Natural inhibitors of fibrinolysis.
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Antibodies, Bacterial↗
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Changes in plasminogen activator inhibitor 1 and tissue-type plasminogen activator during exercise in patients with coronary artery disease.
As depressed fibrinolysis is implicated in the pathogenesis of coronary artery disease, we have studied the activation of fibrinolysis during maximal, symptom-limited exercise in a group of 68 men. After exercise they were divided, according to their coronary angiography and exercise 201Tl emission computed tomography results, into three groups. Group 1: persons with normal exercise 201Tl emission computed tomography results and no underlying diseases who served as controls; group 2: patients with coronary artery disease without exercise-induced myocardial ischemia, and group 3: patients with coronary artery disease with transient, exercise-induced myocardial ischemia. Before and at peak exercise we measured the plasminogen activator activity (PAA) in the euglobulin fraction of plasma by an amidolytic method and the concentrations of tissue plasminogen activator (t-PA), activator-inhibitor complex - plasminogen activator inhibitor 1 (PAI-1) complexed with t-PA - and total PAI-1 by enzyme immunoassay. The concentration of free PAI-1 in plasma was calculated by subtraction of the concentration of activator-inhibitor complex from that of total PAI-1. Under basal conditions, group 3 had significantly higher free and total PAI-1 levels than group 1. There were no statistically significant differences between the three groups in PAA, t-PA, and activator-inhibitor complex levels. At peak exercise, group 1 showed the highest release of t-PA accompanied with highest increases in PAA as well as in activator-inhibitor complex, the proportion of released t-PA antigen not bound to PAI-1 being highest in group 1. Free PAI-1 decreased significantly, but there were no differences between individual groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Evidence for reduced fibrinolytic activity in unstable angina at rest. Clinical, biochemical, and angiographic correlates.
BACKGROUND: The goal of this study was to evaluate the role of the fibrinolytic system in patients with unstable angina at rest associated with transient electrocardiographic changes. METHODS AND RESULTS: Tissue plasminogen activator activity in plasma was comparable among patients with unstable angina (n = 17), patients with stable exertional angina (n = 10), and control patients with normal coronary arteriograms (n = 8). In contrast, plasminogen activator inhibitor-1 (PAI-1) activity in plasma was elevated in the unstable angina group (21.67 +/- 9.52 AU/ml) as compared with either the stable angina group (12.01 +/- 7.06 AU/ml, p less than 0.02) or the controls (12.49 +/- 8.54 AU/ml, p less than 0.02). Coronary angiography performed within 24 hours after the last anginal episode showed a similar extent of coronary artery disease in the unstable and stable angina groups. However, intracoronary thrombi were observed in eight patients in the unstable angina group while no thrombus was noted in the stable angina group (chi 2 = 7.22, p less than 0.01). CONCLUSIONS: We conclude that patients with unstable angina at rest have a reduced fibrinolytic activity and an increased incidence of intracoronary thrombi. It is postulated that elevated PAI-1 activity in the presence of coronary arterial wall injury may be an important factor leading to the development of acute coronary syndromes.
Angina Pectoris↗
Endogenous fibrinolytic system in chronic large-vessel thromboembolic pulmonary hypertension.
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a disorder characterized by pulmonary arterial hypertension as a consequence of organized thrombotic material in the central pulmonary arteries. Incomplete resolution of acute pulmonary emboli is believed to be pathogenically important; however, the mechanism for poor thrombus dissolution remains to be explained. We undertook this study to assess the major determinants of plasma fibrinolysis in patients with CTEPH (n = 32). METHODS AND RESULTS: Immunological and functional levels of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) were quantified in platelet-poor plasma (PPP) from patients with CTEPH as well as age-matched controls. Although basal PPP t-PA antigen levels (CTEPH mean, 29.5 ng/ml; control mean, 2.7 ng/ml) and PAI-1 antigen levels (CTEPH mean, 55.8 ng/ml; control mean, 21.0 ng/ml) were higher in the CTEPH group, no between-group differences were detected in the enzymatic activities of these two molecules. The CTEPH group demonstrated a greater rise in t-PA antigen (CTEPH mean rise, 53.0 ng/ml; control mean rise, 5.6 ng/ml) and PA activity (CTEPH mean rise, 10.5 IU/ml; control mean rise, 1.2 IU/ml) than controls in response to an experimentally induced venous occlusion. Immunoprecipitation and fibrin autography of PPP from two patients with markedly elevated basal t-PA antigen levels demonstrate that the t-PA antigen was present in PPP primarily in complex with PAI-1. CONCLUSIONS: Although abnormalities of the fibrinolytic system were detected, neither a high resting plasma PAI-1 activity nor a blunted response of t-PA to venous occlusion can be invoked as an etiology for CTEPH:
Adolescent↗
Plasminogen activator and plasminogen activator inhibitor in human preovulatory follicular fluid.
To evaluate the roles of plasminogen activator (PA) and PA inhibitor (PAI) in human ovulation, we obtained follicular fluid and granulosa cells from individual preovulatory follicles of patients undergoing gamete intrafallopian tube transfer. The follicular fluid samples (n = 25) were analyzed for total tissue-type PA antigen, PA enzyme activity by fibrin autography, PAI activity, PAI type 1 (PAI-1) antigen, and PAI-1 mRNA. The follicular fluid of preovulatory follicles contained low levels of total tissue-type PA antigen (less than 1 ng/mL). Fibrin autography experiments indicated little or no detectable PA activity associated with free or unbound PA. The results of the PAI activity assay and PAI-1 antigen determination support the concept of a relative abundance of PAI compared with PA. Hybridization analysis was used to measure the relative amounts of granulosa cell PAI-1 mRNA. The levels of PAI-1 mRNA correlate with follicular fluid PAI concentrations in individual follicles. Taken together, these results support the idea that there is very little free, or active, PA in follicular fluid of human preovulatory follicles, but there is an abundance of PAI. Furthermore, PAI-1 produced by the granulosa cells may represent a major form of PAI in follicular fluid.
Antigens↗
Nitration of human plasminogen by RAW 264.7 macrophages reduces streptokinase-induced plasmin activity.
Despite many years of study, clinical trials of new drugs to prevent thrombosis have often been disappointing. Part of the problem lies in our incomplete understanding of the regulation of plasminogen activation and/or inhibition in vivo. We have previously shown that in vitro nitration of plasminogen in plasma by peroxynitrite resulted in decreased plasmin activity. We hypothesized that macrophages may be agents of plasminogen nitration and designed this study to prove this hypothesis. We first better characterized our previous observations using purified plasminogen instead of whole plasma, studied the time and concentration dependence of these reactions, and co-incubated plasminogen with macrophages, as well as with non-inflammatory cells as controls, to assess nitration and impaired activity. When plasminogen (10 micromol/L) is incubated in the presence of SIN-1 (0.01-2 mmol/L), plasmin activity (generated by streptokinase) is reduced in a time- and concentration-dependent fashion. We performed experiments incubating human plasminogen in the presence of murine RAW264.7 macrophages, allowing for free diffusion of reactive oxygen species, while preventing the action of proteases. In this way we show that incubation of plasminogen with macrophages also decreases plasmin activity, while increasing nitration of the molecule, an effect that is already apparent after 2 h and reaches a plateau of 60% inhibition after 24 h of incubation. This effect appears specific for macrophages, since 31EG4 murine mammary cells used in parallel and under the same conditions failed to produce any deleterious changes in plasminogen. Our data on quick functional inactivation of plasminogen by nitration, mediated by macrophages, adds a new pathophysiological dimension to our previous work showing plasminogen as a target for peroxynitrite damage. Nitrosative stress may be implicated in impaired fibrinolysis. New therapeutic approaches for nitrosative stress in atherosclerosis and diabetes should limit the formation of superoxides and peroxynitrite.
Animals↗
Tissue plasminogen activator inhibition in diabetes mellitus.
Depression of fibrinolysis may be relevant to the vascular complications of diabetes mellitus. Plasminogen activator inhibitor (PAI) is an important inhibitor of fibrinolysis in humans, and we have found basal activities of PA inhibition to be elevated in patients with diabetes compared with a reference group of healthy subjects (mean +/- SD 268 +/- 268 vs. 105 +/- 48%; P less than .0001). With a monoclonal antibody, it was shown that high inhibition values were due to PAI-1. No differences in PA inhibition were noted in relation to type of diabetes, diabetic treatment, or presence or absence of vascular complications. Basal PA inhibition did not correlate with in vivo (B beta 15-42 antigen) or ex vivo (fibrin plate) fibrinolytic activity or HbA1. In patients with non-insulin-dependent diabetes mellitus, treatment with the anabolic steroid stanozolol significantly reduced PA inhibition. These findings suggest a further abnormality of fibrinolysis in diabetes, but the lack of a relationship among other measures of fibrinolysis renders its biologic significance uncertain.
Antibodies, Monoclonal↗
Insulin-like growth factor I stimulates proliferation, migration, and plasminogen activator release by human retinal pigment epithelial cells.
The migration of retinal pigment epithelial (RPE) cells from their normal anatomic position to a new position in the vitreous cavity is a critical feature of proliferative vitreous retinopathy. To determine if insulin-like growth factor I (IGF I), which is present in the vitreous fluid of diabetics, stimulates RPE cells, we examined the effects of IGF I on the proliferation, chemotaxis, and release of plasminogen activator by these cells. At the concentrations of IGF I tested, significant proliferation of RPE cells is seen. Significant chemotaxis of the RPE cells also is seen at all the concentrations of IGF I tested. The mean number of migrating cells per high-powered field in control studies was 43 +/- 13 (x +/- SEM), and for IGF I at 2.5 ng and 50 ng/ml the mean numbers of migrating cells were 96 +/- 17 and 483 +/- 62, respectively (P less than 0.001 for each comparison). The IGF I response was noted to be dose-dependent. The chemotactic response noted at 50 ng/ml of IGF I was greater than the positive chemotactic control of 10% fetal calf serum. Addition of alpha IR-3, an IGF I receptor antibody, eliminated the IGF I chemotactic response. The effect of IGF I on the secretion of plasminogen activators was assessed using an immunological assay for tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). Media conditioned by RPE cells have measureable levels of PAI and t-PA antigen. IGF I supplementation resulted in an increase of t-PA secretion and PAI secretion over basal levels. These studies support a role for IGF I in modulating RPE cell function.
Antibodies, Monoclonal↗
Hormonal regulation of the release of plasminogen activators and of a specific activator inhibitor from endometrial tissue in culture.
Two types of plasminogen activator (PA), t-PA (tissue type) and u-PA (urokinase type), are released from endometrial tissue in organ culture, as judged by immunological identification and molecular weight. Addition of estradiol to the medium greatly enhanced the release of u-PA, whereas that of t-PA was not low. Addition of progesterone, on the other hand, after priming of the endometrial tissue with estradiol, resulted in a much lower release of both types of PA. This pattern of PA release in response to hormonal stimulation in vitro agrees with previous observations of the PA activity of endometrial secretion in vivo. Endometrial tissue also released a PA inhibitor with molecular weight of approximately 50,000, which complexed both t-PA and u-PA. In cultures stimulated with estradiol the amount of free u-PA increased gradually during incubation and minor amounts of free t-PA appeared after 4-6 days culture. The amount of complexes, and thus the amount of PA inhibitor also increased under influence of estradiol. In cultures stimulated with progesterone, on the other hand, only minor amounts of free u-PA and no free t-PA was detected. The inhibitor might be of either the endothelial or the placental type, or both.
Culture Techniques↗
Insulin resistance and changes in the blood coagulation-fibrinolysis system after a glucose clamp technique in patients with type 2 diabetes mellitus.
We investigated the relationship between changes in insulin resistance and blood coagulation-fibrinolysis following institution of a glucose clamp (GC) in patients with type 2 diabetes mellitus. We studied 35 type 2 diabetic patients (19 males and 16 females, mean age at 58.3 +/- 11.9 years) and 10 healthy subjects. The hyperinsulinemic euglycemic GC technique was performed using on artificial pancreas. The degree of insulin resistance was determined from the glucose infusion rate (GIR) calculated from the GC technique. The GIR in type 2 diabetic patients was markedly reduced compared to that in healthy subjects. The GIR was significantly and negatively correlated with the body mass index and the serum concentrations of the fasting immunoreactive insulin (FIRI). The plasma concentrations of thrombomodulin (TM) and tissue plasminogen activator (tPA) in the diabetic patients were significantly higher than those in the healthy subjects. The plasma concentrations of plasminogen activator inhibitor 1 in the diabetic patients tended toward higher than those in the healthy subjects. The elevated plasma concentrations of TM and tPA in diabetes were significantly lowered following a GC technique. Patients with advanced nephropathy had significant higher concentrations of TM and tPA compared to healthy subjects. We concluded that diabetic patients have abnormalities in the blood coagulation-fibrinolytic system that can be improved by the GC technique.
Albuminuria↗
[Behavior of parameters of the blood coagulation and fibrinolytic system in patients with peripheral arteriosclerotic angio-organopathy and in patients after acute phlebothrombosis].
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Arteriosclerosis↗
[Influence of aging and circadian fluctuation of fibrinolytic factors to the responses of these factors during venous occlusion test in healthy subjects].
This study was aimed to clarify the influence of aging and circadian fluctuation of fibrinolytic factors to changes of tissue plasminogen (t-PA) and its inhibitor (PAI-I) during venous occlusion test. Venous occlusion was achieved by application of a sphygmomanometer cuff to the upper arm of elderly healthy subjects (n = 12) and young healthy subjects (n = 12) at 10:00 am and 4:00 pm. Plasma concentration of t-PA, free PAI-1 and total PAI-1 were measured by ELISA. The activity of t-PA was measured by bioimmunoassay using monoclonal antibody for t-PA. Circadian variation was observed in the change of t-PA activity and total PAI-1. These were highly increased in the evening. However, this phenomenon was different between age groups and increase of t-PA activity occurred in elderly subjects, whereas PAI-1 was observed in young subjects. In conclusion, circadian variation and the influence of age should be considered to evaluate results of venous occlusion test.
Adult↗
[Effects of chronic mercury poisoning on blood coagulation and fibrinolysis systems].
OBJECTIVE: To investigate the effects of chronic mercury poisoning on blood coagulation and fibrinolysis systems, and the possible mechanism. METHODS: Twenty-seven patients with chronic mercury poisoning were studied with 30 healthy people as control. Thrombomodulin (TM), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI), interleukin-13 (IL-13), interleukin-18 (IL-18), soluble intercellular adhesion molecule-1 (SICAM-1) were examined with ELISA methods, and superoxide dismutase (SOD) and lipid peroxidation (LPO) was examined with chemical catalysis methods. Two to three weeks after treatment with reduced glutathione, tiopronin and daidzein, blood was used for determin the above items again. RESULTS: (1) The concentration of TM in patients [(2.36 +/- 0.16) ng/ml] was significantly lower than in the control [(4.36 +/- 0.24) ng/ml] (P < 0.01), while TM tended to be higher after treatment [(4.82 +/- 0.34) ng/ml] (P < 0.05). (2) The concentration of t-PA in patients [(3.44 +/- 0.34) ng/ml] was significantly lower than in the control [(4.52 +/- 0.16) ng/ml] (P < 0.05), and was higher significantly [(5.63 +/- 0.58) ng/ml] after treatment (P < 0.05); The concentration of PAI in patients [(48.23 +/- 3.59) ng/ml] was significantly higher than in the control [(31.59 +/- 2.13) ng/ml] (P < 0.05), but after treatment no significant change [(50.71 +/- 4.29) ng/ml] was found (P > 0.05). (3) The activity of SOD in patients [(953.85 +/- 9.56) U/g Hb] was significantly lower than in the control [(1,308.75 +/- 10.21) U/g Hb] (P < 0.01), and was higher significantly [(1,217.95 +/- 6.29) U/g Hb] after treatment (P < 0.05); and the concentration of LPO in patients [(9.53 +/- 0.26) nmol/ml] was significantly higher than in the control (P < 0.05), and significantly lower [(7.29 +/- 0.35) nmol/ml] after treatment (P < 0.05). (4) The concentrations of IL-13 [(35.93 +/- 5.28) pg/ml], IL-18 [(28.79 +/- 2.53) pg/ml], SICAM-1 [(603.16 +/- 29.12) ng/ml] were significantly higher than those in the controls (P < 0.05, P < 0.01), but no significant difference was found after treatment. CONCLUSION: Dysfunction of the TM/protein C system and t-PA/PAI system (i.e. the decrease of anti-coagulation activity and the inhibition of the function for the fibrolysis system) may play a key role in the secondary hypercoagulable state induced by chronic mercury poisoning.
Adult↗
Plasminogen activator production by human retinal endothelial cells of nondiabetic and diabetic origin.
The authors examined the effect of insulin-like growth factor 1 (IGF 1), epidermal growth factor (EGF), and acidic fibroblast growth factor (AFGF) on the synthesis by human retinal endothelial cell (HREC) of plasminogen activators (PA; tissue-type [t-PA] and urokinase-type [u-PA]) and plasminogen activator inhibitor (PAI). Immunologic and functional assays for t-PA, u-PA, and PA1 were conducted with cell lines derived from three diabetics and three nondiabetic controls. Confluent HREC of nondiabetic origin did not respond to IGF I (100 ng/ml) with any change of t-PA antigen in the medium (10.7 +/- 1.1 ng/ml unstimulated versus 10.1 +/- 0.8 ng/ml) stimulated, P = not significant). Likewise AFGF and EGF caused no significant change of t-PA levels. Both IGF I and EGF caused a significant increase of t-PA from HREC of diabetic origin (9.6 +/- 0.8 ng/ml unstimulated versus 16.6 +/- 1.9 ng/ml IGF I-stimulated, P less than 0.001, and 14.6 +/- 2.7 ng/ml EGF-stimulated P less than 0.005). Supplementation of AFGF had no effect on HREC of diabetic origin. In confluent cultures, only small quantities of u-PA were detected. After wounding confluent cultures, u-PA activity was associated with cells migrating from the wound edges. Functional PA activity was also measured by chromogenic assay. Results further supported a predominance of t-PA activity being produced by confluent HREC in culture. These results suggest that modulation of PA production by HREC is influenced by exposure to growth factors, by the state of confluency, and the origin of the cells (diabetic vesus nondiabetic).
Aged↗
The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia.
In disseminated intravascular coagulation (DIC) with acute promyelocytic leukemia (APL) in the absence of severe infection, marked fibrinolysis was noted in comparison with normal levels of antithrombin III, which is a major inhibitor of the coagulation system. Increased plasminogen activator inhibitor-1 (PAI-1) antigen levels in plasma from patients with septicemia decreased the ratio of the plasma clot lysis rate induced by an anti-alpha 2-plasmin inhibitor monoclonal antibody to the tissue-type plasminogen activator (t-PA) concentration. This decrease was not as prominent in plasma from patients with DIC, especially those with APL. To explore the character of PAI-1 in these plasmas, we measured the specific activity of PAI-1 by determining the ratio of active PAI-1 antigen to t-PA-unbound PAI-1 antigen. To calculate the amount of active PAI-1 antigen, the amount of t-PA/PAI-1 complex before and after the addition of a fixed amount of t-PA to the sample was measured by a sandwich solid-phase enzyme-linked immunosorbent assay using anti-PAI-1 and anti-t-PA monoclonal antibodies. The assay to measure total PAI-1 antigen used three monoclonal anti-PAI-1 antibodies and had similar sensitivities to free active, latent, vitronectin-bound and t-PA-bound PAI-1. The specific activity of PAI-1 decreased in patients with DIC (43.7% +/- 30.6%) and in DIC cases with APL (10.3% +/- 6.0%) in comparison to patients with septicemia (83.7% +/- 20.2%) or normal controls (85.8% +/- 27.3%). In DIC associated with APL, degraded forms of PAI-1 were detected in plasma by immunoblotting. These results suggest that a decrease in the specific activity of PAI-1 and an increase in secondary fibrinolysis result in a hyperfibrinolytic state in DIC patients with APL.
Antibodies, Monoclonal↗
[Plasminogen activator inhibitors from neoplastic tissues].
This article contains a survey of works, published in the last few years on plasminogen activators inhibitors in neoplastic tissues. These inhibitors belong to a heterogenous group of proteins, having different molecular weights and specific ways of acting. They exemplify immunological relationship to known inhibitors of fibrinolysis from normal tissues--i.e. the inhibitors from endothelial cells--(PAI-1) and placental inhibitor--(PAI-2). To PAI-1 type belong: acid-stabile inhibitor of fibrinolysis with Mr 50,000 from HTC hepatoma cells in rats, acid-labile inhibitor Mr 42,770 produced by HepG2 human hepatoma cells; the inhibitor with Mr 54,000 from HT 1080 human cells from fibrosarcoma and single-chain acid-stabile inhibitor with Mr 50,000 from MJZJ melanoma cells. In PAI-2 type we can mention the inhibitor with Mr 47,000 from U-937 histiocytic lymphoma cells.
Animals↗
A plasma clot lysis assay based on the release of fibrin degradation products: application to the diagnosis of hypofibrinolytic states.
Using a monoclonal antibody-based assay, we measured the fibrin degradation product release in the supernatant of plasma clots obtained before and after venous occlusion (VO) in 30 patients with definite or suspected vascular thrombosis (19 definite and 2 suspected deep vein thrombosis, 6 recurrent superficial thrombophlebitis, 3 arterial occlusions of lower limbs). tPA and PAI-1 concentrations were determined using ELISA assays; the post-occlusion values were corrected for haemoconcentration. The increase in tPA during VO was correlated with haemoconcentration (r = 0.74), but 3 patients had ineffective VO (less than 2% increase in proteins). The fibrinolytic response to VO was evaluated using the shortening of the time necessary for the release of 200 micrograms of fibrin degradation products per mg of fibrinogen (delta T 200). Two among the 27 patients with effective VO were bad responders with a delta T 200 less than 3 h (whereas all the others had delta T 200 greater than 10 h). These patients had respectively a deficient tPA release (delta tPA = 1 ng/ml) and an elevated PAI-1 level at rest (33 ng/ml). Several other patients were bad responders in terms of tPA release or of shortening of the euglobulin clot lysis time but they had a normal delta T 200. This plasma clot test reflects the ability of free tPA to bind to fibrin (the amount of which depends on the level of tPA and PAI-1), and may be useful in the diagnosis of a hypofibrinolytic state.
Adult↗
[Fibrinolytic system and hyperinsulinism].
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Arteriosclerosis↗