Dilute blood clot lysis time and electrophoretic lipoprotein fractions in a population sample of healthy Romanians.

Serum total lipids and cholesterol, electrophoretically determined lipoprotein concentrations, serum pseudocholinesterase and dilute blood clot lysis time were determined in 630 healthy subjects (287 men and 343 women) aged 20-60, working in the food industry. A high incidence of over-weight was noted ranging from 22.4% in women aged 20-40 to 58.7% in men aged 41-60. Over-weight subjects presenting higher levels of serum cholesterol, total lipids and of the pre-beta electrophoretic fraction also had a higher pseudo-cholinesterase activity and a more delayed clot lysis time than normal-weight subjects matched as to age and sex. When the material was divided into quintiles for pre-beta- and beta-lipoproteins, a highly significant delay of fibrinolysis was noted in the fourth and fifth quintiles for pre-beta-lipoproteins, but no significant changes of lysis time occurred with increasing concentrations of beta-lipoproteins. Possible explanations of the abovementioned findings are briefly discussed.

Effects of some benzodiazepine derivatives on Triton WR-1339-Induced hyperlipidaemia in rats.

Oral administration of the benzodiazepines (diazepam, lorazepam, chlordiazepoxide, bipotassium chlorazepate) in Triton WR-1339-induced (200 mg/kg, blood collection 18 h later) hyperlipidaemia in rats elicited marked decrease of serum total lipids, total cholesterol and triglyceride levels, and alterations in free fatty acid and free glycerol content. The optimal doses for diazepam, lorazepam, chlordiazepoxide and bipotassium chlorazepate were estimated to be 5 mg/kg. Other benzodiazepines, namely oxazepam, medazepam and nitrazepam, elicited only minor changes in serum lipids levels, while with grandaxin no change was observed. The optimal doses of diazepam and lorazepam brought about the same changes in serum lipid content as did clofibrate (90 mg/kg, p. o.). If diazepam, lorazepam, chlordiazepoxide and bipotassium chlorazepate were administered in doses of 5 mg/kg in Triton WR-1339-treated rats (blood collection taken 3 h later), a significant decrease of total lipids and triglyceride levels was observed. The free glycerol level only altered after the administration of chlordiazepoxide, which brought about a significant reduction.

Alpha 2-antiplasmin, plasminogen activator inhibitor (PAI) and dilute blood clot lysis time in selected disease states.

This paper is an attempt to assess the relevance of the inhibitors of fibrinolysis for clot lysis in selected disease states and to discuss the mechanisms leading to acquired abnormal levels of such inhibitors. When compared to 20 control subjects the 30 hypertriglyceridemic patients (14 with type IIb and 16 with type IV) displayed significantly (p less than 0.001) increased plasma plasminogen activator inhibitor (PAI) activity (221 +/- 88% and 290 +/- 104% respectively; mean +/- SD), moderately (p less than 0.01) increased alpha 2 antiplasmin (alpha 2AP) level (112 +/- 11% and 115 +/- 16%) and accordingly an obviously prolonged dilute blood clot lysis time (DBCLT). Neither PAI activity and alpha 2AP level nor DBCLT were significantly different from controls in the 10 patients with hyperlipoproteinemia type IIa. The 18 patients with severe hepatic cirrhosis had low alpha 2AP level (59 +/- 19.7%) and accelerated clot lysis, while mean PAI activity (160 +/- 87%) was slightly (p less than 0.05) increased. In the 17 nephrotic patients alpha 2AP was increased (115 +/- 12%) while PAI activity was similar to controls and DBCLT rather shorter. Two liver secretion enzymes, namely serum cholinesterase and plasma protein C, were found to be decreased in cirrhotic patients, similar to control values in hyperlipoproteinemia type IIa and obviously increased in nephrotic patients as well as in hypertriglyceridemic subjects. The relevance of PAI and alpha 2AP for clot lysis was considered in relation to data in the literature concerning the behaviour of t-PA and factor XIII.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased ristocetin-cofactor in acute myocardial infarction: a component of the acute phase reaction.

When compared to the values obtained in healthy normal-weight, normolipemic controls, the plasma level of ristocetin-cofactor (VIII:R-cof.) was found to be much higher in patients with acute myocardial infarction and in postoperative conditions (4--5 days after a major surgical intervention). A lesser increase of VIII:R-cof. was noted in atherosclerotic patients without acute occlusive accidents and no significant changes of this plasma factor could be observed in hyperlipemic subjects without obvious clinical atherosclerosis. Serial studies emphasized a tendency towards normalization of plasma VIII:R-cof. as the acute phenomena of a myocardial infarction subsided. The above mentioned data suggest that the high levels of VIII:R-cof. recorded in myocardial infarction are mainly caused by a systemic acute phase reaction and to a lesser extent by endothelial damage. Delayed clearance of VIII:R-cof. subsequent to a hepatic dysfunction or to a modified pattern of protein metabolism during the above mentioned acute phase reaction might also contribute to the high level of this plasma factor.

Plasma factor XIII and platelet factor XIII in hyperlipaemia.

Plasma factor XIII activity measured by a quantitative assay was found to be significantly higher in hypertriglyceridaemic patients (type IV and combined hyperlipoproteinaemia), as compared to normolipaemic controls. No such elevation in plasma factor XIII activity was found in patients with type Ha hyperlipaemia. Plasma pseudocholinesterase was found to parallel the elevated factor XIII activity in hypertriglyceridaemic subjects. In contrast, platelet factor XIII activity was not raised in hyperlipaemic subjects, and plasma factor XIII was found to be normal in a normolipaemic subjects with thrombocythaemia. It was concluded that there is no significant contribution from platelets to plasma factor XIII activity, and that the observed increase in plasma factor XIII in hypertriglyceridaemia results from enhanced hepatic synthesis of the enzyme.

Tissue-type plasminogen activator (t-PA) and dilute blood clot lysis time in nephrotic patients.

When compared to normal weight normolipidemic control subjects, dilute blood clot lysis time was found to be obviously (p less than 0.001) prolonged in hypertriglyceridemic patients without proteinuria and slightly (p less than 0.05) accelerated in hyperlipidemic nephrotic patients in spite of their very high levels of plasma fibrinogen. As a result the ratio plasma fibrinogen (mg/dl) per clot lysis time (minutes) was 1.241 +/- 0.08 (X +/- SEM) in control subjects, 0.574 +/- 0.07 in hypertriglyceridemic patients and 2.69 +/- 0.172 in nephrotic patients. This finding suggesting that a larger amount of fibrin is rather readily dispersed from dilute blood clots of nephrotic patients was associated with higher levels of plasma t-PA:Ag (9.45 ng/ml +/- 1.18 in nephrotic patients versus 5.8 ng/ml +/- 1.23 in controls before venous occlusion and respectively 33.1 ng/ml +/- 3.83 versus 20.3 +/- 3.40 in controls after venous occlusion). Plasminogen activator activity of the euglobulins as assessed by the bovine fibrin-agarose plate was significantly higher in nephrotic patients only after venous occlusion. Plasma samples of nephrotic patients exerted a more potent inhibition of fibrinolysis in a urokinase activated system. This effect was, however, mainly due to the high levels of alpha 2 macroglobulin in nephrotic plasma which apparently have little influence on dilute blood clot lysis time.

Comparative behaviour of the components of the factor VIII complex in acute myocardial infarction.

The three components of the factor VIII complex: VIII coagulant (VIII:C), VIII related antigen (VIII R:Ag) and the VIII related von Willebrand factor (VIII R:WF) were studied in patients with acute myocardial infarction (AMI). Using a carefully standardized technique for the determination of VIII R:WF, a significantly higher R:WF level was found in 32 patients compared to 19 control subjects, confirming our previous results. However VIII R:AG was increased to an even greater extent, resulting in a VIII R:Ag/VIII R:WF ratio of 1.58 +/- 0.084 in patients, compared to 1.21 +/- 0.045 in controls. A similar increase of the VIII R:AG/VIII:C ratio was noted in the 13 patients in whom VIII:C was investigated. In 7 patients with severe AMI who could be investigated twice the plasma levels of both VIII R:Ag and VIII R:WF were found to be lower a week after the acute event than during the first 48 hours. However the VIII R:Ag/VIII R:WF ratio was not significantly reduced after 7 days. Acute phase reaction and endothelial injury resulting in release of multimers which are less polymerised are probably involved in the above changes.

Similar behaviour of lecithin:cholesterol acyltransferase and pseudocholinesterase in liver disease and hyperlipoproteinemia.

Using exogenous substrate for its assay, lecithin:cholesterol acyltransferase (LCAT) was found to be decreased in liver disease and higher than normal in endogenous hypertriglyceridemia. LCAT activity was positively correlated with serum cholesterol and triglyceride. However in the six patients with excessive hypertriglyceridemia (type V), LCAT activity was lower than in type IV hyperlipoproteinemia. LCAT activity was not changed significantly in type II-a hyperlipoproteinemia. A striking parallel was noted between plasma LCAT and serum pseudocholinesterase activity. It suggested that both these liver secretion enzymes might be induced by an accelerated turnover of serum lipids and lipoproteins. Pathogenical implications of these findings are briefly discussed.

Increased serum gamma-glutamyltransferase in hypertriglyceridemia: comparison with serum pseudocholinesterase.

Both gamma-glutamyltransferase (gammaGT) and pseudocholinesterase (PCE) were found to be increased in hypertriglyceridemic subjects. High values of gammaGT were noted in alcoholic subjects and especially in those with either increased serum triglyceride or alanine aminotransferase higher than 16 mU/ml, while PCE was not significantly changed in alcoholic subjects. Although both enzymes were strongly correlated with the logarithm of serum triglyceride and the prebeta electrophoretic fraction, there were striking differences concerning their behavior in various hypertriglyceridemic subjects. PCE activity was high even in moderate hypertriglyceridemias but its correlation with serum triglyceride had a tendency to flatten with increasing concentration of triglyceride. However, increase of gammaGT was rather characteristic for gross hypetriglyceridemia. Short-term, triglyceride-lowering therapy was accompanied by a tendency to normalization of gammaGT, while PCE values were not influenced. An attempt was made to interpret these changes of serum-enzyme activity in hypertriglyceridemia in connection with mechanisms of lipoprotein synthesis and with the pathogeny of hyperlipemic conditions.

Increased plasma antithrombin III level in hyperlipidemic subjects.

When compared to values obtained in healthy normolipidemic normal weight control subjects, the plasma antithrombin III level determined by immunological, clotting and thrombin-agarose diffusion techniques was found to be obviously decreased in patients with decompensated cirrhosis of the liver and slightly but significantly increased in hyperlipidemic and especially in hypertriglyceridemic subjects. Plasma antithrombin III was positively correlated with serum cholesterol level, the logarithm of serum triglyceride concentration and serum pseudocholinesterase activity. A weaker correlation between plasma fibrinogen and antithrombin III was noted in the investigated clinical material. It is suggested that the accelerated fatty acid and lipoprotein turnover occurring in many subjects with type IIb and type IV hyperlipoproteinemia might be accompanied by an enhanced hepatic protein synthesis involving various liver secretion enzymes and clotting factors as well as antithrombin III.

Serum pseudocholinesterase and ceruloplasmin in various types of hyperlipoproteinemia.

Starting from previous observations emphasizing an increased pseudocholinesterase (PCE) activity in obese and hyperlipemic subjects, the behaviour of this enzyme and of ceruloplasmin was studied in connection with changes of serum lipids and lipoproteins in various types of hyperlipoproteinemia. When compared to values detected in 67 middle-aged normal weight normolipemic subjects, PCE activity was found to be significantly greater (smaller than 0.001) in the 49 overweight subjects without obvious hyperlipemia but presenting a moderate increase of the prebeta electrophoretic fraction. PCE activity was much higher in lean or overweight subjects with endogenous hypertriglyceridemia (68 patients with type IV and 86 patients with mixed hyperlipemia). The slight increase of mean values of PCE activity in the 53 subjects with type II-a was due mainly to overweight subjects, while this enzyme's activity was not significantly changed in lean subjects with pure hypercholesterolemia. PCE activity was positively correlated with serum triglyceride (r equals 0.540; p smaller than 0.001) and the prebeta electrophoretic fraction (r equals 610; p smaller than 0.001). The correlation with beta-lipoproteins was not significant. Ceruloplasmin levels were not significantly changed. It is suggested that elevation of PCE activity could be connected to mechanisms leading to an increased secretion rate of lipoproteins.

Clinical studies on plasma fibronectin and factor XIII; with special reference to hyperlipoproteinemia.

When compared to age-matched normal weight normolipidemic control subjects, plasma factor XIII, plasma fibronectin and serum cholinesterase levels were found to be markedly decreased in patients with decompensated cirrhosis of the liver, not significantly changed in hyperlipoproteinemia type IIa (heterozygous subjects) and increased in hypertriglyceridemic subjects (type IIb and IV) as well as in hyperlipidemic nephrotic patients. A possible accelerated hepatic synthesis of certain plasma proteins including factor XIII and fibronectin in patients with the nephrotic syndrome as well as in endogenous hypertriglyceridemia is envisaged. It is also considered that mural thrombi, richer in factor XIII and fibronectin, would be more resistant to fibrinolysis and more readily attached to subendothelial structures.

Plasma fibronectin in overweight men and women: correlation with serum triglyceride levels and serum cholinesterase activity.

When compared with 67 age- and sex-matched normal weight control subjects, the 71 overweight patients displayed obviously higher levels of plasma fibronectin. For a similar body mass index (BMI) the 16 overweight men younger than 45 years had a significantly (P < 0.01) higher plasma fibronectin level (455 +/- 99.3 mg/l; mean +/- SD) than the 16 age-matched overweight women (351 +/- 105 mg/l) while there was no significant difference between the 22 overweight men (446 +/- 89.2 mg/l) and the 17 overweight women (475 +/- 111 mg/l) older than 45 years. Particularly high plasma fibronectin levels were noted in the five women with upper body (android) obesity. Plasma fibronectin was positively correlated with BMI, serum triglyceride concentration, plasma fibrinogen and serum cholinesterase activity. It is considered that metabolic disturbances related to upper body obesity may lead to an enhanced hepatic secretion of VLDL and of several plasma proteins including fibronectin.

Serum zinc and copper in hyperlipoproteinemia.

Starting from experimental observations demonstrating that a high ratio of zinc to copper led to hypercholesterolemia in rats, serum Zn and Cu levels were measured by atomic absorption spectrophotometry in 65 normolipemic controls and in 100 subjects with various types of hyperlipoproteinemia (HLP). Serum Zn levels did not significantly differ from control values in any type of HLP. However, hyperlipoproteinemic patients with obvious clinical atherosclerosis displayed significantly lower serum-Zn concentration than hyperlipo-proteinemic subjects without clinical symptoms. On the other hand, when compared to control subjects, serum Cu levels were not found to be decreased, but rather increased, in hyperlipoproteinemic patients with or without atherosclerosis. As a result, the Zn∶Cu ratio appeared to be lower than normal in hyperlipoproteinemic patients with cardiovascular disease. It is conceivable that changes of these trace elements should be rather connected to vessel injury and associated disease than to HLP which, at least in humans, is not accompanied by a high Zn∶Cu ratio.

Pseudocholinesterase changes in anesthesia using pancuronium.

Pseudocholinesterase activity was investigated in three groups of unselected patients. A slight rise of the enzyme was found during surgery under local anesthesia with lidocaine. In general anesthesia with thiopentone and halothane, the pseudocholinesterase activity diminished. The inhibition was more pronounced when pancuronium had been injected. From these data one may conclude that pancuronium must be carefully given in patients with low level of pseudocholinesterase when other drugs inhibiting the enzyme activity, like succinylcholine, procaine and propanidid, are used.

[Serum lipids and gamma-glutamyltransferase in acute pancreatitis]. / Les lipides sériques et la gamma-glutamyltransférase dans la pancréatite aiguë.

An obvious hypertriglyceridemia was detected in 22.8% of the 57 investigated patients with acute pancreatitis. A type IV or V hyperlipoproteinemia could precede the onset of pancreatitis but the level of serum triglyceride greatly increased during the acute attack and had a tendency towards normalization later on. Increased serum gamma-glutamyltransferase activity was found to be especially high in alcoholic patients and in those presenting biliary disease.

Thrombotic tendency in diabetes mellitus. Revisiting and revising a study initiated 30 years ago.

Studies initiated 30 years ago emphasized that dilute blood clot lysis time was longer in obese diabetic patients than in normal weight diabetics. It was also later reported that when compared to obese women with gluteal and femoral adiposity, the age matched men with abdominal obesity displayed a more delayed clot lysis, higher triglyceride levels and higher cholinesterase activity, as well as more increased concentration of plasminogen activator inhibitor-1 (PAL-1). According to authors' investigations and data in the literature, impaired fibrinolysis in overweight hypertriglyceridemic subjects are mainly due to increased plasma levels of coagulation factor XIII and PAI-1. It could also be demonstrated that plasma clotting factors VII and VIII activities as well as plasma fibrinogen and von Willebrand factor levels were higher in patients with type 2 diabetes and abdominal obesity than in diabetics without obesity. Such findings are supporting data in the literature, insisting on the pathogenic relevance of intraabdominal obesity and of the subsequently enhanced release of fatty acids and of proinflammatory cytokines in the portal flow. Surprisingly anticoagulant plasma proteins C and S levels were found to be increased in overweight and hyperlipidemic patients considered to be at risk for thrombotic complications. Recent data in the literature had however demonstrated that circulating protein C zymogen acquires anticoagulant activity only after its binding to specific receptors on endothelial cell membrane, while proinflammatory cytokines may disrupt this activating interaction with vascular endothelia.

Controversy on high density lipoprotein raising therapy.

Decreased high density lipoproteins (HDL) plasma levels are a recognized independent risk factor for atherosclerotic cardiovascular disease. Attempts were therefore initiated to pharmacologically raise plasma HDL cholesterol, and the most impressive increase was obtained by inhibiting cholesteryl ester transfer protein (CETP) by means of the synthetic compound torcetrapib. Clinical trials were however disappointing, as torcetrapib increased mortality and did not reduce the progression of atherosclerosis. According to some view, it was claimed that CETP inhibition is unfavourable and that development of this class of compounds should be abandoned. Controversy nevertheless stimulated research on HDL structure, heterogeneity and functions which are not limited to reverse cholesterol transport and exert antioxidant and antiinflammatory actions. It could also be demonstrated that the deleterious effects of torcetrapib are compound specific, including its tight binding to CETP on HDL particles, thereby blocking both neutral lipids and phospholipid transfer from HDL to other lipoproteins, and would also exert an off-target effect by increasing plasma sodium and decreasing potasium concentrations (an aldosterone-like effect). As the structure of CETP was elucidated, it became possible to design CETP inhibitors that lack such off-target toxicity and may successfully slow the progression of atherosclerosis. Noteworthy, mice and rats naturally lacking CETP are resistant to diet induced atherosclerosis, while rabbits with high CETP levels are very susceptible. Families with deficient activity and exceptional longevity had also been reported.