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Biomedical subjects

S Levy-Toledano

Publications and source records attributed to S Levy-Toledano.

At least 73 records · Page 4Linked to original sources
PubMed1983

Evidence that abnormal platelet functions in human Chédiak-Higashi syndrome are the result of a lack of dense bodies.

The structure and functions of platelets from three patients with the Chédiak-Higashi syndrome were examined. Electron-microscopic observations revealed a large reduction in the number of serotonin-storage granules or dense bodies but otherwise normal ultrastructure and normal amounts of alpha-granules and catalase-positive granules. The number of mepacrine-labeled granules was also reduced. Platelets contained normal amounts of beta-thromboglobulin and Platelet Factor 4. The platelet release reaction studied with thrombin as the inducer was impaired. The serotonin uptake by the patients' platelets was low and not inhibited by reserpine, and its metabolism was increased. These findings clearly show that platelets from human Chédiak-Higashi syndrome are deficient in the storage pool of dense granule substances and suggest that this granule defect has an influence on the release mechanism of other granule constituents.

Blood Platelets↗
PubMed1982

Selective stimulation of human platelet lipoxygenase product 12-hydroxy-5,8,10,14-eicosatetraenoic acid by chlorpromazine and 8-(n,n-diethylamino)-octyl-3,4,5-trimethoxybenzoate.

Stimulation of human platelets by thrombin and by the Ca2+ ionophore A23187 leads to a rapid Ca2+-dependent activation of phospholipases that release membrane-bound arachidonic acid for oxidation by a cyclooxygenase and lipoxygenase enzymes into so-called eicosanoids. Chlorpromazine and the intracellular calcium antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) inhibited the release of eicosanoids, as estimated by a quantitative glass capillary-gas chromatography analysis. TMB-8 was more efficient for thrombin- than for ionophore-induced eicosanoids liberation. Chlorpromazine, the more potent inhibitor, was active at the same concentration against either inducer. The reduction of oxidative metabolism by the cyclooxygenase pathway was more pronounced than reduction in the lipoxygenase pathway. When exogenous arachidonic acid was added to the platelets, both drugs stimulated selectively the production and the formation rate of 12-hydroxy-5,8,10,14-eicosatetraenoic acid by a factor of 2-2.5 in the absence of variation of cyclooxygenase products. Therefore, the stimulation of the lipoxygenase metabolite by the two drugs was obtained with both endogenous and exogenous arachidonic acid. This selective stimulation by drugs of a lipoxygenase product in the absence of inhibition of cyclooxygenase is the first reported of this type and suggests a differential control for the two oxidation enzymes. These findings emphasize the importance of a simultaneous quantitative analysis of both oxidation pathways.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1982

Human platelet activation in the absence of aggregation: a calcium-dependent phenomenon independent of thromboxane formation.

In response to ionophore A 23187, thrombasthenic and EDTA-treated control platelet-rich plasmas (PRP) undergo a change in light transmission (LT) accompanied by a normal 14C-serotonin (5HT) release and thromboxane (TX) synthesis in the absence of aggregation. Ultrastructural qualitative electron microscopy revealed central apposition of organelles and loosely packed platelets in both models, while a central gel mass appeared only in thrombasthenic patients. Quantitative analysis of this ultrastructural change showed an increase in the elongation and a decrease in the circularity coefficients of thrombasthenic platelets, indicating a shape change with pseudopod formation, while EDTA-treated platelets underwent a shape change in the absence of pseudopod formation. Morphometric analysis showed that the ionophore caused extensive degranulation in both types of platelets (decrease of the granule volume), which occurred in the presence of contraction of thrombasthenic PRP (decrease of the SCS plus granule volume) but in its absence in EDTA-treated platelets. The change in LT was not inhibited by aspirin, suggesting a dissociation between release of 14C-5HT and TX formation. Moreover, it was not inhibited by creatine phosphate plus creatine phosphokinase, prostaglandin E1, or cytochalasin and/or colchicine. It was not dependent on ADP, cAMP, or the integrity of microfilaments and microtubules. However, chlorpromazine, TMB 8, and dibucaine, which interfere with intracellular membrane transport of Ca2+, inhibited this platelet activation (change in LT, 14C-5HT release and TX synthesis.

Aspirin↗
PubMed1981

[Congenital anomalies of the human blood platelet, models for understanding mechanisms of platelet secretion: gray platelet disease].

The fundamental role of different platelet glycoproteins and proteins in platelet function is well known. Glycoproteins II b and III a, missing from platelets of patients with Glanzmann's thrombasthenia, appear to play a role in the mechanism of platelet cohesion. Platelet adhesion to sub-endothelium components depends on the binding of von Willebrand factor to the platelet membrane and this is defective in the Bernard Soulier syndrome which is characterised by the absence from the platelets of membrane glycoprotein Ib. The gray platelet syndrome is a new platelet disorder characterized by the absence of alpha granules and a reduced platelet aggregation response associated with an abnormal dense body section. Analysis of the protein and glycoprotein content of gray platelets has shown that they lack or have markedly reduced concentrations of the alpha granule proteins. It would appear that proteins secreted from the alpha granules may play a role during the later stages of platelet secretion leading to platelet aggregation.

Blood Platelet Disorders↗
PubMed1981

Gray platelet syndrome: alpha-granule deficiency. Its influence on platelet function.

The ultrastructure, cytochemistry, biochemistry, and functions of platelets from two patients with the familial gray platelet syndrome are described. Ultrastructural studies showed a lack of alpha-granules in the megakaryocytes in the vicinity of a marrow myelofibrosis and/or in platelets. A normal number of mitochondria and a slight increase of dense bodies was confirmed by labeling the whole patient with mepacrine. Platelet peroxidase (in the dense tubular system) and catalase-positive granules (revealed by the cytochemistry) were present. Platelets from both patients had severe deficiency of beta TG either after tritonization (less than 4% of normal) or thrombin treatment (less than 15% of normal), and the plasma beta TG levels were slightly increased. Functional studies of these platelets showed an uptake of [14C]5HT inhibited by reserpine similar to that in the control platelets. Thromboxane formation was within normal limits in the presence of arachidonic acid, ADP, collagen, or ionophore A23187, indicating that (1) the cyclooxygenase/thromboxane synthetase systems were not altered and (2) the phospholipase activities were not impaired. Although the platelet adhesion to prepolymerized fibrillar type III collagen and the ADP-, arachidonic acid-, and ionophore A23187-mediated aggregations were apparently normal, in every case the release of [14C]5HT was either at the low side of the normal range or decreased. This abnormality was increased when collagen or thrombin was added to either PRP or washed platelets from both patients, where at the same time, the aggregation and the release were markedly reduced. The results suggest that alpha-granules or their content has an influence on not only the platelet aggregation but also the dense bodies involved in the [14C]5HT release reaction.

Adolescent↗
PubMed1981

Defective alpha-granule production in megakaryocytes from gray platelet syndrome: ultrastructural studies of bone marrow cells and megakaryocytes growing in culture from blood precursors.

The ultrastructure and cytochemistry of megakaryocytes from two patients with a familial gray platelet syndrome are described. Although the Golgi zones appeared normally developed, the megakaryocytes lacked alpha-granules. Catalase-containing particles were normal in number. In immature megakaryocytes, granules measuring from 0.05-0.1 mu and having an electron-dense core occurred in the Golgi area. These granules, which are considered as the precursors of alpha-granules in normal megakaryocytes, appeared unable to mature, and their number decreased with the megakaryocyte maturation. The presence of dense material in distended demarcation membranes and/or vacuoles suggested that their content was discharged. It is suggested that myelofibrosis present in the bone marrow from these two patients may be related to the possible excretion of a polypeptide growth factor normally contained in the alpha-granules. Megakaryocytes grown by the plasma clot procedure from blood precursors isolated from the two patients also did not exhibit alpha-granules, which were replaced by vacuoles. Our findings suggest that the lack of alpha-granules in gray platelets may be related to a defective megakaryocyte-committed cell, and evidence is presented which suggests that the precursors of alpha-granules are produced but that their contents are then lost.

Blood Platelets↗
PubMed1979

Further studies on a specific platelet antibody found in Bernard-Soulier syndrome and its effects on normal platelet function.

An IgG antiplatelet antibody found in a multitransfused patient with Bernard-Soulier syndrome (BSS), reacted with a normal platelet surface antigen of 150 000 daltons which was similar to the glycoprotein missing from BSS platelets. The BSS platelet antibody (BSS-Pab) aggregated all control platelets which then released ADP and 5-HT and synthesized thromboxane. When mixed with the antibody, BSS platelets did not aggregate, did not release ADP and 5-HT and failed to synthesize thromboxane. The BSS-Pab was not inactivated by incubation with BSS platelet stroma. While the antibody did not aggregate thrombasthenic platelets, its aggregating activity was lost after incubation with their stroma. The BSS-Pab did not provoke ADP or 5-HT release or thromboxane synthesis in thrombasthenic platelets or in the platelets of a patient with platelet cyclooxygenase deficiency or in normal platelets treated with indomethacin. The aggregating, release and synthetic responses of platelets after binding of BSS-Pab to its membrane antigen (probably glycoprotein I) requires the presence of glycoprotein IIb and/or IIa and the normal metabolism of arachidonic acid.

Antibodies↗
PubMed1978

Acquired IgG antibody occurring in a thrombasthenic patient: its effect on human platelet function.

In subagglutinating amounts, an IgG antibody isolated from the plasma of a polytransfused thrombasthenic patient (L) inhibited ADP-, epinephrine-, collagen-, and thrombin-induced aggregation of normal human platelets. The inhibition of ADP-induced aggregation was strongly diminished following the prior incubation of the antibody with control human platelet stroma but not with the stroma prepared from the platelets of two different thrombasthenic patients. The IgG(L) did not affect the binding of 14C-ADP to control human platelet membranes and did not inhibit the ADP-induced shape change. Bovine factor VIIIVWF-induced agglutination and ristocetin-induced aggregation of control human platelets were not inhibited in the presence of the antibody. The IgG(L) strongly inhibited ADP-induced retraction of reptilase clot and thrombin-induced clot retraction. This antibody therefore induced a thrombasthenialike state in normal human platelets, suggesting that the antigenic site recognized by the antibody plays a central role in the later stages of the mechanism of platelet aggregation induced by physiologic aggregation-inducing agents.

Adenosine Diphosphate↗
PubMed1977

Adhesion and aggregation of human platelets to rabbit subendothelium. A new approach for investigation: specific antibodies.

An SgG antibody occurring in a recently transfused thrombasthenic patient inhibited all the ADP-mediated aggregations and platelet-platelet interaction (thrombus formation) on rabbit aorta subendothelium; another IgG antibody occurring in a multitransfused Bernard-Soulier patient inhibited ristocetin and bovine factor VIII mediated aggregation and platelet-subendothelium interaction.

Animals↗
PubMed1977

Effect of somatostatin on platelet aggregation and plasma factor VIII level in normal man.

As impairment in coagulation and platelet function has been reported following acute administration of somatostatin, a reevaluation of the effects of the cyclic and linear form of the peptide was undertaken. In vitro somatostatin had no effect by itself on platelet aggregation and no effect on ADP- or ristocetin-induced aggregation. In vivo ten healthy men infused with cyclic or linear somatostatin (loading dose of 250 microgram and three hour-infusion with 1,500 microgram) and five control subjects were investigated during the infusion and for three hours after the end of the infusion. With this dose, sufficient in man for maintaining plasma growth hormone and insulin at fasting levels under arginine stimulation, no abnormalities in platelet count, in ADP-induced platelet aggregation and in plasma VIII von Willebrand factor, factor VIII procoagulant activity and factor VIII related antigen levels were observed.

Adenosine Diphosphate↗
PubMed1977

Molecular defect in platelets from patients with bernard-soulier syndrome.

An IgG antibody isolated from the serum of a patient with the Bernard-Soulier syndrome induced platelet agglutination in the platelet-rich plasma of 50 normal subjects regardless of their ABO, KOa, KOb, HLA, or PlA1 types. This antibody was nonreactive with platelets from three other Bernard-Saulier syndrome patients. Indirect immunoprecipitation tests using this serum (or purified IgG) and soluble membrane antigens labeled with 125I that had been extracted from normal platelets by the nonionic detergent Nonidet P-40 gave a single radioactive peak at 150,000 MW in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These findings strongly suggest that the antigenic determinant reacting with this antibody is absent from platelets of Bernard-Soulier syndrome patients and that the deficient molecule is of 150,000 MW. The role of this molecule in subendothelial adhesion and macromolecular-mediated aggregations is discussed.

Antibodies↗
PubMed1976

Acquired von Willebrand's syndrome and thrombopathy in a patient with chronic lymphocytic leukaemia.

This paper reports the biological data found during an acquired bleeding disorder occurring in a 65-year-old woman affected with chronic lymphocytic leukaemia. They consists of haemostatic abnormalities which resemble an presently undescribed association of an acquired von Willebrand's syndrome with a thrombopathy. von Willebrand abnormalities were temporarily corrected by infusion of normal cryoprecipitate and reproduced in vitro by the incubation of normal platelets with the patient's IgA. The platelet defect was partially corrected after corticotherapy. The possible relationship of the associated defects is discussed.

Aged↗
PubMed1976

Bernard-Soulier syndrome: a new platelet glycoprotein abnormality. Its relationship with platelet adhesion to subendothelium and with the factor VIII von Willebrand protein.

A decreased platelet adhesion to rabbit aorta subendothelium (Baumgartner technique) is confirmed in the Bernard Soulier (giant platelet) syndrome. Electron microscope techniques using a purified antibody against Factor VIII/von Willebrand protein, revealed an apparently normal presence of the Factor VIII/von Willebrand protein on the Bernard Soulier platelets. Electrophoretic characterization of the major protein and glycoprotein components of the Bernard Soulier platelets following sodium dodecyl sulfate solubilization indicated a relatively normal protein content but suggested a reduced content of the 155,000 molecular weight major platelet glycoprotein. This was confirmed by a reduced release of high molecular weight acidic glycopeptides following incubation of washed Bernard Soulier platelets with trypsin. It is proposed that this abnormality may be related to the previously reported reduced sialic acid content and the reduced electrophoretic mobility of the Bernard Soulier platelets and that a glycoprotein reduced or abnormal in the Bernard Soulier platelets is necessary for the normal adhesion of platelets to subendothelium.

Adult↗