Biomedical subjects

L Mussoni

Publications and source records attributed to L Mussoni.

At least 37 records · Page 2Linked to original sources

PubMed1994

Association of increased fibrin turnover and defective fibrinolytic capacity with leg atherosclerosis. The PLAT Group.

Patients with peripheral arterial disease have a high risk of death from cardiovascular events. As defective fibrinolysis associated with leg atherosclerosis has been suggested as a predisposing factor, we sought a relation among decreased fibrinolysis, the presence of leg atherosclerosis and the incidence of thrombotic events in a case-control study nested in the PLAT. Fifty-eight patients with coronary and/or cerebral atherothrombotic disease, free of leg atherosclerosis at Doppler examination, were compared with 50 atherosclerotic patients with leg involvement. High D-dimer (153.0 vs 81.3 ng/ml, p < 0.001) and tPA antigen before venous stasis (14.4 vs 11.8 ng/ml, p < 0.03), and low tPA antigen (6.7 vs 15.6 ng/ml, p < 0.01) and fibrinolytic activity released after venous stasis (fibrinolytic capacity: 113.2 vs 281.4 mm2, p < 0.001) were found in patients with leg atherosclerosis. D-dimer and fibrinolytic capacity, in addition to age, were selected by stepwise discriminant analysis as characterizing patients with leg atherosclerosis. Moreover, higher D-dimer and tPA inhibitor characterized patients with leg atherosclerosis who subsequently experienced thrombotic events. These findings constitute evidence of high fibrin turnover and impaired fibrinolytic potential in patients with leg atherosclerosis. Thus impaired fibrinolysis may contribute to the prothrombotic state in these patients.

Aged↗

PubMed1993

Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. The PLAT Group.

A case-control comparison within the framework of the prospective, multidisciplinary PLAT Study was performed to assess whether altered baseline fibrinolytic variables were associated with an elevated risk of ischemic thrombotic events in patients with documented coronary, cerebral, and/or peripheral atherosclerotic disease. Fibrinogen, D-dimer, tissue plasminogen activator (t-PA) antigen, and fibrinolytic activity before and after venous stasis (delta = difference between the two values), t-PA inhibitor, and lipid levels in 60 atherosclerotic patients with a thrombotic event during the first year of follow-up were compared with those in 94 atherosclerotic patients without such events, who were matched for age, sex, and diagnosis at enrollment. Events were associated with a higher release of delta t-PA antigen (P = .047), higher D-dimer (P = .024), and higher t-PA inhibitor (P = .001) levels. delta Fibrinolytic activity was correlated inversely with t-PA inhibitor (P < .01) and triglycerides (P < .05). D-Dimer was also correlated with systolic blood pressure (P < .01). Atherosclerotic patients at higher risk of thrombotic ischemic events are characterized by increased fibrin turnover and impaired fibrinolytic activity due to high t-PA inhibitor levels. This hemostatic disequilibrium may participate with conventional risk factors such as elevated triglyceride levels and systolic blood pressure in the multifactorial mechanism of ischemic sequelae in patients with preexisting vascular atherothrombotic disease.

Aged↗

PubMed1993

Increased synthesis of plasminogen activator inhibitor-1 by cultured human endothelial cells exposed to native and modified LDLs. An LDL receptor-independent phenomenon.

The effects of native and acetylated low density lipoproteins (LDLs and acetyl-LDLs, respectively) on the release of plasminogen activator inhibitor type 1 (PAI-1) by cultured human umbilical vein endothelial cells (ECs) were evaluated. LDL and acetyl-LDL incubated with ECs for 16-18 hours increased the PAI-1 antigen levels in conditioned medium. At a concentration of 100 micrograms/mL, LDL and acetyl-LDL increased PAI-1 by 10.8 and 12.0 ng/mL, respectively (p < 0.05 and p < 0.01 versus control). The increases in PAI-1 antigen levels exerted by the lipoproteins paralleled the changes in PAI-1 activity. The effect of LDL and acetyl-LDL was concentration dependent and specific for PAI-1 because tissue-type plasminogen activator and expression of procoagulant activity were not affected by either lipoprotein. In addition, total protein synthesis evaluated in [35S] methionine-labeled ECs was not affected, and studies with cycloheximide showed that the effect of LDL and acetyl-LDL on PAI-1 release was due to de novo protein synthesis. Experiments using the C7 monoclonal antibody against the LDL receptor and binding-defective LDL indicated that the effect of LDL on the synthesis of PAI-1 was not dependent on the interaction of the LDLs with their specific receptors. Finally, extensive oxidation of LDL prevented and even reversed the effect of LDL on PAI-1 release by ECs. It is concluded that LDL specifically increases the synthesis of PAI-1 by ECs with mechanisms that are not receptor mediated.

Cells, Cultured↗

PubMed1993

Effect of atherogenic lipoproteins on PAI-1 synthesis by endothelial cells.

Cultured human umbilical vein endothelial cells (EC) exposed to native and acetylated low density lipoproteins (LDL and acetyl-LDL) show an increased synthesis of PAI-1. Confluent EC monolayers were incubated for 16-18 hours in medium 199 with or without different concentrations of LDL and acetyl-LDL and PAI-1 antigen levels were measured in conditioned medium. LDL and acetyl-LDL increased the release of PAI-1 by EC in a concentration-dependent manner. The effect was specific for PAI-1 because tissue type plasminogen activator (t-PA) and expression of procoagulant activity were not affected by either lipoprotein. The observation that native and acetyl-LDL, which are known to interact with different receptors on EC, exert the same stimulatory effect on PAI-1 release rules out the possibility of an involvement of the LDL receptor in mediating this effect. Experiments carried out incubating native LDL in the presence of a monoclonal antibody against LDL receptor and using binding-defective LDL with a reduced affinity for the LDL receptor (approximately 50% with respect to normal LDL) further excluded an involvement of the classical LDL receptor in mediating the effect of the lipoproteins on PAI-1 synthesis by EC.

Arteriosclerosis↗

PubMed1992

Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridaemia.

The effects of bezafibrate 400 mg/day (slow release formulation) on plasma lipids/lipoproteins and on selected haemostatic parameters were evaluated in a double blind cross-over study in patients with Type IIb and IV hyperlipoproteinaemia. Placebo treatment did not influence any of those parameters, but the drug significantly reduced plasma triglycerides (-45%) and VLDL cholesterol, as well as causing a 12% fall in total cholesterol and a 20% increase in HDL cholesterol. Apo AI levels were significantly increased following bezafibrate and Apo B was reduced by about 20%. In addition to changes in the plasma lipid profile, bezafibrate reduced the sensitivity of platelets to the aggregatory effect of collagen, with no effect on TXB2 production. Fibrinogen levels after bezafibrate treatment were significantly lowered, the effect being more marked in patients with hyperfibrinogenaemia. Bezafibrate did not influence the plasma fibrinolytic profile. It is concluded that bezafibrate, besides its beneficial effects on the plasma lipoprotein profile, can exert beneficial changes on specific haemostatic parameters.

Adult↗

PubMed1992

Treatment with low dose metformin in patients with peripheral vascular disease.

Low dose metformin (500 mg b.i.d.) was tested in 11 patients with symptomatic peripheral vascular disease (PVD) in an open design. At -1, 0, 1, 4, 7 months the major lipid and lipoprotein parameters, arterial function, and fibrinolytic activity were monitored. Arterial function changes were similar to those found with a high dose (850 mg t.i.d.) metformin but plasma lipids did not change to an appreciable extent. Post-ischaemic blood flow, by plethysmography, rose 30%; the exercise capacity, evaluated by treadmill test, also increased significantly by 105.7% for relative and 53.3% for absolute claudication. Total fibrinolytic activity did not change during the treatment but the antigens of two of the major components of the fibrinolytic system, i.e. t-PA and PAI-1, were significantly reduced at the end of the study. This study gave results quite consistent with those obtained with higher metformin doses, associated with a potentially higher risk of lactic acidosis.

Aged↗

PubMed1992

Hypertriglyceridemia and regulation of fibrinolytic activity.

A relation between elevated triglyceride (TG) levels and alterations of the fibrinolytic system has been recognized in studies of patients with coronary heart disease. In this investigation, the total fibrinolytic activity and the levels of specific components of the fibrinolytic system were evaluated in plasma samples from a highly selected group of patients with type IV hyperlipoproteinemia before and after a dietary treatment aimed at reducing TG levels. The fibrinolytic response of type IV patients was comparable to that of normolipidemic subjects, whereas tissue-type plasminogen activator antigen levels before and after venous occlusion (p less than 0.01) and resting plasminogen activator inhibitor-1 (PAI-1) antigen (p less than 0.01) and activity (p less than 0.01) were significantly higher in hypertriglyceridemic subjects compared with controls. After dietary treatment, a 22% reduction in TG levels was attained in type IV patients, with no appreciable modification of fibrinolytic parameters. The analysis of the single-patient data revealed a tendency toward normalization of PAI-1 levels only in those patients who showed a TG reduction greater than or equal to 20%. Very low density lipoproteins (VLDLs) from both normal and type IV patients concentration-dependently stimulated PAI-1 release by endothelial cells and HepG2 cells, with the effect of VLDL from type IV patients being more pronounced on HepG2 cells. The release of PAI-1 induced by VLDL in competent cells may thus account for the elevated levels of this antifibrinolytic protein that occur in hypertriglyceridemic patients.

Adult↗

PubMed1990

Decreased fibrinolytic activity in juvenile chronic arthritis.

The basal fibrinolytic activity in 17 children with active juvenile chronic arthritis (JCA) was investigated. It was found that patients with JCA, and particularly those with the systemic form, show decreased plasma fibrinolytic activity and a marked increase in plasminogen activator inhibitor. Additionally, it was found that patients with systemic JCA, but not those with the polyarticular or pauciarticular form, have increased circulating levels of tissue-type plasminogen activator, and endothelial cell protein, suggesting possible endothelial cell participation in systemic JCA.

Arthritis, Juvenile↗

PubMed1989

Increased expression of urokinase mRNA in bovine aortic endothelial cells treated with propranolol.

Propranolol, a beta-adrenergic blocker agent widely used in a number of cardiovascular disorders, increases plasminogen activator (PA) activity in confluent bovine aortic endothelial cells (BAEC). This effect is time and dose dependent (10-100 microM). Hybridization studies with specific cDNA showed that propranolol was able to induce an increase in urokinase mRNA expression in a dose and time dependent manner. The propranolol effect seems to be specific for urokinase mRNA, because it does not affect a-actin mRNA expression. Cycloheximide, similarly to propranolol, also increases urokinase mRNA, indicating that the gene expression may be regulated by some rapidly turning over protein. When compounds were used in combination, a superinduction phenomenon was observed.

Animals↗

PubMed1989

The inhibitory effect of aspirin on fibrinolysis is reversed by iloprost, a prostacyclin analogue.

The reduced fibrinolytic response after aspirin intake may be due to prevention of prostacyclin production. The effect of iloprost (a stable prostacyclin analogue) was tested on the fibrinolytic activity (euglobulin lysis area on fibrin plate [E.L.A.], t-PA antigen, PAI activity and PAI-1 antigen) of plasma drawn after venous stasis test from six healthy male volunteers, who each received all the following treatments according to a single-blind randomized cross-over design: placebo, iloprost, aspirin + placebo, aspirin + iloprost. The mean E.L.A. value after venous occlusion was significantly higher than the basal level after every treatment but aspirin. Within each treatment group the t-PA antigen levels in response to venous stasis were significantly higher than the basal ones. PAI-1 antigen levels did not change significantly before and after venous stasis either within or among the treatment groups. These data are consistent with the hypothesis that the mechanism related to aspirin's effect on fibrinolysis is mediated by suppression of vessel wall prostacyclin production. Aspirin's inhibitory effect on fibrinolysis was in fact prevented by replacing endogenous prostacyclin with iloprost. Iloprost enhances fibrinolytic activity reduced by aspirin, but not by promoting t-PA release or by inhibiting release of the specific inhibitor, PAI-1.

Adult↗

PubMed1989

Tissue-type plasminogen activator release in response to epinephrine in perfused rat hindlegs.

We have studied the mechanism of release of plasminogen activator (PA) activity induced by epinephrine in the perfused rat hindleg model. Epinephrine perfusion at the dose of 12.5 microM caused a slighter effect on PA activity but an immediate increase in the perfusion pressure. At 25 microM, epinephrine induced a marked increase in PA activity that reached the maximum level at the end of the drug perfusion. The same response was induced by repeated stimulations with epinephrine (25 microM) only if the second stimulus was given 20-25 min apart from the first one. PA release could be blocked by propranolol (300 microM), a nonspecific beta-blocker, and not by phentolamine, a nonspecific alpha-blocker, unless used at very high concentrations (1,250 microM). Perfusion with dibutyryl adenosine 3',5'-cyclic monophosphate (DbcAMP) alone induces an immediate and transient increase in PA activity, but no potentiation could be demonstrated if theophylline was perfused together with epinephrine. The released PA has been characterized on the basis of molecular weight and immunological criteria as t-PA- and u-PA-like molecules in basal conditions. Epinephrine perfusion induced an increase only in the t-PA-like protein. These data indicate that the release of t-PA-like activity observed after epinephrine perfusion is mainly mediated by beta-receptors and is independent from its vasoactive action.

Animals↗

PubMed1989

Possible mechanisms of fibrin deposition in the hypereosinophilic syndrome.

Patients with the hypereosinophilic syndrome (HES) are at increased risk of thrombosis and have signs of fibrin deposition in the myocardial cavity; the pathogenesis of these complications is still unknown. We have studied a 51-year-old man affected by HES with heart, lung, skin, and gastrointestinal involvement. Routine laboratory parameters of the hemostatic system were normal with the exception of blood fibrinolytic activity. The latter was evaluated by both diluted blood clot lysis time and euglobulin lytic activity on fibrin plates before and after 10 min venous occlusion. The fibrinolytic activity measured on four occasions during a 3-month period, was impaired both in basal conditions and following venous occlusion. Platelet studies on two different occasions before and during therapy showed spontaneous platelet aggregation, lowered threshold concentrations of various aggregating agents, reduced platelet regeneration time and increased plasma beta-thromboglobulin concentration. The patient's polymorphonuclear cells (more than 75% eosinophils) were devoid of any procoagulant activity (PCA). Instead, patient's mononuclear cells studied before therapy generated significantly higher PCA on stimulation by endotoxin than cells from control subjects. The procoagulant response to endotoxin decreased markedly during therapy. The observed abnormalities could, at least partially, contribute to fibrin deposition in HES.

Blood Coagulation Factors↗

PubMed1989

Catecholamines do not induce fibrinolytic activity increase in cultured bovine endothelial cells.

This study has investigated the catecholamine involvement in the fibrinolytic modulation of cultured bovine aortic endothelial cells (BAEC). Adrenaline and isoproterenol, at concentrations ranging from 10 to 100 microM, were unable to modulate the fibrinolytic response of these cells. beta-Adrenergic binding studies using 3H-CGP 12177 as radioligand evidenced the presence of about 23,113 +/- 2,065 sites/cell, with a KD of 1.23 +/- 0.29 nM. Isoproterenol stimulated cAMP accumulation at concentrations ranging from 1 to 100 microM, with a maximal accumulation of 30 pmol/10(6) cell. Hence, in our experimental conditions BAEC, although possessing functional beta-adrenergic receptors, were unable to increase any fibrinolytic activity in response to catecholamines.

Animals↗

PubMed1988

Defective fibrinolytic response in atherosclerotic patients--effect of iloprost and its possible mechanism of action.

Plasma fibrinolytic activity and tissue-type plasminogen activator (t-PA) were defective in response to venous stasis in five out of ten patients with peripheral occlusive artery disease. Discontinuous infusions of iloprost, a stable synthetic analogue of prostacyclin, restored a normal fibrinolytic response in all five patients but did not induce a parallel increase of plasma t-PA. These findings suggest that in addition to the possible benefits due to its vasodilatory and antiplatelet activity, iloprost may improve the fibrinolytic activity in patients with atherosclerotic disease, providing them with further antithrombotic protection. The profibrinolytic effect of iloprost seems not to depend on its ability to induce vascular t-PA release. Rather, it might be related to its inhibitory effect on PAI release from platelets, endothelial cells and/or hepatocytes. Venous occlusion test represents an easy diagnostic approach to fibrinolytic defects, even if related to arterial disease, and may help select patients who need therapeutic intervention.

Adult↗

PubMed1988

Macrophages associated with murine tumours express plasminogen activator activity.

The fibrinolytic activity of cancer cells has been repeatedly implicated in mechanisms of local spread and tumour invasiveness. Mononuclear phagocytes associated with solid tumours might also contribute to fibrin dissolution at the tumour/host interface through the expression of plasminogen activator (PA) activity. We have investigated the PA activity of tumour-associated macrophages (TAM) from 4 transplanted murine tumours in syngeneic hosts; peritoneal macrophages (native and thioglycolate-elicited) from both tumour-bearing and control animals were studied as reference cells. TAM from 3 tumours (MSV, mFS6, MN/MCAI) had basal levels of PA activity (20% plasminogen-independent) comparable to or higher than those of thioglycolate-elicited peritoneal macrophages from the same tumour-bearing animals. TAM isolated from 1 tumour (MS2) had a PA which was very low (60% plasminogen-independent), but higher than the activity of unstimulated peritoneal macrophages. Molecular analysis of PA by SDS-PAGE electrophoresis and fibrin autography revealed in all macrophages a single species having an apparent MW of 48 kDA. It thus appears that, in some experimental neoplasms, tumour cell vicinity may represent an in vivo stimulus for macrophage PA expression.

Animals↗

PubMed1988

Expression of plasminogen activator as a marker of stimulation in tumor-associated macrophages.

Tumor-associated macrophages (TAM) are a peculiar subpopulation of resident phagocytes with activities possibly important at the tumor host interface. Among these activities the production of proteases could obviously influence tumor cell detachment and migration from the primary. We have evaluated the expression of plasminogen activator (PA) in different types of murine tumors with differing immunogenic capacity. In TAM from all tumors studied the expression of PA was markedly greater than that of resident peritoneal macrophages. The fact that PA was similarly enhanced in peritoneal macrophages responding to a standard stimulation (thioglycolate) and in TAM suggests that the expression of PA is part of a more general cellular inflammatory response to injury.

Animals↗

PubMed1987

Depressed fibrinolysis in patients with acute leukaemia.

The fibrinolytic system was studied in 46 patients with acute leukaemia at diagnosis. Untreated patients (with the sole exception of the M3 subgroup) showed an inhibition of fibrinolytic activity, measured by the euglobulin lysis time and area. This inhibition was accompanied by reduced t-PA antigen and t-PA inhibitor activity. No correlation was found between the above-mentioned fibrinolytic parameters and the biochemical haematological values considered, nor with clinical and/or laboratory features of DIC, fever, liver failure. The decrease in immunological plasminogen and functional alpha 2-antiplasmin, showed a significant correlation with the presence of clinical and/or laboratory signs of DIC, as diagnosed on the basis of concomitant increase in fibrin monomers, plasmatic fibrinopeptide A and serum FDP.

Adolescent↗

PubMed1987

Modulation of endothelial cell functions by different molecular species of interleukin 1.

Different molecular species of interleukin 1 (IL 1) were examined for the spectrum of responses elicited in human endothelial cells (HEC), including synthesis of prostacyclin (PGI2), tissue-type procoagulant activity (PCA), platelet activating factor (PAF), and plasminogen activator inhibitor (PA-I). The IL 1 preparations utilized for the present study included a natural, partially purified IL 1, a preparation purified to homogeneity with extensive homology with the derived aminoacid IL 1 beta (pI7) sequence denominated "22K factor," murine recombinant IL 1 alpha, human recombinant IL 1 alpha (pI5) and beta (pI7). Natural, partially purified IL 1, a mixture of alpha and beta species, induced the entire spectrum of responses in HEC. Production of PA-I was elicited by all forms of IL 1 tested. PGI2 and PCA were elicited by "22K factor" and by human recombinant IL 1 beta and alpha but not by murine recombinant IL 1 alpha. PAF synthesis was stimulated by murine and human recombinant IL 1 alpha but not by human recombinant IL 1 beta and 22K factor. Thus the available different molecular forms of IL 1 elicit largely but not completely overlapping patterns of responses in HEC. The IL 1 pathway of regulation of HEC functions might provide a basis for novel strategies in therapeutically oriented research on vessel wall disorders.

Blood Coagulation↗