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PubMed1991

Regional fibrinolysis following total hip replacement.

The local effect of operative trauma on the fibrinolytic system was studied in ten patients undergoing total hip replacement. Catheters were inserted in the femoral veins on both sides and blood was sampled from these catheters perioperatively. The following fibrinolytic variables were analysed in plasma and related to the different steps of surgery: tissue plasminogen activator (t-PA) activity, t-PA antigen and plasminogen activator inhibitor (PAI-1) activity. During surgery PAI-1 activity and t-PA antigen in the operated limb were significantly increased compared with preoperative values. There was a significant difference in PAI-1 activity and t-PA antigen between the operated and the non-operated limbs during surgery and within one hour postoperatively. During fixation of the femoral implant there was a significant difference between the operated and the non-operated limbs in t-PA activity. Thus the regional fibrinolytic response to trauma was dissociated from the response in the non-operated limb. The clinical relevance of the observed alterations in regional fibrinolysis, as related to thrombogenic mechanisms after hip surgery, remains to be elucidated.

Aged↗
PubMed1991

Gemfibrozil predictably lowers triglycerides but does not significantly change plasminogen activator inhibitor activity in hypertriglyceridemic patients with a history of thrombosis.

Impaired fibrinolysis due to high plasminogen activator inhibitor levels is present in patients with a variety of thrombotic diseases. Plasminogen activator inhibitor levels correlate with triglyceride levels and are elevated in patients with hypertriglyceridemia. Treatment of asymptomatic hypertriglyceridemic patients with diet or medication results in improvement of fibrinolytic parameters. To determine if similar improvements in fibrinolysis occur during treatment of hypertriglyceridemia in patients with a history of venous thrombosis and impaired fibrinolysis due to high plasminogen activator inhibitor levels, 5 patients were given gemfibrozil. Triglyceride levels and fibrinolytic response to venous occlusion were determined before and after 30 days of treatment. Gemfibrozil therapy resulted in a predictable decrease in triglyceride levels in all patients, a reduction that was statistically significant (p = 0.04). There was no significant change in fibrinolytic variables during gemfibrozil therapy. Independent factors appear to control the plasminogen activator inhibitor and triglyceride levels in patients with a history of venous thrombosis.

Cholesterol↗
PubMed1992

Effects of defibrotide on fibrinolytic activity in diabetic patients with stable angina pectoris.

18 type II diabetes mellitus patients with coronary artery disease (CAD) have been studied. Tissue plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor (PAI) antigen and activity, thrombin-antithrombin III (TAT) complexes were determined in blood samples. Diabetic CAD patients showed higher TAT levels with clearly increased PAI levels whereas t-PA levels levels were similar in patients and controls. Long term defibrotide treatment induced marked changes in fibrinolytic parameters of these diabetic patients with CAD with increased t-PA activity, that could be related to an evident reduction of PAI antigen and activity. Drugs able to modulate PAI activity may be useful in clinical conditions at high risk of thrombotic vascular complications like diabetics with stable angina.

Aged↗
PubMed2004

Vitamin E improves fibrinolytic activity in patients with coronary spastic angina.

INTRODUCTION: The fibrinolytic system has a major role as a defense mechanism against thrombus formation. Net fibrinolytic activity in plasma reflects the balance between tissue-type plasminogen activator and plasminogen activator inhibitor (PAI). PAI is the main factor determining overall fibrinolytic activity. MATERIALS AND METHODS: We examined the effects of oral administration of vitamin E, an antioxidant, on fibrinolytic activity and oxidative stress in patients with coronary spastic angina. Forty patients with coronary spastic angina were randomly assigned into two treatment groups, either vitamin E group (alpha-tocopherol acetate, 400 mg/day) or placebo group by means of computerized system. PAI activity and thioredoxin, a marker of oxidative stress, levels were measured before and at the end of 1 month treatment. RESULTS: Before treatment, the levels of PAI activity and thioredoxin were increased in patients with coronary spastic angina as compared with control subjects (n=17) (PAI activity levels: 13.6+/-1.4 vs. 7.6+/-2.2 IU/ml, p<0.05, thioredoxin levels: 22.8+/-1.7 vs. 16.0+/-1.4 ng/ml, p<0.05). In patients with coronary spastic angina, administration of vitamin E decreased both PAI activity and thioredoxin levels (PAI activity levels: 14.7+/-1.7 to 7.5+/-1.6 IU/ml, p<0.01, thioredoxin levels: 23.3+/-2.4 to 15.1+/-2.5 ng/ml, p<0.01), whereas placebo had no effect on these variables. CONCLUSIONS: Oral administration of vitamin E improved fibrinolytic activity and the improvement was associated with a decrease in oxidative stress. Administration of vitamin E is possible to be an effective adjunct therapy of coronary spasm in the absence of coronary atherosclerosis.

Administration, Oral↗
PubMed1988

Fibrinolytic activity and species of plasminogen activator in human tears.

In studies on the fibrinolytic system in human tears, we examined the species and activity of plasminogen activator (PA). In fibrinolysis enzymography, the lytic bands and molecular weights of 64 and 52 kDa, on the fibrin-agarose detector membrane. The dissolved band of 64 kDa was quenched by adding antihuman tissue type-PA (t-PA) IgG to the fibrin-agarose detector membrane, and that of the 52 kDa band was quenched by adding anti-human urokinase type PA (u-PA) IgG. In reverse fibrinolysis enzymography, no inhibitory activity to PA or plasmin was observed on the fibrin-agarose membrane. These findings suggested that t-PA and u-PA coexist and that the PA inhibitor is scanty in human tears. We estimated the fibrinolytic activities of t-PA and u-PA respectively, using anti-human u-PA and t-PA IgG by amidolytic assay. Fibrinolytic activity of t-PA in human tears was 5.2 +/- 1.3 I.U. ml-1 (n = 6), and that of u-PA was 2.8 +/- 0.5 I.U. ml-1 (n = 6). To investigate the origin of PA present in tears, we carried out Todd's fibrinolysis autography and immunohistochemical study. Localization of PA activity and t-PA antigen were confirmed in the corneal epithelial cells and the vascular endothelial cells of the conjunctival vessels. The corneal epithelium and conjunctival vessels may produce PA and play some part in the secretion of PA into tears.

Animals↗
PubMed1989

Plasminogen activator and its inhibitor in the experimental corneal wound.

Anterior keratectomy was performed to 10 eyes of 8 adult rabbits. The animals were killed 3-24 hr after wound closure. The corneas were excised and subjected to histochemical demonstration of urokinase-type plasminogen activator (u-PA), tissue-type PA (t-PA) and plasminogen activator inhibitor [PAI-1) using commercial antibodies. A strong immunoreaction for u-PA, a weaker reaction for PAI-1 and a very weak t-PA-like immunoreaction appeared in the anterior stroma of the wounded area. None of the antisera used showed any immunostaining in the cornea outside the wound. The role of the plasminogen activator-plasmin system in the healing of the corneal wound is discussed.

Animals↗
PubMed1987

Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations.

Increased levels of an endogenous inhibitor of tissue-plasminogen activator (t-PA) have been thought to relate to the genesis of acute myocardial ischemia. To examine the role of the rapid inhibitor of t-PA, plasma samples were analyzed from 75 patients with chest pain syndrome undergoing coronary angiography (mean age 57 years), 24 patients with clinically documented coronary artery disease (unstable angina, positive exercise stress test or previous history of myocardial infarction; mean age 58 years) and 15 young normal subjects (mean age 26 years). Plasma t-PA inhibitor levels were similar in age-matched patients regardless of the absence or presence (and degree) of coronary artery disease. Plasma t-PA inhibitor levels correlated significantly with age (r - 0.46, p less than 0.005), suggesting an age-dependent decrease in fibrinolytic activity. Plasma t-PA inhibitor levels also correlated significantly with serum triglyceride levels (r - 0.60, p less than 0.001), but not with coronary risk factors such as serum cholesterol, diabetes, hypertension, serum uric acid levels or body weight. Association of high levels of inhibitor of t-PA with hypertriglyceridemia may be of importance in the development of coronary thrombosis, especially in elderly patients. Nonetheless, this study does not suggest a pathogenic role of t-PA inhibitor in coronary atherosclerosis.

Adult↗
PubMed1985

Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.

Certain risk factors for myocardial infarction have been linked with disturbances in fibrinolytic activity. The recent development in our laboratory of new sensitive and specific methods for determination of tissue plasminogen activator (t-PA) activity and antigen, as well as the discovery of a new rapid inhibitor of this enzyme, enabled us to study fibrinolytic function in detail in a representative population of postinfarction patients. Seventy-one patients (62 men and 9 women) who had survived a myocardial infarction before the age of 45 were compared with 50 healthy subjects of similar age, three years after the infarction. Low t-PA activity after venous occlusion, mostly explained by high plasma levels of the t-PA inhibitor and to some extent by impaired release of t-PA from the vessel wall, was a frequent finding in the patients. The level of t-PA inhibitor was positively and significantly correlated with levels of serum triglycerides. Our data suggest that reduced fibrinolytic capacity due to increased plasma levels of a rapid inhibitor of t-PA may have pathogenetic importance in myocardial infarction, particularly in patients with hypertriglyceridemia.

Adult↗
PubMed2003

Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors.

Tissue plasminogen activator (tPA), a neuronal as well as the key fibrinolytic enzyme, is found concentrated on demyelinated axons in multiple sclerosis lesions together with fibrin(ogen) deposits. The decreased tPA activity in normal-appearing white and grey matter and lesions of multiple sclerosis is reflected in diminished fibrinolysis as measured by a clot lysis assay. Nonetheless, peptide products of fibrin, including D-dimer, accumulate on demyelinated axons-the result of fibrinogen entry through a compromised blood-brain barrier (BBB). Analysis of tissue samples on reducing and non-reducing polyacrylamide gels demonstrates complexes of tPA with plasminogen activator inhibitor-1 (PAI-1) but not with neuroserpin, a tPA-specific inhibitor concentrated in grey matter. As total tPA protein remains unchanged in acute lesions and the concentration of PAI-1 rises several fold, complex formation is a probable cause of the impaired fibrinolysis. Although the tPA-plasmin cascade promotes neurodegeneration in excitotoxin-induced neuronal death, in inflammatory conditions with BBB disruption it has been demonstrated to have a protective role in removing fibrin, which exacerbates axonal injury. The impaired fibrinolytic capacity resulting from increased PAI-1 synthesis and complex formation with tPA, which is detectable prior to lesion formation, therefore has the potential to contribute to axonal damage in multiple sclerosis.

Adult↗
PubMed1992

Increased plasminogen activator inhibitor and tissue plasminogen activator levels in subjects with electrocardiographic abnormality indicative of ischaemic heart disease: a cross-sectional study in Norsjö, Sweden.

The plasma levels of tissue plasminogen activator (tPA) antigen concentration and plasminogen activator inhibitor (PAI) activity were measured in a random sample of 260 subjects, 30, 40, 50, or 60 years of age. Electrocardiographic Q, ST and/or ST-T changes, suggestive of definite or possible ischaemic heart disease (IHD), were found in 21% of the 50-year-old and 37% of the 60-year-old subjects. As compared to subjects lacking such signs, plasma tPA and PAI levels were significantly increased in the 60-year-old group, and PAI tended to be increased in the 50-year-old group. Previous case-control studies, usually performed at specialized centres and liable to sampling biases, have suggested an association between increased PAI levels and ischaemic heart disease. This cross-sectional population study provides independent data that patients with electrocardiographic signs of IHD have increased levels of both PAI and tPA antigen.

Adult↗
PubMed1992

Stimulation by retinoids of tissue-type plasminogen activator secretion in cultured human endothelial cells: relations of structure to effect.

Retinoic acid induces tissue-type plasminogen activator (t-PA) but not plasminogen activator inhibitor-1 (PAI-1) expression in cultured human umbilical vein endothelial cells (HUVEC). To further investigate the relation between the structure of the retinoids and their ability to induce t-PA synthesis in vitro, 11 analogues were studied in HUVEC culture. The retinoid analogues were classified into one of three groups according to their t-PA-inducing potential. Group 1 showed little induction (0.9- to 1.9-fold after 48 h) at concentrations between 10(-8) and 10(-6) M. Group 2, which includes all-trans-retinoic acid, induced t-PA threefold to fivefold at 10(-6) M but had little effect at 10(-8) M (less than threefold). Group 3, which comprises arotinoid acid (RO-13-7410) and RO-13-6307, induced t-PA antigen secretion fivefold at 10(-8) M. The retinoids of groups 2 and 3 had a terminal carboxyl group and alkyl substitution of the lipophylic head of the retinoid skeleton. The group 3 retinoids also contained an aromatic ring. The t-PA-inducing activity of these third-generation retinoids correlates to some extent with other activities, including regression of papilloma, keratinization in vivo, and clonal inhibition of tumor cell lines in vitro. Some of the retinoids caused a small but significant (up to 1.5-fold at 24 h) increase in PAI-1 antigen secretion. The group 3 retinoids appear to be sufficiently potent inducers of t-PA secretion to warrant further investigation in in vivo animal models.

Cell Survival↗
PubMed1996

Plasminogen activator system in pemphigus vulgaris.

Pemphigus vulgaris (PV) is caused by autoantibodies against desmosomes and is characterized by intra-epidermal blisters. The pathology of PV has been linked with plasminogen activation in lesional epidermis. The plasminogen activator system (PA system) consists of urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), as well as the two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In keratinocytes, uPA binds to a specific cell surface receptor for uPA (uPA-R = CD87) in an autocrine manner. Cell-bound uPA is regulated by PAIs. The central PA system component plasminogen, which is present in plasma and interstitial fluids, is bound to the keratinocyte surface via plasmin(ogen) binding sites, where it can be activated by uPA-R-bound uPA. Cell surface-associated plasmin then mediates pericellular proteolysis. As the topographical organization of the distinct PA system components in lesional epidermis of PV remained elusive, we have performed the present immunohistological analysis of lesional and non-lesional epidermis of PV. In keratinocytes directly involved in the epidermal split formation, plasmin(ogen) was stained in nine of 10 cases, uPA-R and uPA in four of 10 cases and PAI-2 in seven of 10 cases. Together, acantholytic plasmin(ogen)+ keratinocytes appeared in three different phenotypes: uPA-R+/uPA+ and PAI-2+, uPA-R-/uPA- and PAI-2+, as well as uPA-R-/uPA- and PAI-2-. Our findings demonstrate that, in acantholytic keratinocytes of PV, PAs and PAIs appear as differentially regulated components of the PA system.

Adult↗
PubMed1987

Absence of functional activity of tissue plasminogen activator in patients with severe forms of von Willebrand's disease.

Some patients with von Willebrand's disease do not respond to stimuli such as venous occlusion and infusion of a vasopressin analogue DDAVP. In these patients, fibrinolytic activity is not enhanced and von Willebrand's factor is not released into the blood. Skin biopsies and cryostat sections were used to study the fibrinolytic activity of skin vessels and localization of tissue plasminogen activator (t-PA) in three patients with severe form of von Willebrand's disease. On fibrin films, no fibrinolysis developed around the skin vessels of the patients; however, using specific polyclonal and monoclonal antibodies to t-PA, and peroxidase coupled specific IgG, presence of t-PA antigen was demonstrated in endothelial cells (EC) of all of them. In plasma no t-PA activity was detected either before or after venous occlusion although t-PA inhibitor activity was in a normal range. Small amounts of t-PA antigen was measured in blood by ELISA. From these results, it is concluded that in patients with severe forms of von Willebrand's disease, t-PA present in EC is not functional and can not transform plasminogen into plasmin.

Adolescent↗
PubMed1990

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.

Adult↗
PubMed1990

Plasma levels of endothelial-derived haemostatic factors in autoimmune thrombocytopenia and haemolytic anaemia.

The endothelial cell-synthesized haemostatic factors tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI) and von Willebrand factor (vWF) were assayed in a cross-sectional study of patients with immune thrombocytopenia (ITP) (n = 12) and autoimmune haemolytic anaemia (AIHA) (n = 3), and compared with a simultaneously selected contrast group of other hospitalized patients with obscure blood cytopenia at the time of sampling. All three factors were grossly elevated in both the study group and the contrast group. In the autoimmune patient group, the three haemostatic variables were significantly correlated with orosomucoid levels, demonstrating the acute-phase nature of the increased levels of vWF, tPA and PAI. These findings support the view that haemostatic factors of the vessel wall are implicated in the pathophysiology of a wide spectrum of diseases.

Adult↗
PubMed1992

Tissue-type plasminogen activator-mediated activation of plasminogen on the surface of group A, C, and G streptococci.

The interaction of Glu-plasminogen with group A, C, and G streptococci and subsequent formation of surface-associated plasminogen by tissue-type plasminogen activator (t-PA) were studied. Binding of 125I-Glu-plasminogen to streptococci greatly facilitated its activation to 125I-Glu-plasmin by exogenous t-PA, whereas activation in the absence of bacteria took place only slowly. Glu-plasmin formed on the streptococcal surface was further converted to the Lys form. Similar activation and modification took place also in the presence of plasminogen-depleted plasma, containing functional t-PA and plasmin inhibitors, indicating that the surface-associated enzymes were protected against these inhibitors. Lys-plasminogen was 10- to 30-fold more potent than Glu-plasminogen or Glu-plasmin in inhibiting the binding of 125I-Glu-plasminogen to streptococci. This indicated a higher affinity of the Lys form towards plasminogen-binding molecule(s) on the streptococcal surface. The surface-associated plasmin was also enzymically active as judged by digestion of chromogenic substrate S-2251. Surface-associated plasmin activity was observed only when the incubations were carried out in the presence of t-PA and Glu-plasminogen or human plasma as the source of plasminogen. Under these conditions, soluble enzymatic activity was also recovered in the supernatant of group A streptococci. This favors the idea that plasmin can be released from the bacterial surface. The findings provide a mechanism for streptococci to adopt proteolytic activity by binding a host-derived enzyme zymogen on their surface, where the subsequent activation then takes place. The results suggest a role for surface-associated plasmin activity in tissue tropism and tissue invasiveness of streptococci.

Aprotinin↗