L. Mannucci

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.

Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients.

In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome, a multicenter double-blind placebo controlled, parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance. These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion. Gemfibrozil reduced plasma triglyceride levels (P<0.001), whereas it increased free fatty acids (P<0.05) and high density lipoprotein cholesterol levels (P<0.05). In those patients reaching normalization of plasma triglyceride levels (triglyceride reduction > or =50%) (n=15), insulin levels (P<0.05) as well as the insulin resistance index were reduced by gemfibrozil treatment, suggesting an improvement of the insulin resistance index in this patient subgroup. Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization.

Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridaemia

SummaryThe 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.

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.

Effects of aggregating agents and of blood cells on the aggregation of whole blood by impedance technique

In this study the effects of different aggregating agents on platelet rich plasma (PRP) and whole blood (WB) aggregation, as determined by the optical and the impedance method, are evaluated. While the response of PRP to PAF, epinephrine and sodium arachidonate was comparable using the two methods, significantly greater amounts of collagen and ADP were required to obtain 50% aggregation of PRP. In addition, when the response of WB to the aggregation induced by different agents was compared to that of PRP (impedance method), no difference between WB and PRP was detected, with exception for ADP and sodium arachidonate induced aggregation. In vitro data on the aggregation of PRP induced by collagen and ADP in the presence of different concentrations of red cells and of white cells, suggest that WC and RC may affect PRP aggregation only in selected experimental conditions.

Indobufen is a potent inhibitor of whole blood aggregation in patients with a high atherosclerotic risk

The newly developed method, based on the quantitation of changes in electrical impedance, to determine platelet aggregation in whole blood was applied to the evaluation of the effects of Indobufen, a well known inhibitor of platelet rich plasma aggregation. The platelet antiaggregatory activity of the drug after single (200 or 400 mg) and repeated doses (200 mg or 200 mg b.i.d. for 1 week) was determined on whole blood aggregation and thromboxane B2 formation by platelet rich plasma of 16 patients with high risk of atherosclerosis. At 2 hr after the single dose treatments, Indobufen significantly reduced the whole blood aggregation induced by 0.5-2 micrograms/ml collagen. At 24 hr from the intake of the drug the aggregation was significantly inhibited in patients who ingested the 400 mg dose only. As far as the repeated administrations are concerned, it appears that the inhibition of whole blood aggregation and thromboxane B2 formation by platelets reached 12 hr after the last drug administration was comparable to the degree of inhibition achieved 2 hr after Indobufen intake. It is concluded that Indobufen orally administered to patients with high risk of atherosclerosis is a potent inhibitor of whole blood aggregation.

Relationship between fibrinolytic and metabolic variables: a study in patients attending a lipid clinic

We investigated the relationship between plasma levels of metabolic and fibrinolytic variables in 163 fasted patients attending a lipid clinic. Of these patients, 118 had hypertriglyceridaemia (HTG) and 45 had normotriglyceridaemia (NTG). In HTG, basal fibrinolytic activity, ie tissue plasminogen activator (t-PA) activity, was impaired as a result of high plasminogen activator inhibitor type 1 (PAI-1) antigen and activity. Multiple stepwise regression analysis identified insulin and triglyceride levels as independent determinants of plasma PAI-1 levels (R2 = 0.18; P = 0.0001). When the patients were stratified into tertiles according to their levels of triglyceride and insulin, PAI-1 antigen levels were found to increase with rising levels of triglyceride in each insulin tertile. In contrast, the increase of PAI-1 with rising insulin levels was evident in the highest triglyceride tertile. In addition, subjects in the lowest tertile of both triglyceride and insulin had the lowest PAI-1 antigen levels, and subjects in the highest tertile of both triglyceride and insulin had the highest levels of PAI-1. Both basal and stimulated levels of t-PA antigen were significantly higher in HTG than in NTG. Multiple stepwise regression analysis identified triglyceride level as the sole major determinant of t-PA antigen levels (R2 = 0.13; P = 0.00003). The observation that both insulin and triglycerides correlate with PAI-1, whereas triglycerides were involved only in the increased secretion of t-PA, suggests that these two proteins are regulated by different mechanisms.

In Vitro Effects of Iloprost on Platelet Aggregation in Normal and Hypercholesterolemia Subjects

Prostacyclin (PGI2) is a naturally occurring prostaglandin released by vascular tissues, which possesses platelet antiaggregatory and vasodilatory properties [1]. PGI2 interacts with specific receptors on platelets, and it increases intracellular cAMP levels through activation of the adenylate cyclase enzyme [2]. Platelets of patients suffering from pathological conditions associated with increased platelet aggregability displayed, in vitro, reduced sensitivity to the inhibitory effects of PGI2 [3, 4]. Previous studies by our group have shown that in patients with type Ila hypercholesterolemia, higher concentrations of PGI2 were required to inhibit the in vitro-induced platelet aggregation, in comparison with platelets from normolipidemic subjects [5]. The alterations observed in platelets from type Ila patients were not due to differences in the capability of PGI2 to stimulate platelet adenylate cyclase [5].