Bernard-Soulier syndrome.

Bernard-Soulier syndrome (BSS) is a rare autosomal bleeding disorder characterized clinically by prolonged skin bleeding time, normal clot retraction and thrombocytopenia with large and morphologically abnormal platelets, and biochemically by the absence of platelet membrane glycoproteins (GP) Ib, V and IX. GP Ib and GP IX exist in the platelet membrane as a heterodimer complex which acts as the major receptor mediating platelet adhesion to blood vessel subendothelium. Studies with BSS platelets have proved particularly rewarding in the investigation of the GP Ib-IX complex as a multifunctional receptor protein. The transmembrane complex contains binding domains for von Willebrand factor, thrombin, fibrin and quinine/quinidine drug-dependent antibodies as well as an attachment site on the cytoplasmic side of the membrane for a platelet cytoskeleton. In addition, the internal segment of the beta-chain of GP Ib contains a cyclic AMP-dependent protein kinase-associated phosphorylation site which appears to regulate platelet reactivity. Limited proteolytic cleavage of the complex, in particular the GP Ib alpha-chain, has allowed immunological and functional characterization of three distinct domains; a 45 kDa segment at the N-terminal end of the alpha-chain of GP Ib, which contains binding sites for von Willebrand factor and thrombin, a 90 kDa highly glycosylated region of GP Ib alpha and a membrane-associated region consisting of the remnant of GP Ib alpha disulphide-linked to GP Ib beta and non-covalently-complexed with GP IX. This membrane-associated region contains the antigenic epitope(s) for quinine/quinidine drug-dependent antibodies. It is highly probable that the future study of platelets from patients with the Bernard-Soulier syndrome will further clarify the role of the GP Ib-IX complex in platelet physiology.

Adrenoceptor status and cardiovascular function in ageing.

Adrenoceptor function is an important determinant of the physiological control of the circulation and of the response to drugs acting via the sympathetic nervous system and on the vasculature. There is little consistent evidence for an age-dependent change in alpha-adrenoceptor function though the response to various vasoconstrictor agents including alpha 1 agonists has been shown to change with ageing. These changes seem to reflect structural or functional factors and are not specific for receptor types. In the case of beta-adrenoceptor mediated responses there is evidence for both a decrease in response as well as age-related changes in the functioning of various components of the beta-adrenoceptor system, including receptor affinity, which is decreased. It may well be that decreased beta-adrenoceptor function with ageing contributes to altered cardiovascular control and to decreased efficacy of beta-adrenoceptor blocking drugs in elderly hypertensives.

Interaction between platelets and lupus anticoagulant.

10 consecutive patients fulfilled the diagnostic criteria for lupus anticoagulant. 4 had concomitant systemic lupus erythematosus, 1 Waldenstrom's disease and 5 had no apparent underlying disease. Only the case with Waldenstrom's disease presented a bleeding tendency, with bleeding time greater than 20 min; the others had a history of thrombotic complications. A defect of platelet aggregation induced by ADP, epinephrine, collagen and arachidonic acid was documented in the Waldenstrom's disease case whose lupus anticoagulant was an IgM. In the others, lupus anticoagulant, identified as IgG immunoglobulins, produced no aggregation abnormalities. However, beta-thromboglobulin levels in platelets, plasma and urine were consistent with a pattern of platelet activation in all cases. IgG immunoglobulins separated from sera of 6 patients showed lupus anticoagulant activity, with no effects on platelet aggregation of normal platelet-rich plasma, but they induced secretion of beta-thromboglobulin from normal platelets.

Platelet dysfunction in malaria.

Platelet function tests including platelet aggregation, PF3, bleeding time and clot retraction were studied in 48 malarial patients. The suppression of platelet aggregation was demonstrated in both P. vivax and P. falciparum infection. However, this abnormality was more prominent in malarial patients who had systemic complications and bleeding. The recovery of the impaired platelet aggregation was observed at period of 7 and 14 days after parasitemia in malarial patients without and with systemic complications. The correlation between the suppression of platelet aggregation and thrombocytopenia was observed. From this study, bleeding in malaria are operated by two mechanisms: thrombocytopenia and severely depressed platelet aggregation.

[Functional properties of thrombocytes and inhibitors of proteolytic enzymes of the blood in patients with acute forms of ischemic heart disease]. / Funktsional'nye svoistva trombotsitov i ingibitory proteoliticheskikhfermentov krovi u bol'nykh s ostrymi formami ishemicheskoi bolezni serdtsa.

Blood platelet activity and levels of proteinase inhibitors and proteolytic components were assessed in patients with progressive angina of effort, spontaneous angina and acute myocardial infarction. alpha 1-antitrypsin and alpha 2-macroglobulin were shown to be involved in fibrinolysis regulation and kininogenesis. In acute myocardial infarction, there was a close inverse correlation between platelet release and blood kallikrein levels.

Pathological changes in cerebral arteries following experimental subarachnoid hemorrhage: role of blood platelets.

The role of blood platelets in producing early intimal changes in cerebral arteries following subarachnoid hemorrhage (SAH) was examined by using 18 cats. Experimental SAH was produced by a rupture of the proximal portion of the right middle cerebral artery. Following SAH, the scanning electron microscope revealed that structural alterations in the intimal layer of major cerebral arteries occurred as early as 2 hours and became more severe by 48 hours. Vascular alterations, which were predominantly detected in the ruptured vessel, consisted of endothelial cell corrugation, detachment, crater formation, intimal adhesion of platelets and red blood cells, intimal thrombi, and reendothelialization. When cats were pretreated prior to SAH with an anti-platelet-aggregating agent, OKY-1581, the intimal blood elements and thrombi were clearly reduced, and reendothelialization was not observed. However, endothelial cell changes in the OKY-1581-treated group were very similar to those occurring in the nontreated group. While these results suggest that bioactive substances contained within blood platelets, such as growth factors, serotonin, and norepinephrine, have little effect on producing endothelial cell injury, platelets may be important in the initiation of reendothelialization following vessel injury.

Platelet and vessel associated prostacyclin and thromboxane A2/prostaglandin endoperoxide receptors.

Synthetic stable analogues of thromboxane A2 (TXA2), cyclic endoperoxides (PGH2) and prostacyclin (PGI2) opened up new opportunities for investigating the mechanisms of action of these compounds. They proved to be useful pharmacological probes for characterizing PGI2 and TXA2/PGH2 receptors. Over the past few years, new synthetic antagonists with high specificity allowed the modulation of biological responses to endogenous eicosanoids. These compounds will, therefore, considerably promote our understanding of the biological function and significance of arachidonate metabolites. The present review summarizes current concepts that have arisen concerning platelet and vascular PGI2 and TXA2/PGH2 receptors, their transmembrane signal transduction, as well as their possible implications in the pathophysiology of cardiovascular disease.

Platelet contribution to cancer cell growth and migration: the role of platelet growth factors.

Blood platelets contain several growth factors and inhibitors. The better known among them are named platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta), active as modulators of growth of normal mesenchymal and epithelial cells. Cancer cell growth in vitro seems to be independent of the effects of exogenous peptides, but dependent on the cell ability to release autocrine growth factors, similar to PDGF or TGF beta. In addition, platelet-associated growth factors and inhibitors, which are able to induce a fibrotic response in connective tissue cells, might also play a role to modulate the desmoplastic reaction surrounding the tumor.

Platelet contribution to the formation of metastatic foci: the role of cancer cell-induced platelet activation.

Platelets are thought to be involved in the development of blood borne metastasis. Ultrastructural and experimental studies demonstrate that association between tumor cells and platelets with subsequent activation of the coagulation cascade takes place in malignancy. Several hypotheses have been proposed to explain the mechanisms by which tumor cells activate platelets including generation of thrombin, ADP release and involvement of arachidonate metabolism. Perfusion studies with human homologous systems showed that intact tumor cells and tumor cell microvesicles were able to induce platelet thrombogenicity under defined flow conditions. The presence of divalent cations and plasma factors was necessary for the cancer cells to exert their activating capacity. These results suggest a role for platelets in the development of secondary metastasis as well as in the thrombotic events of malignancy.

Role of the coagulation system in tumor-cell-induced platelet aggregation and metastasis.

The ability of tumor cells to initiate coagulation and subsequent platelet aggregation is believed to facilitate the metastatic process. The mechanism by which tumor cells initiate thrombotic alterations is unclear. We have purified a plasma membrane protein platelet aggregating activity/procoagulant activity (PAA/PCA) from several rodent tumors which initiates the coagulation of homologous plasma and aggregation of homologous platelets by a mechanism independent of factor VII. This protein does not possess any proteinase activity; however, its activity is dependent upon the presence of factor X. In addition, PAA/PCA requires reconstitution with phospholipid for expression of activity. These results suggest that tumor cells express a unique protein which possesses procoagulant activity resulting in thrombin generation. Thrombin is responsible for subsequent tumor-cell-induced platelet aggregation.

Platelet viability (aggregation, migration, recovery) after radiolabelling from hypercholesterolemics using various tracers (oxine, oxine-sulphate, tropolone, MPO).

Earlier results indicated a diminished labelling efficiency and recovery negatively linked to actual cholesterol and lipoprotein values in hyperlipoproteinemics. This study was designed to examine whether other alternative tracers exhibit similar results and to study the influence on platelet viability in the presence or absence of PGI2. We demonstrate that no substantial difference occurs between the four tracers concerning labelling efficiency and recovery in normo- and hypercholesterolemics. Cholesterol severely affects the labelling parameters for all the tracers to a comparable extent. The absolute platelet function varies considerably, however, the percent changes in normo- and hypercholesterolemics seen before and after the labelling procedure do not differ significantly. PGI2 improves recovery in general, however, without affecting labelling efficiency or in vitro viability testing. As prolonged incubation further increases labelling efficiency, the presence and extent of hyperlipoproteinemia should be known in order to avoid poor labeling and viability and subsequently poor clinical results.

Role of platelet membrane in enhancement of tumor cell adhesion to endothelial cell extracellular matrix.

Tumor cell adhesion to subendothelial matrix in the presence of platelets and plasma has been examined in vitro using an entirely homologous system of rat Walker 256 carcinosarcoma cells, matrix laid down by rat aortic endothelial cells and rat platelets and plasma. In the presence of platelets or platelets plus plasma, tumor cell adhesion was significantly enhanced when compared to adhesion in the absence of platelets. In the presence of plasma alone (0.1%), we observed no significant increase in tumor cell adhesion. In order to determine which platelet factors contribute to the enhancement of tumor cell adhesion by platelets, we subjected washed rat platelets to mechanical lysis or thrombin stimulation followed by centrifugation. The membrane fractions and supernatant fractions containing platelet attachment proteins were compared for their abilities to support tumor cell adhesion to subendothelial matrix. Platelet membranes were also recombined with platelet supernatant fractions to determine if platelet attachment proteins or platelet membranes required the presence of the other to enhance tumor cell adhesion. Platelet supernatant fractions which contained release reaction proteins (confirmed by polyacrylamide gel electrophoresis) did not enhance tumor cell adhesion. Purified thrombospondin, fibronectin, beta-thromboglobulin, platelet derived growth factor, and serotonin had no effect on tumor cell adhesion. Platelet membrane containing fractions affected tumor cell adhesion to subendothelial matrix as follows: (a) platelets formed an adhesive bridge between tumor cells and the subendothelial matrix as demonstrated by scanning electron microscopy; (b) intact platelets and thrombin stimulated platelets were the most effective at facilitating tumor cell adhesion; (c) preparations containing partially lysed platelet ghosts were more effective in supporting tumor cell adhesion to subendothelial matrix than were preparations containing completely lysed platelet membrane fragments; (d) recombination of platelet supernatant fractions with mechanically lysed platelets did not enhance their ability to support adhesion; (e) fixed platelets, either alone or in combination with platelet supernatant fractions, failed to enhance adhesion. These data indicate that platelet enhanced tumor cell adhesion appears to be dependent on platelet membrane factors including receptor mobility, rather than intraplatelet components.