels were higher in the cerebral infarction subgroup only. Stepwise logistic regression analysis (with correction for age, sex, history of hypertension, diabetes mellitus, and heart disease) showed TPA antigen level to be an independent discriminator between the cerebral infarction subgroup and control subjects (P = .0001), whereas the corresponding difference for PAI-1 antigen levels just failed to reach significance (P = .05). TPA antigen levels were correlated with concentrations of serum cholesterol (Spearman's rho = 0.15; P < .05), serum triglyceride (rho = 0.33; P = .0001), and plasma homocysteine (rho = 0.19; P < .01). PAI-1 antigen levels were correlated with serum triglyceride levels only (rho = 0.41; P = .0001). At reexamination after 2 to 4 years, neither TPA nor PAI-1 levels had changed significantly from the baseline values. In stroke patients, high TPA antigen concentrations may indicate an activation of the fibrinolytic system or may be due to a delayed clearance of TPA complexed with inhibitors. High PAI-1 antigen concentrations in patients with cerebral infarction represent increased fibrinolytic inhibition. The findings in this longitudinal study suggest that TPA and PAI-1 antigen concentrations both differ little between the acute and convalescent phases after stroke.

Plasminogen Activator Inhibitor 1 (PAI-1) in Plasma: Its Role in Thrombotic Disease

Impaired fibrinolytic function, mainly due to an elevation of the plasma PAI-1 concentration, is a common finding in patients with thrombotic disease. Unfortunately, regarding patients with idiopathic deep vein thrombosis (DVT), no reliable prospective or genetic studies have been published. Concerning postoperative DVT, preoperatively increased PAI-1 level seems to predict a postoperative DVT in patients subjected to hip surgery. Several longitudinal cohort studies of patients with manifest coronary heart disease (CHD) have linked elevated plasma PAI-1 or tPA antigen concentrations to future cardiovascular events, particularly myocardial infarction. Before PAI-1 can be regarded as a risk factor in the conventional epidemiological sense, its relationship to myocardial infarction must be demonstrated in prospective studies of healthy populations. Regulation of the plasma concentration of PAI-1 is complex and at present not well understood. Multiple interactions with disturbances of both carbohydrate and lipoprotein metabolism are evident. Many studies have been carried out in cultured cells, but data can hardly be transformed into human pathophysiology. It seems that both environmental and genetic factors are of importance for the plasma PAI-1 concentration. Recently, knowledge of the importance of genetic factors involved in the regulation of plasma PAI-1 concentration has become available. Interestingly, preliminary data suggest that the 4G/5G polymorphism located within the PAI-1 promoter is connected to CHD. More data on larger patient groups are needed and will certainly shed new light on the importance of impaired fibrinolytic function in the etiology of CHD in the near future.

Plasminogen activator inhibitor-1 antigen concentrations during insulin and oral glucose tolerance tests in obese man

In vitro studies have shown that insulin increases plasminogen activator inhibitor-1 (PAI-1) synthesis and secretion in cells of hepatic origin. However, in vivo studies have failed to demonstrate an acute or chronic effect of insulin infusions on PAI-1 concentrations in man. To investigate the effects of exogenous insulin infusion compared to endogenous insulin secretion, 8 obese subjects underwent an insulin tolerance test (ITT) and an oral glucose tolerance test (OGTT). During ITT, insulin levels rose from (median, range) 8 (5–18) μU ml −1 at time 0 to 140 (40–500) μU ml −1 after 30 min before falling to 12.5 (6–32) μU ml −1 at 90 min. Plasma glucose fell from 3.9 (3.1–4.7mmol −1 at time 0 to 1.8 (1.1–2.6)mmol 1 −1 after 30min. During OGTT plasma insulin rose from 6·5 (5–26) μU ml −1 at time 0 to 102 (9–300) μU ml −1 after 60 min and 74 (17–25) μU ml −1 after 2h. Plasma glucose was 4.3 (3.6–4.7) mmol l −1 at time 0 and 8.1 (2.0–10.3) and 6.2 (4–9.8) mmol 1 −1 after 60 and 2 h respectively. During OGTT growth hormone levels were 1.8 mU l −1 at time 0 and fell gradually to 0.8 mU l −1 after 90 min and were 1.1 (0.6–11) at 2h. During ITT growth hormone rose from 1.0 mU I −1 at time 0 to 50.5 mU 1 −1 after 60min. There were no changes in insulin-like growth factor-1 in either group. PAI-1 concentrations were 31.1 ng ml −1 at time 0 and showed a gradual fall to 22.3 and 18 ng ml −1 after 60 and 120min of OGTT. During ITT PAI-1 was 15.4ng ml −1 at time 0 and 14.8 and 18.4ng ml −1 after 60 and 90min. The results confirm that exogenous insulin does not acutely regulate PAW concentrations. The high portal (endogenous) insulin concentrations seen during OGTT in these patients do not seem to have measurable effects on hepatic PAI-1 output.