Hypo-fibrinolysis in patients with hypertension and elevated cholesterol

To test the hypothesis that increased blood pressure and hyperlipidaemia result in changes in the fibrinolytic system, 84 subjects with both hypertension and elevated serum cholesterol levels (the high risk group) were compared with 55 controls matched with respect to age, sex and body mass index (BMI). Plasminogen activator inhibitor (PAI-1), and tissue plasminogen activator (tPA) antigen and activity were measured before and after venous occlusion. In the high risk group, tPA activity was significantly lower both before and after venous occlusion and PAI-1 levels were significantly higher. In a multivariate analysis the triglyceride levels, diastolic blood pressure and cholesterol levels were independently associated with the PAI-1 levels. Diastolic blood pressure was independently and inversely associated with resting tPA activity. We conclude that patients with hypertension and hyperlipidaemia have a reduced activity of the fibrinolytic system, an effect which is unrelated to differences in age, sex, smoking or BMI.     

Hypofibrinolysis in patients with hypercoagulability: The roles of urokinase and of plasminogen activator inhibitor

The prevalence of abnormalities of fibrinolysis in patients with venous thromboembolism is as yet unknown. Defined abnormalities include congenital dysfunction and deficiency of plasminogen, and probably impaired plasminogen activation secondary to elevated levels of plasminogen activator inhibitor type 1 (PAI-1) or to impaired release of tissue plasminogen activator (tPA). In this preliminary study, we analyzed plasma samples from 21 patients for whom an investigation for possible thrombophilia was requested. Twenty of the patients had venous thromboembolism, and one had arterial thrombosis at an early age. Two patients had deficiency of protein C or protein S, but no other recognized biochemical disturbances related to thrombophilia were identified. Patient samples and plasma from 25 normal controls were assayed for tPA activity, PAI-1 activity, and urokinase (uPA) activity and antigen. tPA activity and antigen were not significantly different in patients than in controls. PAI-1 activity was significantly greater in patients (P < 0.0001). uPA activity was not different in the two groups. However, uPA antigen was significantly reduced in patients compared to controls (P = 0.001). These data suggest that hypofibrinolysis leading to a risk of thrombosis may be caused not only by elevated PAI-1 activity but also by reduced total uPA concentration. © 1993 Wiley-Liss, Inc.     

THE EFFECTS OF CHRONIC SMOKING ON THE FIBRINOLYTIC POTENTIAL OF PLASMA AND PLATELETS

We studied tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) in healthy individuals divided by smoking habit into current smokers, former smokers and non-smokers (who had never smoked). Plasma PAI-1 antigen was significantly higher in smokers than in non-smokers with intermediate levels in former smokers. A similar trend was observed for plasma PAI activity but this did not reach statistical significance. Platelet PAI-1 and plasma t-PA were not significantly different when comparing the three groups. After venous occlusion t-PA rose significantly in all groups; no significant change in plasma PAI-1 was observed. The ratio of t-PA to PAI-1 in plasma was similar in non-smokers and former smokers but lower in smokers, suggesting that there is at least partial restoration of plasma fibrinolytic potential after smoking cessation. Plasma PAI-1 antigen and PAI activity correlated with estimated pack-years of cigarettes smoked among smokers and former smokers. When all subjects were studied collectively, plasma PAI-1 correlated strongly with plasma t-PA and triglycerides; plasma t-PA also correlated strongly with triglycerdes.
We conclude that chronic smoking is associated with impaired fibrinolysis in plasma and that this largely reflects elevated plasma PAI-1 in smokers. Smoking does not appear to affect the response to venous occlusion. The postulated effect of chronic smoking on plasma PAI-1 may be mediated by the influence of smoking on triglycerides and insulin resistance. Stopping smoking appears to return impaired fibrinolysis towards normal. Smoking does not quantitatively affect the platelet pool of PAI-1. Smoking habit should be controlled for in clinical analyses of PAI-1 and t-PA.     

高血压病人纤维蛋白原水平及纤溶系统功能研究

为了解高血压病人的血栓形成倾向,我们随机选取了４１例高血压病人及３４例正常血压者,分别观察了他们的纤维蛋白原及血浆组织型纤溶酶原激活物（ｔＰＡ）抗原及纤溶酶原激活物抑制物－１（ＰＡＩ－１）的含量。结果表明,高血压病人血浆纤维蛋白原水平无明显变化,但ｔＰＡ抗原含量减少,ＰＡＩ－１的水平增加。提示高血压病人存在内源性纤溶功能受损     

Reduced plasminogen activator inhibitor activity in high consumers of fruits, vegetables and root vegetables

We studied a cross-sectional sample of 260 subjects aged 30-60 years, in order to assess the relation between food intake habits and factors of the fibrinolytic system. Plasma samples of tissue plasminogen activator (tPA) antigen, and plasminogen activator inhibitor (PAI-1) activity were obtained for the assay. The dietary pattern was determined using a food frequency questionnaire, according to which the subjects were grouped as high, low or medium consumers. The subjects who were high consumers of fruit, vegetables, and root vegetables showed the lowest levels of PAI-1, those who were low consumers had the highest levels, whereas the medium consumers showed intermediate values. The tPA levels did not differ between the three groups, and there were no significant differences in other variables that covaried with PAI-1 levels, such as age, anthropometric variables, or serum lipid levels, which could confound the PAI-1/food pattern relationship. The data, which show that a frequent intake of fruit, vegetables, and root vegetables--foodstuffs rich in vitamin C and fibre--is associated with lower PAI-1 levels, are consistent with increased activity of the fibrinolytic system and thus a reduced risk of thromboembolic and cardiovascular disease in subjects who exhibit this food intake pattern.     

脑血栓形成病人血浆及脑脊液t-PA及其PAI-1含量的观察

目的：研究动脉粥样硬化性脑血栓形成病人血浆及脑脊液组织型纤溶酶原激活物（t-PA)及其抑制物（PAI-1）含量的变化及其临床意义。方法：采用双抗体夹心固相酶联免疫吸附法（ELISA）检测35例脑血栓形成病人血浆和其中31例病人脑脊液t-PA及PAI-1抗原含量，与35例正常对照组血浆和其中20例对照组脑脊液进行比较。结果；脑血栓形成组血浆t-PA含量高于对照组，PAI-1含量显著高于对照组；其脑脊液t-PA,PAI-1含量均显著高于对照组，脑脊液中t-PA,PAI-1的含量分别与血浆中t-PA,PAI-1的含量，分别与血浆中t-PA,PAI-1的含量呈正相关；脑血栓形成组病人神经功能缺损评分与血浆及脑脊液t-PA,PAI-1抗原含量呈正相关。结论：脑血栓形成病人纤溶活性明显下降，t-PA及PAI-1参与了脑血栓形成之病理过程；t-PA及PAI-1抗原含量是反映体内纤溶活性的两个重要指标；可用血浆或脑脊液t-PA,PAI-1的含量作为判断病情的参考指标之一。     

Low level of tissue plasminogen activator activity in non-diabetic patients with a first myocardial infarction

OBJECTIVE: To explore the role of tissue plasminogen activator (tPA) activity and plasminogen activator inhibitor type 1 (PAI-1) in survivors of a first myocardial infarction (MI). Insulin and proinsulin were analysed as potential risk factors. DESIGN: Case-control study in northern Sweden. SUBJECTS: A total of 115 patients under 65 years of age with a first MI were enrolled and recalled for further examination 3 months later. Twenty-seven patients were excluded, 17 with known diabetes and 10 who did not come to the follow-up, giving a final number of 88 patients, 73 men and 15 women. Patients were age- and sex-matched with control subjects drawn from the local cohort in the MONICA population survey 1994. MAIN OUTCOME MEASURES: We compared MI patients and controls using univariate and multiple regression analyses including odds ratios (OR). RESULTS: PAI-1 activity, fibrinogen, postload insulin and -proinsulin were significantly higher and tPA activity significantly lower in MI patients in the univariate analysis. In a multiple regression analysis, including also age, sex and cardiovascular risk factors, these parameters were divided in quartiles. The lowest quartile of tPA activity was significantly associated with MI (OR = 19.1; CI 3.0-123) together with the highest quartiles of fibrinogen (OR = 25; CI 5.2-120) but other variables were not. CONCLUSION: Low tPA activity, i.e. low fibrinolytic activity, characterized nondiabetic subjects after a first MI which is not explained by concomitant disturbances in metabolic and anthropometric variables.     

Fibrinolytic characteristics and their significance in malignant, tuberculous and cirrhotic pleural and ascitic fluids

The fibrinolytic characteristics and clinical pathological significance of pleural and ascitic fluid were studied in patients with malignant tumour, tuberculosis or liver cirrhosis. Urokinase plasminogen activator (uPA) and urokinase plaminogen activator receptor (uPAR) levels were measured by enzyme-linked immunoadsorbent assay and tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), plasminogen (Plg), plasmin (Pl) and alpha(2) plasmin inhibitor (alpha(2)PI) by colorimetric assay. uPA and uPAR levels were higher in malignant tumour and tuberculosis compared with liver cirrhosis, whereas tPA levels were significantly higher in liver cirrhosis and malignant tumour than in tuberculosis patients. Tuberculosis patients showed statistically higher PAI-1, Plg and Pl concentrations than malignant tumour patients, which, in turn, were higher than those in liver cirrhosis patients. alpha(2)PI levels were markedly higher in malignant tumour and liver cirrhosis than in tuberculosis. In the malignant tumour group, only uPA level was significantly different between the samples that contained cancer cells and those that did not. We found significant differences between the fibrinolytic characteristics in pleural and ascitic fluid in patients with malignant tumour, tuberculosis and liver cirrhosis. The analysis of several fibrinolytic parameters could help to determine the quality of pleural and ascitic fluid, and also to further understand the pathological processes of these diseases.     

Markedly impaired fibrinolytic balance contributes to cardiovascular risk in adults with growth hormone deficiency

CONTEXT: Adults with GH deficiency (GHD) have multiple cardiovascular risk factors, including an unfavorable lipid profile and body composition as well as impairments in endothelial function and cardiac performance. We hypothesized that GHD is associated with elevated levels of plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of plasminogen activation in the circulation. OBJECTIVE: The objective of the study was to determine the fibrinolytic profile of adults with GHD in comparison with controls. STUDY DESIGN AND PARTICIPANTS: This was a prospective, observational study including 12 adults with GHD. Twelve gender-, age-, and body mass index-matched adults served as controls. MAIN OUTCOME MEASURES: The primary outcome measures were circadian plasma PAI-1 antigen with corresponding tissue-plasminogen activator (tPA) activity values. Endothelial function was assessed by flow-mediated vasodilation and fibrinolytic potential by venous occlusion test. RESULTS: Adults with GHD exhibited an unfavorable 24-h fibrinolytic profile characterized by a mean 62% elevation in PAI-1 antigen (2.77 ng/ml after adjustment for baseline PAI-1; P = 0.049) in the setting of a mean 24% reduction in tPA activity (-0.17 IU/ml after adjustment for baseline tPA; P = 0.003). Fibrinolytic response was defective in GHD, as demonstrated by a sustained elevation in PAI-1 activity greater than 4 IU/ml after venous occlusion [7.2 IU/ml (interquartile range 0.8-17.4); P = 0.018]. Endothelial function was impaired in GHD, as quantified by percent flow-mediated vasodilation over 120 sec [area under the curve 3.8 (interquartile range -2.4 to 7.9) vs. 12.8 (interquartile range 2.1-19.4); P = 0.043]. CONCLUSIONS: Adults with GHD demonstrate alterations in plasma fibrinolytic balance, including elevated levels of PAI-1 antigen with decreased tPA activity. These changes may contribute to the increased cardiovascular morbidity within this population.     

Does chronic smoking influence fibrinolytic potential in Type 1 diabetes mellitus?

Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) were studied in 18 smokers and 18 closely matched non-smokers, all of whom had Type 1 diabetes mellitus (DM). None of the patients had advanced complications of diabetes. The t-PA and PAI-1 antigen levels were measured in plasma before and after venous occlusion, and were normal in Type 1 diabetes regardless of smoking status. Platelet PAI-1 levels were also measured and were found to be normal both in smokers and non-smokers. In smokers with Type 1 DM, plasma PAI-1 was significantly correlated with triglycerides. The normal fibrinolytic potential found in smokers with diabetes contrasts starkly with the significantly elevated plasma PAI-1 reported in smokers without diabetes. In smokers, triglycerides may effect low levels of PAI-1 release into plasma; this process may be significantly augmented in the presence of smoking-induced insulin resistance. The lack of endogenous insulin release in Type 1 diabetes may obviate the characteristic rise in plasma PAI-1 found in smokers who do not have diabetes. © 1998 John Wiley & Sons, Ltd.     

Plasma concentration of endogenous tissue plasminogen activator and the occurrence of future cardiovascular events

Data from recent prospective studies of hemostasis and thrombosis indicate that the plasma concentration of endogenous tissue-type plasminogen activator (tPA) is often elevated years in advance of a first arterial occlusion. Specifically, among healthy subjects with no prior cardiovascular disease, the risk of future myocardial infarction and stroke appears to be three to four times higher among subjects with high baseline levels of tPA antigen as compared to subjects with lower levels. Whether this relationship represents activation of the endogenous fibrinolytic system in response to the presence of preclinical atherosclerosis or is a reflection of elevated concentrations of local plasminogen activator inhibitors is currently unresolved. However, cross-sectional data indicate that the plasma concentration of tPA antigen is related to several traditional atherosclerotic risk factors, including HDL cholesterol, findings that further support a direct relationship between endogenous tPA and vascular risk. In concert with data concerning the primary inhibitors of plasminogen activation, it has been hypothesized that the endogenous fibrinolytic system varies within the general population such that certain individuals are prone to thrombosis, whereas others may be prone to hemorrhage. Thus, observations regarding fibrinolytic activation and inhibition raise the possibility that assessment of the intrinsic fibrinolytic system may prove useful in identifying individuals at increased risk for vascular thrombosis. In addition, available findings suggest that therapeutic agents capable of favorably shifting the net fibrinolytic balance may provide a new strategy for cardiovascular disease prevention.     

Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade

The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between Abeta production and clearance. Enzymes responsible for the degradation of Abeta are not well understood, and, thus far, it has not been possible to enhance Abeta catabolism by pharmacological manipulation. We provide evidence that Abeta catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain Abeta levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades Abeta oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain Abeta. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain Abeta levels, restore long-term potentiation deficits in hippocampal slices from transgenic Abeta-producing mice, and reverse cognitive deficits in these mice.     

冠心病患者血清脂蛋白(a)与纤溶功能的变化及其相关性

目的:观察冠心病(CHD)患者血清脂蛋白a[Lp(a)]、血浆组织型纤溶酶原激活剂(tPA)与纤溶酶原激活剂抑制物-1(PAI-1)活性的变化特点,并探讨它们之间的关系。方法:对124例CHD患者和26例正常人采用双抗体ELISA法测定Lp(a)浓度,发色底物法测定tPA、PAI-1活性。结果:CHD患者中,急性心肌梗死(AMI)和不稳定性心绞痛(UAP)组患者Lp(a),浓度和PAI-1活性均非常显著高于对照组(P<0.01):tPA活性显著低于对照组(P<0.01);陈旧性心肌梗死(OMI)和稳定性心绞痛(SAP)组患者Lp(a)浓度和PAI-1活性均亦高于对照组(P<0.05);tPA活性亦低于对照组(P<0.05)。124例CHD患者相关分析显示:Lp(a)与PAI-1活性呈显著正相关,与tPA活性呈显著负相关(P均<0.001)。结论:冠心病患者Lp(a)显著升高,且与tPA、PAI-1活性有密切相关关系。     

Effect of a Change in the Sleep/Wake Cycle on the Diurnal Variation of Fibrinolytic Parameters

The mechanism underlying the circadian rhythm of fibrinolysis is not well understood. To evaluate the influences of wakefulness and of the intrinsic circadian rhythm on fibrinolytic activity, we examined diurnal changes (8:00 am vs. 8:00 pm) in plasminogen activator inhibitor-1 (PAI-1) activity, tissue plasminogen activator (t-PA) antigen levels, and t-PA activity, as well as in plasma serum cortisol levels, in 10 healthy males (21 ± 2 years) for two consecutive days. On the first day, subjects remained awake all day and night. They slept during the daytime (8:30 am to 5:30 pm) on the following day. PAI-1 activity and cortisol levels were significantly decreased, and t-PA activity tended to increase during the daytime on the first day. On the morning following overnight wakefulness, PAI-1 activity and cortisol levels did not return to the levels of the previous morning. On the second day, the afternoon decrease in PAI-1 activity, but not cortisol levels, was still observed, although its magnitude was substantially attenuated. No significant diurnal changes were observed in the levels of t-PA antigen throughout the study period. These findings suggest that the diurnal variation of fibrinolytic activity may be governed by an intrinsic circadian rhythm of PAI-1, which can be modified by a change in the time of wakefulness.     

Protection by α2-macroglobulin of tissue plasminogen activator against inhibition by plasminogen activator inhibitor-1

Tissue plasminogen activator (tPA) is widely used in the treatment of acute myocardial infarction (MI). However, its thrombolytic efficacy does not correlate with the dose administered. The interactions between tPA, α2-macroglobulin (α2-M), and plasminogen activator inhibitor-1 (PAI-1) were investigated both in vitro and in patients undergoing tPA therapy for MI in an attempt to identify variables that might affect the clinical efficacy of tPA.
Purified α2-M (5.4 mg/ml) protected 16.0% or 22.4% of tPA (12.5 IU/ml) activity from inhibition by PAI-1 at 4 or 8 IU/ml in vitro . Of nine patients treated with 5–20 mega IU of tPA for MI, the plasma activity of tPA remained increased for 15–30 min after the cessation of infusion in eight; the patient who failed to exhibit a persistent increase in tPA activity had a low plasma concentration of α2-M. Total tPA activity, derived from the area under the activity-versus-time curve (AUC), showed a significant inverse correlation with the ratio of the plasma PAI-1 activity to the plasma α2-M concentration. Total tPA activity did not correlate with plasma PAI-1 activity or plasma α2-M concentration alone. Results suggest that α2-M, by binding to tPA, protects the latter against inhibition by PAI-1.     

Venous thrombosis and tissue plasminogen activator release deficiency: a family study

Thrombotic events are often due to fibrinolytic defects such as impaired tissue plasminogen activator (tPA) synthesis and/or release or increased plasminogen activator inhibitor (PAI) levels. In this report we describe four members of a family with a history of recurrent venous thrombosis, who demonstrated defective tPA release after dynamic tests. Two symptomatic patients and one asymptomatic individual showed absent or abnormally low tPA antigen (tPA:Ag) and activity (PA) increases after DDAVP infusion and/or 20 min of venous occlusion. In these patients PAI values were slightly higher than controls. A satisfactory tPA:Ag release was found in the fourth asymptomatic patient. All other coagulation tests were within the normal ranges. This familial defect of the fibrinolytic system seems to be inherited as an autosomal trait.     

The fibrinolytic potential in patients with Cushing's disease: a clue to their hypercoagulable state.

The aim of our study was to determine the fibrinolytic potential in a large group of patients with Cushing's disease. These patients had a significant shortening of the activated partial thromboplastin time and increase in factor VIII/von Willebrand factor complex compared to normal controls. The mean levels of plasminogen, tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor (PAI) activity were significantly higher than in normal subjects, whereas the basal fibrinolytic activity was similar to that seen in the control group. In 17 out of 30 Cushing patients and in 17 normal subjects the fibrinolytic potential was determined with the venous occlusion test. In the Cushing group, the release of t-PA antigen after 20 min of venous occlusion was comparable to that observed in the control group. However, Cushing patients showed a lower fibrinolytic activity than normal subjects, since a lesser shortening of the euglobulin lysis time and a non-significant rise of plasminogen activator activity levels were found. Moreover, in these patients the PAI activity values remained unchanged and significantly increased after venous occlusion test also. In conclusion, the impaired fibrinolytic activation seen in Cushing patients after venous occlusion can be explained by the inhibitory effect of the high PAI levels on plasminogen activators. The defective fibrinolytic potential could further contribute to the hypercoagulable state in Cushing's disease. High PAI levels before surgery may represent an additional risk factor for post-surgical thromboembolic complications in Cushing patients.     

Metformin causes a reduction in basal and post-venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients.

The effects of metformin on the fibrinolytic system were studied pre- and post-venous occlusion in 38 Type 2 diabetic patients in a double-blind, placebo-controlled trial. After a 3-week run-in period, 21 patients received metformin and 17 placebo, for 6 weeks. In the metformin-treated patients basal plasminogen activator inhibitor-1 antigen (PAI-1Ag) fell from 57.4 micrograms l-1 before treatment to 36.1 (p less than 0.05) and 41.0 micrograms l-1 (p less than 0.01) after 3 and 6 weeks therapy. In this group post-venous occlusion PAI-1Ag also fell after 3 weeks (p less than 0.002) and 6 weeks (p less than 0.05) treatment. There were no changes in either basal or post-venous occlusion concentrations of PAI-1Ag in the placebo treated group. The fall in PAI-1Ag was not associated with an increase in basal plasminogen activator activity (PAA) which remained unchanged in both groups. Post-venous occlusion values for PAA in the metformin treated patients were increased at 3 weeks (p less than 0.05) although there was no difference at 6 weeks.     

Effects of imidapril therapy on endogenous fibrinolysis in patients with recent myocardial infarction

Background: Treatment with an angiotensin-con verting enzyme (ACE) inhibitor in patients with myocardial infarction has been shown to modify endogenous fibrinolysis. Hypothesis: We investigated the effects of the ACE inhibitor imidapril on endogenous fibrinolysis in association with the serum ACE activity. Methods: In a randomized, double-blind, placebo-controlled study beginning 4 weeks after uncomplicated myocardial infarction, 15 patients received imidapril (5 mg daily) (imidapril group) and another 15 received placebo therapy (placebo group) for 4 weeks. Blood sampling was performed before the start of administration and on Days 3, 7, and 28 after the start of administration. Serum ACE activity and plasma fibrinolytic variables [plasminogen activator inhibitor (PAI) activity, plasminogen activator inhibitor type 1 (PAI-1) antigen level, and tissue type plasminogen activator (TPA) antigen level] were measured. Results: There was no difference between the imidapril and placebo groups in serum ACE activity or plasma fibrinolytic variables before administration. Serum ACE activity decreased significantly on Days 3, 7, and 28 in the imidapril group. The decrease of PAI activity and PAI-1 antigen levels was significantly less on Days 7 and 28, but not on Day 3. The TPA antigen level in the imidapril group was unchanged. None of the parameters in the placebo group was changed. Conclusion: The ACE inhibitor imidapril modified fibrinolysis, but the effects occurred after the inhibition of serum ACE activity.     

Glycation amplifies lipoprotein(a)-induced alterations in the generation of fibrinolytic regulators from human vascular endothelial cells

Increased lipoprotein(a) [Lp(a)] in plasma is an independent risk factor for premature cardiovascular diseases. The levels of glycated Lp(a) are elevated in diabetic patients. The present study demonstrated that glycation enhanced Lp(a)-induced production of plasminogen activator inhibitor-1 (PAI-1), and further decreased the generation of tissue-type plasminogen activator (t-PA) from human umbilical vein endothelial cells (HUVEC) and human coronary artery EC. The levels of PAI-1 mRNA and its antigen in the media of HUVEC were significantly increased following treatments with 5 μg/ml of glycated Lp(a) compared to equal amounts of native Lp(a). The secretion and de novo synthesis of t-PA, but not its mRNA level, in EC were reduced by glycated Lp(a) compared to native Lp(a). Treatment with aminoguanidine, an inhibitor for the formation of advanced glycation end products (AGEs), during glycation normalized the generation of PAI-1 and t-PA induced by glycated Lp(a). Butylated hydroxytoluene, a potent antioxidant, inhibited native and glycated Lp(a)-induced changes in PAI-1 and t-PA generation in EC. The results indicate that glycation amplifies Lp(a)-induced changes in the generation of PAI-1 and t-PA from venous and arterial EC. This may attenuate fibrinolytic activity in blood circulation and potentially contributes to the increased incidence of cardiovascular complications in diabetic patients with hyperlipoprotein(a). EC-mediated oxidative modification and the formation of AGEs may be implicated in glycated Lp(a)-induced alterations in the generation of fibrinolytic regulators from vascular EC.