Biomedical subjects
Publications and source records attributed to E Dupuy.
Hemostasis disorders are involved in diabetic micro and macroangiopathy. Platelet hyperactivity is related at least in part to an imbalance between thromboxane A2 and prostacyclin. Both hyper and hypoglycemia result in platelet activation.
The authors have developed a sensitive immunoenzymatic method for assaying anti-cardiolipin antibodies in the serum of patients with lupus (SLE). These antibodies were present in the serum of 43/108 SLE patients, particularly in those patients with either false syphilis serology (p less than 0.02) or circulating anticoagulant (p less than 0.05). The mean titre of anti-cardiolipin antibodies was higher in the group with positive VDRL (less than 0.03). The anti-cardiolipin antibody titre was independent of the anti-native DNA antibody titre, but there was a correlation with the anti-denatured DNA antibody titre (p less than 0.02). This correlation can be partially explained by the antigenic similarity (phosphodiester bridge) between the two molecules. The preliminary clinical studies have not shown any correlation between the presence of anti-cardiolipin antibodies and the presence of signs such as thrombocytopenia, haemolysis, cerebral vascular accident, venous thrombosis, recurrent abortion. A longitudinal study of certain patients suggests that the anti-cardiolipin antibodies may disappear at the time of thrombotic accidents, which induces fixation of these antibodies to a platelet or vascular target and as a result of corticosteroid therapy.
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The effects of natural and synthetic sex hormones (10(-8)M) have been studied on human umbilical endothelial cell proliferation and prostacyclin production. 17 B estradiol and progesterone had no effect on cell multiplication. Ethinyl-estradiol increased proliferation when the initial plating density was 40,000 cells/cm2. However, the production of 6-keto PGF1 alpha induced by the Ca++ ionophore A 23187 was not different between control, 17 B estradiol-or ethinyl estradiol-treated cultures. These results demonstrate an in vitro effect of synthetic estrogen, ethinyl estradiol on endothelial cell proliferation. At the present time it is however difficult to correlate these results with the clinical observation of an increase in thromboembolic complications in women under oral contraceptives.
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The availability of fibrinogen receptors on platelets after ADP stimulation, was investigated in order to analyze platelet hyperaggregability induced by heparin. Unfractionated heparin increased the binding of fibrinogen on ADP-treated platelets. The results varied according to both the donor platelets and the kind of heparin preparation used. Beef lung heparin was more active than porcine intestinal mucosa heparin (P less than 0.001). Low molecular weight (LMW) heparin fractions however did not significantly increase the binding of fibrinogen to ADP-treated platelets. The effect of standard heparin and LMW heparin on the aggregation of normal platelets induced by the addition of plasma from patients with heparin-induced immune thrombocytopenia was also studied. Concerning heparin-induced immune thrombocytopenia we have shown that the plasma cofactor present in some patient plasma may induce platelet aggregation both in the presence of standard-heparin and in the presence of LMW heparin fractions. Therefore, one has to be careful when replacing standard heparin by LMW heparin or heparinoids since each patient may react differently.
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The diagnosis and treatment of apparently idiopathic recurrent thromboembolic disease (RTED) still raise difficult problems. However, recent data suggest that abnormalities of coagulation and fibrinolysis factors are important. Hereditary antithrombin III (AT III) deficiency or abnormal AT III, and hereditary protein C deficiency with autosomal dominant transmission have been associated with severe familiar RTED. More recently, we described a dysfibrinogenemia characterized by abnormal fibrin polymerization and abnormal plasminogen binding to the fibrin clot, responsible for familial RTED. Disorders of fibrinolytic activity in RTED are represented, in 70% of the cases, by reduced release or lack of production by endothelial cells of a vascular plasminogen activator. Hereditary plasminogen deficiency or abnormal plasminogen, although rare, are regularly responsible for RTED.
Venous thrombosis occurred frequently in Behçet's disease. In 12 patients with Behçet's disease of whom 6 have had leg venous thrombosis, some parameters of hemostasis or fibrinolysis have been studied. Platelet count, fibrinogen level, factor VIII coagulant activity, factor VIII antigen, plasminogen and antithrombin III level were in the normal range. Fibrinolytic capacity in response to venous occlusion of the arms was the same in patients and in healthy subjects, in the patients, there was no difference in regard to the occurrence of venous thrombosis. These parameters seemed therefore not able to detect the thrombotic tendency in this disease. These results are discussed with the other reports of the literature.
A preliminary characterization of a fibrinolytic inhibitor released by human umbilical vein endothelial cells in primary culture is reported. This molecule of Mr comprised between 2 X 10(5) and 10(6) and of alpha 2 mobility precipitates at 43% ammonium sulphate saturation and is totally adsorbed on Concanavalin A Sepharose 4 B. A possible relationship with alpha macroglobulins is discussed.
In a child with acute megakaryoblastic leukemia--severe thrombocytopenia and myelofibrosis, EM studies on bone marrow showed a strict topographic relationship between the presence of clusters of abnormal megakaryocytes and the increased number of fibroblasts and extracellular fibers. Megakaryocytes and platelets lacked alpha-granules while the plasma thromboglobulin level was three times the normal level. This suggested that the alpha-granular proteins were synthesized but not retained in alpha-granules. If this occurs, the increased marrow levels of platelet-derived growth factor and factor 4 would favor the proliferation of fibroblasts and the synthesis of collagen, and thereby promote myelofibrosis. After therapy-induced remission, the number of marrow megakaryocytes decreased, the alpha-granules were normally produced, the plasma beta-thromboglobulin level was normal and the myelofibrosis disappeared. These observations suggest that during acute megakaryoblastic leukemia, an acquired gray-platelet syndrome occurs and that the local excretion of alpha-granule proteins triggers the myelofibrosis.
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Blood coagulation factors were measured in 9 patients under 55 years of age with retinal vein thrombosis. A statistical study of the results revealed 2 anomalies: reduced platelet aggregation in the presence of 1,2 M ADP and a decrease of plasminogen. It is difficult to correlate these biological anomalies with the clinical vascular accidents.
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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.
Platelet functions studied in 163 unselected diabetics compared with 163 controls had the following characteristics: hyperagregation induced by ADP (1.2 muM and 0.6 muM), delayed platelet disagregation (ADP: 0.6 muM), normal agregation in the presence of collagen and thrombin. Platelet hyperagregation induced by ADP was marked in both sexes in cases of retinopathy and in women after the age of 50. By contrast, no correlation was demonstrated between the degree of hyperagregation and age, weight, the duration of diabetes, blood glucose control, lipid profile, vascular complications other than retinopathy and the nature of treatment.