Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Nikola Kopková Supervisor: Assoc. Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of diploma thesis: Antiplatelet effects of flavonoids The most common antioxidants in ordinary food are flavonoids. They show antioxidant and anti-aggregation effects and other positive effects on cardiovascular diseases. Flavonoids are promising candidates to be antiplatelet drugs. Although several mechanisms responsible for antiplatelet activity have been suggesteed, only a few have been documented by published studies. The inhibition of blood platelet aggregation by flavonoids is reversible, which is another important factor. Data on thrombin-induced aggregation are controversial, some claim that flavonoids have no effect, the others says they have positive effects. (In the case of quercetin and genistein, inhibition of aggregation induced by thrombin was documented). The effect on arachidonic acid in the aggregation cascade is well documented, but there are several inconsistencies resulting from the use of different materials. Other mediators of aggregation are phospholipase A2, which plays a key role in the formation of inflammatory mediators. In this case, it has been shown that mainly genistein is capable of...

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Copies of author's previously published articles inserted. / Includes bibliographical references. / xiii, 231, [145] leaves, [2] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to analyse the interactions and to identify synergism occurring between the combinations of adrenaline with ADP and 5-HT with ADP ; and to identify the intraplatelet mechanism involved in signalling the initiation of the enhanced aggregation response. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995?

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Platelets have been shown to be a main contributor to thrombus formation in stenotic arteries leading to acute coronary syndromes. It is thought that increased activation and adhesion of platelets under variable shear and complex flow conditions contribute to thrombosis. The objective of this work was to evaluate the relationship between asymmetric stenosis hemodynamics and platelet adhesion using in-vitro models developed to properly simulate physiological conditions. In this study, platelet rich plasma was circulated through stenotic and straight coronary artery models. Adhesion results were obtained by post-perfusion fluorescent labelling and imaging of adhered platelets. Analysis of platelet area coverage has shown maximum adhesion occurs in the distal region of the stenosis. Most likely this is due to increased exposure time of platelets to the wall of the recirculation zone following the stenosis and that exposure being directly after a period of high shear stress. This result gives us a better understanding of the importance of both shear and flow conditions in coronary artery thrombosis.

Copies of author's previously published articles inserted. / Bibliography: leaves 267-303. / xviii, 304 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Experiments described in the thesis address the anti-aggregatory effects and mechanism of action of the prophylactic anti-anginal agent perhexiline maleate. In particular, it was sought to examine if perhexiline had an anti-aggregatory effect which may contribute to its proven therapeutic efficacy. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2000

Thesis (Mech.E)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1980. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Bibliography: leaves 355-373. / by Martin J. Forbes. / Mech.E

Arterial thrombus forms from the capture and accumulation of circulating platelets on a stenosis. As the thrombus grows, the lumen becomes further stenotic producing very high shear rates as the blood velocities increase through the narrowed cross-section. This study explores the molecular binding conditions that may occur under these pathologic shear conditions where circulating platelets must adhere quickly and with strong bonds. Platelets binding in an arterial stenosis of >75% are subject to drag forces exceeding 10,000 pN. This force can be balanced by 100 simultaneous GPIb-vWFA1 bonds of 100 pN each. The number and density of GPIb on platelets is sufficiently high; however, platelet capture under high shear would require the density of A1 receptors to be increased to over 416 per square micron. A computational model is used to determine platelet capture as a function of shear rate, surface receptor density, surface contact and kinetic binding rate. A1 density could be increased by a combination of vWF events of: i) plasma vWF attach to the thrombus surface and elongate under shear; ii) the elongated vWF strands create a net with 3-D pockets; and iii) additional vWF is released from mural platelets by activation under shear. With all three events, A1 density matches the existing high GPIbα densities to provide sufficient multivalency for capture at 100,000 s-1 with greater than 170 bonds per platelet. If the on-rate is greater than 108 M-1s-1, then a platelet could be captured within 15 microseconds, the amount of time available to form bonds before the platelet is swept away. This mechanism of platelet capture allows for the rapid platelet accumulation in atherothombosis seen clinically and in high shear experiments.