Levels of tissue-type plasminogen activator and plasminogen activator inhibitor 1 in disseminated intravascular coagulation syndrome

Since disseminated intravascular coagulation (DIC) may directly reflect the abnormal regulation of the fibrinolytic system by endothelial cells, we have measured the levels of tissue-type plasminogen activator (t-PA), type 1 PA inhibitor (PAI-1) and t-PA . PAI-1 complex which is formed as a result of interaction on the two factors, in the plasma of patients with DIC (n = 51) and healthy controls (n = 42). Antigens of t-PA, PAI-1 and t-PA . PAI-1 complex were significantly increased in the DIC plasma (36.4 +/- 25.1, 106.8 +/- 54.7 and 46.6 +/- 34.5 ng/ml, respectively) compared with those in normal plasma (8.5 +/- 4.3, 54.4 +/- 21.2 and 8.6 +/- 3.5 ng/ml, respectively). The molar ratio of t-PA to PAI-1 was much higher in the DIC plasma (1:3) than in normal plasma (1:6), which caused enhancement of the whole fibrinolytic activity in the DIC plasma. These changes resulted in significant consumption of plasminogen, alpha 2-plasmin inhibitor (alpha 2-PI) and a significant increase of plasmin . alpha 2-PI complex (PPI) and D-dimer. These results suggest that t-PA and its specific inhibitor PAI-1 both of which are secreted from endothelial cells into blood, play an important role on the progress of DIC.     

Plasminogen activator and plasminogen activator inhibitor activities in a reference population

The influence of age, gender, and aspirin ingestion on plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activities was studied in a reference population of 35 men and 35 women between the ages of 20 and 65 years. The t-PA values (mean +/- SD) in the women before and after 5 minutes of venous occlusion were 3.8 +/- 1.4 and 7.8 +/- 4.4 micrograms/L, respectively; in men these values were 3.3 +/- 1.2 and 8.8 +/- 8.9 micrograms/L. Men had higher mean PAI levels than did women (5.0 vs. 2.5 kU/L). T-PA showed an inverse relationship to PAI in both sexes. There was a negative correlation of t-PA levels with age, whereas PAI levels were positively correlated. The ingestion of a single dose of aspirin (650 mg) did not alter PAI or t-PA activities. This study indicates that factors such as age and sex may need to be considered when reference populations are developed for clinical studies of fibrinolysis.     

Familial thrombophila associated with high levels of plasminogen activator inhibitor

A family with defective fibrinolytic abnormalities and recurrent thrombotic events is described. Impaired fibrinolysis was associated with high activity and concentration of fast-acting plasminogen activators inhibitor (PAI-1). Acquired conditions associated with PAI-1 increase were excluded. After venous occlusion testing, a different behaviour of fibrinolytic activity inhibition was seen in the family members. In the propositus and in two relatives only tissue (t-PA) plasminogen activity inhibition was found; in two other members, both t-PA and urokinase-type plasminogen activities were completely inhibited by the high PAI-1 levels. This fibrinolytic defect seems to be familial and transmitted as an autosomal trait.     

t-PA activity, antigen and PAI-1 antigen levels in blood obtained from the patients with cerebral infarction

Tissue plasminogen activator (t-PA) produced by endothelial cells exerts a powerful effect on the course of thrombosis, embolism, or arteriosclerosis. However, the fluctuations of fibrinolytic system in the patients with cerebral infarction (CI), have yet to be demonstrated. This study was designed to investigate t-PA activity, t-PA antigen and plasminogen activator inhibitor-1 (PAI-1) antigen levels in the CI patients. The mean t-PA activity, t-PA antigen and PAI-1 levels in patients were 0.53 +/- 0.64 IU/ml, 10.9 +/- 5.2 ng/ml and 23.0 +/- 14.9 ng/ml, and the normal ranges were 0.02-0.28 IU/ml, 1.0-7.0 ng/ml and 5.3-45.0 ng/ml, respectively. Almost all the patients were plotted out to the abnormal range by scattergrams relating t-PA activity to t-PA antigen, and no daytime fluctuations of the above three parameters in the patients differed from those in normal controls. When CI patients were followed up to the 8th hospital day, abnormal fluctuations were also observed. Consequently we suggest that this information may help to attain the more progressive treatment or the preventive therapy of CI.     

The activation of plasminogen by tissue plasminogen activator is not enhanced by different heparin species as assessed in vitro with a solid-phase fibrin method

The aim of this study was to evaluate the effect of several heparin species (standard heparin, heparin of low molecular weight: IC 831422, heparin of high affinity for antithrombin III: IC 831435, and heparin of low affinity for antithrombin III: IC 831436) on the different steps of the fibrinolytic mechanism i.e., interaction of tissue-type plasminogen activator (t-PA) with plasminogen activator inhibitor-1 (PAI-1), binding of t-PA and plasmin(ogen) to fibrin and activation of plasminogen on the fibrin surface, in the presence of plasma proteins and factors that modulate fibrinolysis. Fibrinolytic and plasmin amidolytic activities were measured in the presence and absence of heparin. The spectrophotometric assays were performed in the presence and absence of solid-phase fibrin using selective chromogenic substrates for plasmin and saturating concentrations of plasminogen.The overall fibrinolytic activity, the amidolytic activity of mixtures of t-PA or urokinase with plasminogen in the absence of fibrin, the binding of t-PA and plasmin(ogen) to fibrin and the t-PA/PAI-1 interaction were not modified by heparin. In contrast, the activation of plasminogen by fibrin-bound t-PA decreased as a function of the concentration of heparin. Although this effect was not significant at concentrations usually used in routine heparin therapy (0.1 to 1 iu/ml) it might have some relevance when heparin is injected in bolus doses.In conclusion, by using a solid-phase fibrin method which allows the analysis of t-PA/PAI-1 balance, data were obtained indicating that the heparin species tested here neither competed with fibrin for the binding of t-PA, nor potentiated the activation of plasminogen at the fibrin surface.     

Fibrinolytic changes during acute vascular damage induced by Mediterranean spotted fever

Hemostatic abnormalities and microvascular injury have been described in patients with Mediterranean spotted fever (MSF). Rickettsial vasculitis comprises endothelial injury and the immune and phagocytic host response. Only indirect evidence of activation of the fibrinolytic system has been reported in MSF, but no data on plasma levels of their main components, tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1), in this disease are available. To obtain quantitative information on the ‘in vivo’ activation of the fibrinolytic system during the acute and subacute phase of the endothelial damage, several fibrinolytic components were studied in 28 MSF patients. Upon admission (day 1), patients showed a significant increase both in t-PA (30±20 ng/ml) and in PAI-1 antigen levels (55±30 ng/ml) as compared with normal levels (9±4 ng/ml and 11±4 ng/ml, respectively). The levels of PAI-1 activity were also increased (median: 7U/ml, range: 0–24 U/ml), but not significantly (normal values, median: 3 U/ml, range: 0.5–5 U/ml). After remission of the disease (day 30) a significant decrease in t-PA and PAI-1 antigen levels was observed in comparison with day 1, but the PAI-1 antigen concentration remained increased in comparison with normal values. The decrease in the ratio VIII:C/vWF:Ag found in the acute phase of the disease and after 30 days could indicate that the endothelial damage remains after this period. Tissue necrosis factor α (TNFα), a potential modulator of fibrinolytic system during gram-negative sepsis, showed normal values during the acute phase of the disease and at day 30. The data found in this study indicate that the changes observed in the fibrinolytic system during MSF could be due to the endothelial damage found in the acute phase of the disease. The increased plasma PAI-1 levels could contribute to an increase in the risk of venous thrombosis in MSF patients.     

Decreased plasma fibrin degradation products during hormonal stimulation for in vitro fertilisation

In vitro fertilisation with embryo transfer (IVFET) is associated with an increased risk of venous thrombosis. In order to determine to which extent the hormonal preparation required for IVFET could be involved in this complication, we have measured major plasma fibrinolytic components in 13 women before and during the ovarian stimulation. After pituitary desensitization with buserelin, plasma levels of fibrin degradation products (FbDP) and fibrinogen were significantly decreased. Tissue-type plasminogen activator antigen (t-PA), plasminogen activator inhibitor 1 antigen (PAI-1), FbDP and fibrinopeptide A remained unchanged. After a subsequent stimulation by human menopausal gonadotropins, FbDP plasma levels remained low, while fibrinogen returned to normal levels. t-PA antigen and PAI-1 antigen plasma levels decreased and were correlated with increased serum estradiol levels. Therefore, estradiol could be involved in the regulation of the fibrinolytic balance to some extent; during IVFET hormonal preparation, a decreased plasma fibrinolytic capacity can be questioned, thus favouring the appearance of a thrombotic event.     

Organization of the central control of muscles of facial expression in man

The capacity of the vascular endothelium locally to release tissue-type plasminogen activator (t-PA) is critical for effective endogenous fibrinolysis. We determined the influence of ageing and regular aerobic exercise on the net release of t-PA across the human forearm in vivo using both cross-sectional and intervention approaches. First, we studied 62 healthy men aged 22-35 or 50-75 years of age who were either sedentary or endurance exercise-trained. Net endothelial release rates of t-PA were calculated as the product of the arteriovenous concentration gradient and forearm plasma flow to intra-arterial bradykinin and sodium nitroprusside. Second, we studied 10 older (60 ± 2 years) healthy sedentary men before and after a 3 month aerobic exercise intervention. Net endothelial t-PA release was significantly blunted with age in the sedentary men. At the highest dose of bradykinin the increase in t-PA antigen release was ≈35 % less (   P < 0.05  ) in the older (from −1.0 ± 0.4 to 37.8 ± 3.8 ng (100 ml tissue)⁻¹ min⁻¹) compared with young (from 0.1 ± 0.6 to 56.6 ± 9.2 ng (100 ml tissue)⁻¹ min⁻¹) men. In contrast, the endurance-trained men did not demonstrate an age-related decline in the net release of t-PA antigen. After the exercise intervention, the capacity of the endothelium to release t-PA increased ≈55 % (   P < 0.05  ) to levels similar to those of the young adults and older endurance-trained men. Regulated endothelial t-PA release declines with age in sedentary men. Regular aerobic exercise may not only prevent, but could also reverse the age-related loss in endothelial fibrinolytic function.     

Effects of a long-term pharmacological interruption of the renin-angiotensin system on the fibrinolytic system in essential hypertension

To assess the effects of pharmacological interruption of the renin-angiotensin system on the fibrinolysis, tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor-1 antigens (PAI-1) and neurohormones, such as plasma renin activity, norepinephrine, angiotensin II (AII) and IV (AIV) concentrations, were measured in 60 hypertensives. Among them, 48 patients were divided into two groups (25 with 10-20 mg quinapril and 23 with 50-100 mg losartan) who received the drug for 6 months. AII had a weak positive correlation with free PAI-I (n = 60, r = 0.26, p < 0.05) whereas AIV had a strong positive correlation with free PAI-I (n = 60, r = 0.57, p < 0.0001). In both treatment groups, blood pressures were significantly reduced to similar levels after drug treatment. While plasma renin activity increased significantly in both groups after drug treatment, only the losartan group showed significant increases in AII and AIV concentrations. In the quinapril group, there was a significant change in t-PA (p < 0.001) without changes in PAI-1. In the losartan group, free PAI-I and total PAI-I (p < 0.05 for free PAI-I and p < 0.04 for total PAI-I) were significantly increased without a change in t-PA. Thus, quinapril enhanced fibrinolysis but losartan attenuated it. These unique effects of each drug on the fibrinolytic system appear to be associated with changes in AII and AIV concentrations.     

Tissue plasminogen activator, plasminogen activator inhibitors, and activator-inhibitor complex in liver disease.

AIMS--To identify the relative contribution of plasminogen activators, particularly tissue plasminogen activator (t-PA) and specific plasminogen activator inhibitors (PAI-1, PAI-2), to the fibrinolytic changes associated with various types of liver disease or severe chemical and physical damage to the liver. METHODS--Platelet rich (PRP) and platelet poor plasma (PFP) from patients with alcoholic cirrhosis, primary biliary cirrhosis, hepatic malignancy, or paracetamol overdose, or who were undergoing partial hepatectomy or liver transplantation, were assayed for t-PA, PAI-1, t-PA-PAI-1 complex and PAI-2 antigen values using specific enzyme linked immunosorbent assays (ELISAs) developed in this laboratory. RESULTS--Appreciable increases in the plasma concentration of t-PA, PAI-1, and t-PA-PAI-1 were seen in patients with alcoholic cirrhosis, primary biliary cirrhosis, and hepatic malignancy. Liver damage due to paracetamol overdose and partial hepatectomy both resulted in a striking increase in plasma PAI-1 concentration, although concentrations of t-PA and t-PA-PAI-1 complex were less affected. Concentrations of t-PA, PAI-1, and t-PA-PAI-1 complex returned to near normal values after successful liver transplantation in a patient with chronic active hepatitis. PAI-2 was also detected in several patients with chronic liver disorders. CONCLUSIONS--Haemorrhage due to fibrinolytic bleeding is commonly associated with liver disease. The patients studied here all had appreciable increases in circulating t-PA antigen concentrations. This was associated with increased concentrations of PAI-1 antigen and t-PA-PAI-1 complex and the balance between activator and inhibitor did not result in systemic plasmin generation. Reduced PAI-1 activity in cirrhosis or a critical difference in the ratio of t-PA to PAI-1 concentrations may explain the enhanced plasminogen activator activity previously noted in cirrhosis but not metastatic disease. Reduced hepatic clearance of t-PA and t-PA-PAI-1 complex due to impaired liver function may account for increased concentrations of free and complexed t-PA.     

The relationship between plasma t-PA and PAI-1 levels is dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms

Thrombus formation and degradation is partly due to a complex interplay between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1). There is accumulating evidence that plasma levels of t-PA and PAI-1 may be influenced by an interaction between the fibrinolytic and renin-angiotensin systems. The goal of this study was to conduct an exploratory data analysis to determine whether there is evidence that the relationship (i.e. correlation) between plasma t-PA and PAI-1 is influenced by interactive effects of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) and plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphisms in a sample of 50 unrelated African Americans and 117 unrelated Caucasians. In a single-locus analysis, no evidence for heterogeneity of plasma t-PA and PAI-1 correlations among either ACE I/D or PAI-1 4G/5G genotypes was detected. However, using the combinatorial partitioning method for exploratory data analysis, we identified evidence that is suggestive of heterogeneity of plasma t-PA and PAI-1 correlations among multilocus ACE I/D and PAI-1 4G/5G genotypes in African American females, Caucasian females, Caucasian males, but not African American males. From these results, we propose as a working hypothesis that the correlation between plasma t-PA and PAI-1 may be dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. This study supports the idea that interactions between the fibrinolytic and renin-angiotensin systems play an important role in the genetic architecture of plasma t-PA and PAI-1.     

妊娠高血压综合征患者vWF、t-PA、PAI-1的检测分析

目的:探讨妊娠高血压综合征(妊高征)患者内皮细胞功能指标的变化及其临床意义。方法:应用ELISA法及发色底物法测定妊高征患者血浆血管性血友病因子(vWF)、织织型纤溶酶原激活物(t-PA)及纤溶酶原激活抑制物-1(PAI-1)活性。结果:妊高征患者vWF、t-PA、PAI-1较正常非孕组明显升高(P<0.05或P<0.01);妊高征各组患者vWF、PAI-1活性比正常晚孕组显著增高(P<0.05或P<0.01),且病情越重增高越明显;t-PA无明显改变。中、重度妊高征组血浆vWF与PAI-1水平呈直线正相关关系(r=0.723,P<0.05;r=0.765,P<0.05)。结论:妊高征患者内皮细胞功能异常,凝血及纤溶抑制功能亢进。测定血浆vWF和PAI-1水平,对于临床诊断妊高征有重要意义。     

Skeletal muscle dictates the fibrinolytic state after exercise training in overweight men with characteristics of metabolic syndrome

While there is indisputable evidence supporting the beneficial role of aerobic exercise in reducing cardiovascular risk factors, there are few dose-response studies of this relationship. Increasingly, it is thought that the cardiovascular benefits of exercise are significantly influenced by adaptations within skeletal muscle and its vasculature. However, little is known about the molecular mechanisms underlying these adaptations. To address this need, we initiated a study utilizing longitudinal, microarray-based gene expression profiling of serial skeletal muscle biopsies obtained from the study of targeted risk reduction intervention through defined exercise (STRRIDE). STRRIDE participants were overweight and exhibited symptoms characteristic of the metabolic syndrome that typically precedes type II diabetes such as insulin resistance, abnormal lipids and glucose intolerance. Expression data were statistically filtered and sorted into exercise training-responsive clusters based on gene product knowledge. One such cluster included genes that promote the degradation of fibrin clots such as tissue plasminogen activator (t-PA), connective tissue activation peptide III (CTAP III) and tetranectin. The fibrinolytic activity and protein levels of tetranectin, and t-PA and its endogenous inhibitor PAI-1, were subsequently shown to change significantly in both skeletal muscle and serum in response to exercise training. Our data show that the rigors of exercise directly induce fibrinolytic genes and protein cascades, both within muscle, and in the systemic circulation. This finding is particularly significant given that the metabolic syndrome is an independent risk factor for peripheral vascular disease and thrombotic events within the heart and brain. We conclude that aerobic exercise training induces both local and systemic changes in fibrinolysis and vascular homeostasis that are probably protective against cardiovascular disease.     

Fibrinolysis after delivery: caesarean section versus vaginal delivery

Caesarean section is associated with higher risk of thromboembolism than normal vaginal delivery. In order to elucidate if altered fibrinolysis contributes to this increased risk, 15 women who delivered by Caesarean section were observed in the 37th to 40th week of pregnancy, 1 h, 3 and 10 days after delivery and compared to 15 women who delivered vaginally. Before delivery no differences in fibrinolytic variables were observed between the two groups. The immediate post-delivery period was associated with significant (all p<0.05) and similar increases in tissue-type plasminogen activator (t-PA) activity (149 vs 129%, all figures: Caesarean section vs vaginal delivery) and t-PA antigen (46 vs 75%) and significant (all p<0.05) decreases in plasminogen activator inhibitor (PAI) activity (66 vs 69%) and PAI-1 antigen (74 vs 82%) in both groups. Only euglobulin activity was less enhanced (60 vs 159% increase, p<0.05). Three days after delivery all variables, except PAI activity, decreased significantly (all p<0.05) compared to values 1 h after delivery (t-PA activity: 37 vs 41%; t-PA antigen: 43 vs 51%; PAI-1 antigen: 80 vs 58%) and similarly in both groups. From the 3rd to the 10th day euglobulin activity, t-PA activity and t-PA antigen slightly increased. The venous occlusion test, which was performed before delivery, 3 and 10 days after delivery revealed no significant differences in fibrinolytic responses to such stimulation between the two groups investigated. It was concluded that changes in t-PA and PAI-1 observed after Caesarean section are not significantly different from those observed after normal vaginal delivery and therefore presumably do not contribute to increased risk of thromboembolism after Caesarean section.     

卡托普利对家兔急性心肌梗塞早期血小板活化及纤溶活性的影响

本研究观察了家兔急性心肌梗塞（ＡＭＩ）早期血浆血小板α－颗粒膜蛋白（ＧＭＰ－１４０）、血栓素Ｂ２（ＴＸＢ２）、组织型纤溶酶酶原激活剂（Ｔ－ＰＡ）及其抑制物（ＰＡＩ－１）水平的变化及卡托利干预的ＰＡ活性显著降低；相关分析表明，血浆ＧＭＰ－１４０浓度与ＰＡＩ－１活性显著正相关。卡托普利干预后，血浆ＧＭＰ－１４０浓度、ＴＹＸＢ２浓度、Ｔ－ＰＡ浓度、ｔ－ＰＡ含量、ＰＡＩ－１活性均明显降低，而ｔ－ＰＡ活性显     

The fibrinolytic response to exercise at diagnosis and after 12 months in patients with type 2 diabetes mellitus

Objective: To determine fibrinolytic activity and exercise stimulated fibrinolytic capacity in patients with type 2 diabetes mellitus at diagnosis and after 12 months treatment aimed at improving glycaemic control.Subjects: Thirteen patients referred to the hospital diabetic out-patient department with a new diagnosis of type 2 diabetes mellitus were selected for study.Methods: Basal fibrinolytic activity and exercise stimulated fibrinolytic capacity were measured at diagnosis and after 12 months of interventional therapy.Results: Compared with controls basal fibrinolytic activity was depressed in the diabetic patients due to increased levels of PAI-1:Ag 15.1(4.6–20) versus 8.4 (3.0–9.9) ng/ml, p<0.05 and PAI,17.6 (10.9–26.8) versus 6.6 (4.8–13.6) IU/ml, p<0.01. PAI was related to fasting plasma insulin levels r=0.8, p<0.001 and body mass index r=0.7, p<0.01 at diagnosis, but not triglycerides or blood pressure. Median t-PA:Ag was also elevated in the diabetic group 9.8 (6.3–12.1) versus 4.5 (3.1–7.1) ng/ml, p<0.001. The percentage change in ECLT with exercise was inversely proportional to the degree of insulin resistance r=−0.08, p<0.001 and fasting plasma insulin r=−0.65, p--0.02, at diagnosis. Despite an improvement in glycosylated haemoglobin, 8.7 (1.8) to 7.0 (1.2) %, p=0.008, over 12 months, the ECLT increased from 290 (220–315) to 360 (316–375) mins, p<0.05. This was associated with an increase in the PAI-1:Ag/t-PA:Ag ratio from 1.92 (1.63) to 2.48 (0.97), p=0.025. Although t-PA release due to exercise was reduced in the diabetic group (38%) compared to non-diabetic controls (82%) p<0.001, similar results were found after 12 months 54.5% to those at diagnosis 38%, (NS).Conclusion: This study has shown that in a selective group of type 2 diabetic patients, exercise stimulated fibrinolytic capacity is maintained over a 12 month period despite a deterioration in basal fibrinolytic activity.     

Transdermal estradiol does not impair hemostatic biomarkers in postmenopausal women

OBJECTIVE: To evaluate the effect of transdermal estradiol therapy (ET) on coagulation and fibrinolysis markers in postmenopausal women. METHODS: Prospective open trial study in 59 healthy hysterectomized postmenopausal women. Thirty women received transdermal ET (50 microg per day) during 3 months and 29 women formed the untreated arm. RESULTS: Baseline factor VII-tissue factor complex (VIIa-rTF), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) levels decreased significantly (P < 0.01) after therapy. In contrast, tissue-type plasminogen activator antigen (t-PA) levels increased significantly (P < 0.01). After ET, there was no difference in protein C activity (PC), protein S activity (PS), plasminogen (PLG), and antithrombin III (ATIII) levels. None of participants reported thromboembolic events. CONCLUSION: ET elicited a decrement in blood biomarkers implicated in coagulation activation which in turn seemed to improve fibrinolytic activity. These results suggest that transdermal route does not impair thrombotic risk.     

Fibrinolytic activity is not dependent upon exercise mode in post-myocardial infarction patients

In this study we investigated possible differences in fibrinolytic activity in cardiac patients while they performed treadmill and cycle ergometry. Thirteen post-myocardial infarction patients completed two maximal exercise tests on treadmill and cycle ergometers. Blood was collected before and after each exercise test and was analyzed for the fibrinolytic variables, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) activity, and lactate. Maximal oxygen uptake, heart rate, and ventilation were greater (P?P?相似文献