Brook Jg

Platelet interaction with high and low density lipoproteins

Gel-filtered platelets (GFP) from normal human subjects bound both low density lipoproteins (LDL) and high density lipoproteins (HDL). This binding was saturable and 125I-labelled lipoprotein uptake was inhibited by plasma. Platelets are also able to degrade lipoproteins but only to a limited extent. LDL appeared to compete with 125I-labelled HDL for platelet uptake, whereas the ability of HDL to displace 125I-LDL was limited. Cyclohexanedione-treated LDL (CHD-LDL), unlike CHD-HDL, did not compete with [125I]LDL for platelet accumulation, suggesting that arginine residues are necessary for LDL but not HDL binding. Addition of HDL or LDL to GFP did not alter platelet aggregation. However, in the presence of thrombin (0.5 U/ml), 1 mg/ml LDL incubated for 1 h at 23 degrees C enhanced platelet aggregation (215% increase) whereas HDL under similar conditions decreased aggregation by 53%. LDL also shortened the time of maximal aggregation whereas HDL had the opposite effect.

Enhanced in vitro Platelet Aggregation in Hemodialysis Patients

Hemodialysis patients suffer from premature atherosclerosis and various thrombotic and thromboembolic phenomena. Despite enhanced in vivo platelet activity, it is unclear whether in vitro platelet aggregation is increased or reduced in this population. We studied platelet aggregation in response to adenosine diphosphate and to epinephrine in 20 chronic hemodialysis patients and 21 controls. In the patient group the in vitro platelet aggregation was significantly enhanced in response to both aggregating agents. Our study demonstrated that in vitro platelet aggregation is enhanced in patients with chronic renal failure undergoing hemodialysis.

Low density lipoprotein binding to human platelets: Role of charge and of specific amino acids

Abstract Many human and animal cells possess cell surface binding sites, specific for low density lipoproteins. Human platelets are similarly endowed with specific low density lipoprotein receptors. Using chemical modofications of amino acid residues on the low density lipoprotein molecule, we have studied the role of charge and specific amino acids on the binding process. The interaction of the modified low density lipoprotein preparations with gel-filtered platelets and with glass beads was compared. Both cyclohexanedione treated and aceto-acetylated low density lipoprotein did not bind to the platelet surface. However, azo-arsanilated low density lipoprotein bound to the platelets in a manner similar to the binding of native lipoprotein. Cyclohexanedione treated lipoprotein was the only preparation which did not bind to glass beads. The importance of both the presence of the positive charge on the lipoprotein molecule and the availability of specific amino acid residues (arginine and lysine but not tyrosine and histidine) for low density lipoprotein-platelet interaction was thus demonstrated.

Lipid and lipoprotein pattern in thyroid dysfunction and the effect of therapy

Lipid and lipoprotein concentrations were studied in 12 hypothyroid and 11 hyperthyroid female subjects, both before and after therapy, and in 27 age matched female controls. Recognized clinical and laboratory criteria established the diagnosis. Lipoproteins, including the sub-fractions of the high density lipoproteins (HDL), were isolated by preparative ultracentrifugation, and the cholesterol (c) and protein (p) contents of each were determined. Total cholesterol, and in particular HDL-c, were elevated in the hypothyroid patients. The low density lipoprotein (LDL) -c/HDL-c ratio was 1.9 in this group, compared to 2.2 in the control group and 1.35 in the hyperthyroid patients. The HDL-2/HDL-3 ratio in the hypothyroid group was 3.75, as compared to 1.75 in the controls and 4.2 in the hyperthyroid group. Plasma triglycerides were moderately elevated in the hypothyroid patients and were significantly reduced in the hyperthyroid group. Total cholesterol was significantly lower in the hyperthyroid group as compared to the control group. Very low density (VLDL) cholesterol and protein were significantly increased and LDL and HDL cholesterol were reduced in the hyperthyroid patients. On rendering the patients euthyroid, most of these changes were reversed. Thyroid function profoundly affects lipoprotein concentration and composition. The change in the plasma HDL concentrations of the hypothyroid group questions the relationship of this group to arteriosclerosis. Therapy partially corrects the abnormalities, but complete correction may be related to duration of therapy.

Increased Low-Density Lipoprotein Levels After Splenectomy: A Role for the Spleen in Cholesterol Metabolism in Myeloproliferative Disorders

Patients with myeloproliferative disorders demonstrate decreased plasma cholesterol and apolipoprotein B concentrations, and this has been related to the presence of a large spleen. Patients that underwent splenectomy in the past demonstrated normal plasma cholesterol levels. Plasma high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I were also reduced in these patients, but were normal after splenectomy. To study the immediate effect of splenectomy on the plasma lipid pattern, three patients with myeloproliferative disease and a large spleen who were undergoing splenectomy were compared with two control groups, one undergoing orthopedic operations and the second, cholecystectomy. In the control groups, plasma lipids tended to decrease for the first 2 days after surgery and then returned to preoperative levels. After splenectomy, however, plasma cholesterol, low-density lipoprotein (LDL), and apolipoprotein B significantly increased, reaching maximum levels after 4 days. Plasma HDL as well as apolipoprotein A-I decreased 1 day after splenectomy, but then increased over and above their preoperative concentrations. These results suggest an important role for the spleen in cholesterol metabolism in these patients. The spleen appears to be an important site for LDL catabolism in these patients.

High Dose of L-Carnitine Increases Platelet Aggregation and Plasma Triglyceride Levels in Uremic Patients on Hemodialysis

Uremic patients undergoing chronic hemodialysis demonstrate a secondary systemic carnitine deficiency. We studied the effect of carnitine replacement with high doses (L-carnitine, 3 g/day) similar to those used in the treatment of primary systemic carnitine deficiency. 10 uremic patients on hemodialysis were randomly selected into a control group (4 patients) treated by placebo and a treatment group (6 patients) treated by L-carnitine. Plasma lipoprotein concentration and composition as well as platelet aggregation were studied before and after treatment. Following carnitine administration, a paradoxical rise in plasma triglyceride concentration from 180 +/- 66 to 219 +/- 88 mg% (p less than 0.05) was noted. No other significant changes in lipoprotein concentration and composition or in plasma apoprotein A-I and B concentration were observed. Carnitine treatment caused a significant rise in platelet aggregation induced by epinephrine, ADP, and thrombin. These findings suggest a harmful effect of L-carnitine replacement therapy when given in high doses, causing aggravation of uremic hypertriglyceridemia and increased platelet aggregation in patients predisposed to thromboembolic phenomena.

Platelet secretory products increase low density lipoprotein oxidation, enhance its uptake by macrophages, and reduce its fluidity.

Oxidized low density lipoprotein (Ox-LDL) is considered to be involved in the atherogenic process. Factors influencing the formation of Ox-LDL are thus of importance. Oxidation of LDL in a cell-free system in the presence of copper ions was significantly increased (up to 60%) by the presence of platelet-conditioned medium, (PCM) obtained from collagen-activated platelets for the duration of the oxidation period. The effect was time- and dose-dependent and was related to hydrogen peroxide and superoxide production, since PCM-induced enhanced LDL oxidation was inhibited by catalase and by superoxide dismutase, but not by protease treatments. PCM also reduced the fluidity of oxidized LDL by 45%. Upon incubation with a J-774 macrophage-like cell line, PCM-treated Ox-LDL enhanced cellular cholesteryl ester synthesis by 47% and lipoprotein degradation by 41%. Thus platelet secretory products appeared to enhance LDL oxidation through the involvement of oxidative agents. The resulting Ox-LDL demonstrated increased atherogenic properties.

High-density lipoprotein subfractions in normolipidemic patients with coronary atherosclerosis.

The symptoms, ECGs, exercise stress responses, left ventricular perfusion and function, and the topography of obstructive coronary artery disease (3 70% cross-sectional stenosis in the left main, left anterior descending, circumflex, and right coronary arteries and their major branches) were analyzed in 200 patients 65 years of age or older with angina pectoris. Males showed a significantly higher incidence of stenosis of the left main and the left circumflex coronary arteries and poorer left ventricular perfusion than females. One-vessel obstructive disease was found in one-fifth of the aged patients of each sex with angina pectoris.

Increased Platelet Aggregation during Alimentary Hyperlipemia in Normal and Hypertriglyceridemic Subjects

The influence of 2 different fatty meals, rich in either saturated or polyunsaturated fatty acids, on platelet aggregation in 7 normolipemic subjects and in 10 patients with phenotype IV hyperlipemia, was studied. 3 h after ingestion of a saturated- or polyunsaturated-fat-rich meal, plasma triglycerides were similarly increased in both groups. 5 h after ingestion of fat of either origin, the plasma triglyceride level in normal subjects returned almost to the fasting level, whereas in patients with hypertriglyceridemia it was still elevated. Platelet aggregation induced by ADP in platelet-rich plasma significantly increased in the normal group 3 h after both meals, whereas in the patient group it increased only after the saturated-fat-rich meal. These results were not changed 5 h after the meals. Postprandial elevated platelet activity was not correlated with increased plasma triglyceride concentration. No changes were found in washed-platelet aggregation in normal subjects, whereas the patient-derived washed platelets showed increased aggregation after the saturated-fat-rich meal. Plasma chylomicrons prepared from both groups during alimentary hyperlipemia inhibited ADP-induced platelet aggregation as well as thrombin-induced platelet 14C-serotonin release. This study indicates that the intake of fatty meals induces acute disturbance in platelet aggregation, favoring thrombosis. These changes are more comprehensive in hyperlipemic patients and after a saturated-fat-rich meal.

Selective release from platelet granules induced by plasma lipoproteins.

Abstract Platelet hyperactivity in hyperlipoproteinemia was demonstrated in both in in vitro (1–4) and in vivo (5,6) studies. We have previously shown (7,8) specific platelet-binding sites for plasma lipoproteins which mediate platelet functional changes (9–11). Thrombin-induced platelet aggregation and [ 14 C]serotonin release were found to be significantly increased by very-low-density and low-density lipoproteins as well as by lipoprotein-deficient plasma. High-density lipoprotein, the “antiatherogenic” lipoprotein, substantially decreased platelet activity (8–10). In this study we have used the release of serotonin and β-thromboglobulin (located in the dense and α granules, respectively) in order to evaluate the effect of plasma lipoproteins on platelet release from these granules.