Dissertations / Theses on the topic 'Platelet aggregation'
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1
Vanags, Daina M. "Adrenergic and serotonergic potentiation of platelet aggregation /." Title page, summary and contents only, 1993. http://web4.library.adelaide.edu.au/theses/09PH/09phv217.pdf.
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Burgess-Wilson, Michael Edward. "Platelet aggregation in whole blood." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1996. http://arno.unimaas.nl/show.cgi?fid=7393.
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3
Wong, Truman. "Dynamics of platelet shape change and aggregation size-dependent platelet subpopulations." Thesis, McGill University, 1988. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61778.
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4
Riddell, David Ramsey. "Inhibition of platelet aggregation by apolipoprotein E." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287865.
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5
Meikle, Claire K. "Platelet-Leukocyte Aggregation in Lung Cancer Patients." University of Toledo Health Science Campus / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=mco1555937904448281.
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6
Sato, Masami. "Effects of barbiturates on human platelet aggregation." Kyoto University, 2003. http://hdl.handle.net/2433/148488.
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7
Wilson, Andrew. "Ethnicity, coronary heart disease risk and platelet aggregation." Thesis, The University of Sydney, 1996. https://hdl.handle.net/2123/27600.
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Objectives:
Part A. To analyse existing risk-factor studies in the population of Sydney for differences in established risk factors, particularly smoking, blood pressure and blood lipids, between Southern-European-born migrants and Australian-born subjects.
Part B. To examine a sample of Southern-European and Australia-born men without current CHD, of similar socio-economic background to:
i. Compare factors relating to haemostasis and coagulation which have been reported as predictive of CHD risk, especially platelet aggregability, fibrinogen and Factor VIIc levels.
ii. Compare other measures of haemostasis and coagulation which have been reported as varying among ethnic groups.
iii. Examine the determinants of platelet aggregability, especially the nutrient content of their usual diet.
iv. Examine the relations among established risk factor for CHD and measures of platelet aggregability.
8
Bunescu, Andreia. "Cellular markers indicating activation of the hemostatic system : studies on platelets and leukocytes in peripheral human blood /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-759-2/.
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9
Modica, Angelo. "Inflammation, platelet aggregation and prognosis in acute myocardial infarction." Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-32519.
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10
Para, Andrea N. "Preventing rapid platelet accumulation under very high shear stress." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/44726.
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Atherosclerosis is a major cause of mortality in industrialized nations. Atherosclerosis is characterized by plaque deposition which decreases the lumen diameter into a stenosis. The creation of a restriction increases shear rates pathologic levels exceeding 3,500/s. Following plaque cap rupture, thrombus may form from the accumulation of millions of platelets, occluding the vessel, leading to heart attack and stroke. Studies of high shear thrombosis show that platelet activation, GPIIb/IIIa and vWF are involved. However, some recent studies also suggest that high shear aggregation is not dependent on activation or GPIIb/IIIa. Several antiplatelet pharmaceuticals against activation
and GPIIb/IIIa have been proposed, but their efficacy in patients remains mixed. The overall
objective of this project is to determine the factors necessary for thrombosis to occlusion in very high shear regions seen in diseased arteries. Our central hypotheses are that platelet activation and the subsequent conformational change in GPIIb/IIIa are
necessary for thrombosis, and that higher concentrations of vWF in the plasma will
increase thrombosis.
To this end, we developed a new high shear hemodynamic model utilizing 30mLs of whole blood and quantified thrombus thickness, volume accumulation and accumulation rates. We demonstrate that thrombosis to occlusion stems from a second phase of Rapid Platelet Accumulation (RPA). Thrombus accumulation is completely prevented by PGE1 inhibition of platelet activation. Similarly, GPIIb/IIIa blockade via abciximab prevented significant thrombus deposition and RPA. We also found that
increasing plasma vWF levels in high shear regions increased thrombus thickness and
suggestively increased RPA rates. The results clarify the need for activation of mural
platelets for long term thrombus accumulation without the activation of circulating platelets.
11
Allison, Gillian Lenore. "The inhibitory mechanisms of aged garlic extract on platelet aggregation." Thesis, Liverpool John Moores University, 2007. http://researchonline.ljmu.ac.uk/5880/.
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Udovychenko, I. V., T. I. Halenova, and O. M. Savchuk. "European toad glandular secretions components induce platelet adhesion and aggregation." Thesis, Київський національний університет технологій та дизайну, 2020. https://er.knutd.edu.ua/handle/123456789/15574.
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13
Travers, M. "In vitro and clinical investigation of blood-membrane interactions : Influence on platelets and the immune system of membrane structure and antithrombotic agents." Thesis, University of Strathclyde, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382445.
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14
Hurley, Bridget Anne. "Design of an acoustic device to measure platelet adherence and aggregation." Thesis, Georgia Institute of Technology, 1998. http://hdl.handle.net/1853/16379.
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15
Drahos, Karen Elizabeth. "Sulfatides mediate Disabled-2 membrane localization and stability during platelet aggregation." Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/31626.
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Thrombosis, the major cause of heart attack and strokes,1 is triggered by localized clotting of the blood as the result of deregulated platelet aggregation. During the repair of vascular injury, clotting usually occurs when platelets adhere to each other at the site of vascular injury in order to stop bleeding.2 Distinct protein receptors and adhesive ligands together with the blood flow conditions govern this process. One of the negative regulators in platelet aggregation is Disabled-2 (Dab2), a modular protein that is released upon platelet activation to the extracellular platelet surface.3 Dab2 inhibits platelet aggregation through its phosphotyrosine-binding (PTB) domain by competing with fibrinogen for ï ¡IIï ¢3 integrin binding on the activated platelet surface.3 Sulfatides are also found on the platelet surface,4 interacting with adhesive and coagulation proteins5-7 and, thus, they are thought to play a major role in haemostasis and thrombogenesis.
Here, we show that the Dab2 PTB domain specifically interacts with sulfatides through two conserved basic motifs. The sulfatide-binding site overlaps with that of phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) in the PTB domain. Whereas sulfatides recruit the Dab2 PTB domain to the platelet surface, thus sequestering the protein from thrombin-mediated platelet aggregation, the phosphoinositide mediates its internalization. Experimental data support the hypothesis that two pools of Dab2 co-exist at the platelet surface and that the balance between them controls the extent of the clotting response.Master of Science
16
Welsh, John Douglas. "Disabled-2 regulates platelet heterotypic and homotypic aggregation through sulfatide binding." Thesis, Virginia Tech, 2010. http://hdl.handle.net/10919/31695.
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At the site of vascular injury platelet aggregation serves to stem blood flow, initiate the inflammatory response, and stimulate wound healing. Platelets become stimulated, release their granule contents, and become adherent to one another. Platelet granules contain important clotting factors and regulators of aggregation. Disabled-2 (Dab2) is a negative regulator of platelet aggregation released from platelet α-granules. Dab2 binds to the αIIbβ3 integrin, through the PTB domain, and blocks fibrin binding to the integrin which serves as the major cause of platelet-platelet interactions. Dab2 is also capable of binding to sulfatides, through the N-PTB region, expressed on the outer leaflet of adjacent cells. Dab2-sulfatide binding decreases Dab2â s ability to interact with the αIIbβ3 integrin, however sulfatides activate and stimulate platelet-platelet and platelet-leukocyte aggregation. Sulfatide addition to platelets stimulates increased αIIbβ3 integrin and P-selectin expression through stimulation of continued platelet degranulation, and these surface receptors mediate platelet heterotypic and homotypic aggregation.
Here, we show that Dab2 N-PTB binding of sulfatides serves to increase the inhibitory affect of Dab2. Sulfatide stimulation of platelet degranulation can be blocked by the addition of N-PTB. Inhibition of sulfatide induced αIIbβ3 integrin and P-selectin expression result in decreased platelet-platelet aggregation under flow. N-PTB also blocks sulfatide induced platelet-leukocyte interactions and aggregation. Experimental data supports the hypothesis that Dab2-sulfatide binding serves to increase the inhibition of platelet aggregation.
Master of Science
17
Coimbra, Leila Santana. "Influência de drogas antiplaquetárias na reparação da doença periodontal experimental em ratos /." Araraquara : [s.n.], 2010. http://hdl.handle.net/11449/95389.
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Orientador: Luís Carlos SpolidorioBanca: Joni Augusto Cirelli
Banca: Raquel Fernanda Gerlach
Resumo: O objetivo deste trabalho foi avaliar o efeito da administracao da aspirina (Asp), do clopidogrel (Clo) e da ticlopidina (Tic) sobre o processo de reparacao dos tecidos periodontais apos inducao experimental de periodontite em ratos. Primeiramente avaliou-se a acao destas drogas sobre a expressao das citocinas pro-inflamatorias: TNF-α, IL-6 e TXA2 no tecido gengival de 25 ratos subdivididos em 5 grupos (n=5), 15 dias apos a instalacao da ligadura ao redor do primeiro molar inferior. Para avaliacao do reparo dos tecidos periodontais, setenta e dois ratos (Rattus norvegicus albinus, Holtzman) foram distribuídos aleatoriamente em 6 grupos (n=12), sendo 1 controle e 5 submetidos a periodontite atraves da instalacao de ligadura bilateral na regiao de primeiro molar inferior. Apos 15 dias, o grupo controle e um grupo com periodontite foram sacrificados. Para a inducao do reparo dos tecidos periodontais, as ligaduras dos animais dos outros 4 grupos foram removidas e os ratos foram tratados com solucao de NaCl 0.9%, Asp (30mg/kg), Clo (75 mg/kg) e Tic (300 mg/kg), diariamente, via gavagem. Apos 15 dias de tratamento, os animais foram sacrificados, as hemi- mandibulas do lado direito removidas para analise histologica e as do lado esquerdo para avaliacao macroscopica, microtomografia computadorizada e analise da expressao, atividade especifica e co-localizacao das metaloproteinases de matriz (MMPs) -2 e -9 atraves de zimograma e zimografia in situ. Apos a retirada da ligadura, houve reparacao do osso alveolar e reparacao do tecido gengival representado pela recomposicao da arquitetura tecidual do epitélio e do tecido conjuntivo. O tratamento com Asp comprometeu a reparacao óssea alveolar na face mesial e acelerou na area de furca, ao passo que nao influenciou na recomposicao da arquitetura do tecido epitelial e... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The aim of this study was to evaluate the effect of administration of aspirin (Asp), clopidogrel (Clo) and ticlopidine (Tic) in the process of periodontal tissue repair after induction of experimental periodontitis in rats. First, we evaluated the action of these drugs on the expression of pro-inflammatory cytokines: TNF-α, IL-6 and TXA2 in the gingival tissue of 25 rats randomly distributed in five equal groups (n=5), 15 days after ligature placement around lower first molars. For periodontal tissue evaluation, seventy-two rats (Rattus norvegicus albinus, Holtzman) were randomly distributed in 6 equal groups (n=12). One control and 5 submitted to a ligature-induced periodontitis model in the region of lower first molar bilaterally. After 15 days, the control group and a group with periodontitis were sacrificed. To induce periodontal tissue repair, ligatures from the other 4 groups were removed and the rats treated with NaCl 0.9%, Asp (30 mg/kg), Clo (75 mg/kg) and Tic (300 mg/kg) daily by gavage. After 15 days of treatment, animals were killed, the right mandibles were removed for histological analysis and the left side to macroscopic, microtomography evaluation and expression, activity and colocalization of matrix metalloproteinases (MMPs) -2 and -9 by zymogram and in situ zymography. After removal of the ligature, there was repair of the alveolar bone and gingival tissue represented by the restoration of tissue architecture of the epithelium and connective tissue. Treatment with Asp undertook the repair of the mesial alveolar bone and accelerated the repair of furcation area, while not influenced the restoration of tissue architecture and epithelial tissue. Treatment with Tic undertook the repair of mesial alveolar bone and furcation the area, as well as the repair of gingival epithelial... (Complete abstract, click electronic access below)
Mestre
18
Shrum, Jeff. "Platelet adhesion in an asymmetric stenosis flow model." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100235.
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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.
19
Mitander, Maria. "Evaluation of platelet parameters from Advia 2120 and Sysmex XT-2000iV in samples from dogs, horses and cats." Thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9260.
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Haematology instruments using optical and fluorescence techniques have improved the platelet count in domestic animals. There are still some difficulties present, especially when counting cat thrombocytes due to their ability to aggregate and the occurrence of large platelets.
The objective of this study was to evaluate and compare the platelet count, mean platelet volume and platelet crit in dogs, horses and cats on Advia 2120 and Sysmex XT-2000iV.
Fresh blood samples from 64 dogs, 40 horses and 39 cats with various medical conditions were analysed on both instruments. Manual blood smears of all feline samples were scrutiniously analysed to evaluate the aggregation warning flag from Advia.
There was good agreement between the instruments for the optical platelet count in dogs and cats. Slightly higher values were reported from Advia. Samples from horses presented poor correlations for all studied parameters. Platelet clumps appeared in 70% of the 37 scrutinized feline blood smears, while 46% of the samples generated aggregation warning flags from the Advia instrument.
Advia and Sysmex showed good agreement for platelet counts in blood from dogs and cats. Mean platelet volume and platelet crit need further evaluation before conclusions can be made concerning their clinical relevance. The sensitivity of the platelet aggregation warning flag from the Advia instument needs further elevation.
20
Corbett, Eric J. "Effects of Oral L-arginine Supplementation on Platelet Count and Maximal Oxygen Consumption in Healthy Males." University of Akron / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=akron1239596277.
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Willoughby, Scott R. "Inhibition of human platelet aggregation by perhexiline maleate : mechanisms and therapeutic implications /." Title page, contents and summary only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phw739.pdf.
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Mooney, Robert Francis. "The regulation of platelet aggregation by glycoprotein IIb-IIIa receptor and fibrinogen /." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60500.
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We compared both the rate and extent of platelet aggregation with the extent of fibrinogen receptor expression and specific Fg binding to activated platelets, as a function of ADP concentration. Human citrated platelet-rich plasma (diluted ten-fold) was maximally pre-activated by incubating with adenosine diphosphate (ADP) at room temperature and then stirred. Platelet aggregation was determined from the decrease in the total number of particles. The number of fibrinogen receptors or bound Fg was measured from mean fluorescence values obtained with FITC-labelled IgM monoclonal antibody PAC1, and the IgG monoclonal antibody, 9F9, respectively, using flow cytometry. The expression of fibrinogen receptors occurs within seconds of activation. The fraction of platelets with fluorescence values above one critical threshold value increased with increasing activator concentration and correlated linearly with the fraction of platelets recruited into aggregates for ADP (r $>$ 0.9). Aggregation was not rate-limited by fibrinogen receptor expression nor by Fg binding. It appears that each platelet expresses $>$90% of its maximal Fg receptors at a critical ADP concentration i.e, occupancy of ADP receptors. This, in turn, leads to rapid Fg occupancy and platelet aggregation.
23
Kurlak, Lesia Olha. "The influence of membrane properties on platelet aggregation in the human neonate." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272377.
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Wellings, Peter John. "Mechanisms of platelet capture at very high shear." Thesis, Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/39582.
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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.
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Forster, Trevor Henry. "Effect of inhibitors of platelet function in haemostasis." Thesis, Queensland University of Technology, 1986. https://eprints.qut.edu.au/36709/1/36709_Forster_1986.pdf.
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Investigation of the role of platelets in the haemostatic
process has been a high priority for many years. In
spite of this the mechanisms by which platelets help to
maintain vascular integrity in undamaged blood vessels
have not been clearly defined. The concept of
endothelial support suggested by the work of Wojcik, Van
Horn, Webber and Johnson (6) has been controversial as it
implies a direct interaction between platelets and
endothelium. An alternate theory offered has been that
of platelet support by attachment to sub-endothelium
following damage to the endothelial cell layer.
To investigate the proposition that platelets and
endothelial cells were capable of direct interaction, a
reaction system using cultured human umbilical vein
endothelial cells was devised. As a result of
experiments using this model it has been shown that a
direct reaction between platelets and endothelial cells
does occur in vitro.
Experiments and techniques were devised to investigate
both the observed interaction and to assess the effect of
inhibitors of platelet function on the reaction.
Evidence gained by scanning electron microscopy and
transmission electron microscopy indicates that a
specific interaction actively involving endothelial cells
is responsible for the observed attachment of platelets
to these cells.
Studies using aspirin inhibited platelets indicate that a
two stage process is involved
first stage of which is
cyclo-oxygenase pathway. The
in this interaction,
independent of
second stage of
reaction appears to involve an active contribution
endothelial cells via their cyclo-oxygenase pathway.
26
Liu, Qingde. "Molecular and physical determinants of fibrinogen-dependent platelet aggregation and adhesion in flow." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ50213.pdf.
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Liu, Qingde 1963. "Molecular and physical determinants of fibrinogen-dependent platelet aggregation and adhesion in flow." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35909.
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Fibrinogen (Fg) mediates platelet aggregation and adhesion to artificial surfaces by interacting with its receptor, glycoprotein IIb and IIIa complex (GPIIbIIIa, or integrin alphaIIbbeta 3), on the platelet membrane. Considerable evidence has demonstrated that the (H12) on the gamma chain carboxyl terminus is required for the binding of Fg from solution to activated platelet GPIIbIIIa, while the RGD sites, the universal integrin recognition domain on adhesive ligands, are not involved. In this study, using recombinant Fg, well-defined Fg plasmin digestion fragments, and specific monoclonal anit-Fg antibodies, we demonstrated that the same sequence, the H12, or more precisely, the AGDV on the extreme carboxyl terminus of the gamma chain (gamma408--411), is also required for platelet-bound Fg to support platelet aggregation (crosslinking), thus experimentally verifying the "two sticky ends" theory of Fg-mediated platelet aggregation The RGD-containing domains on the Aalpha chains are not involved in aggregation. The AGDV sequence on the gamma chain carboxyl terminus is also necessary and sufficient for activated platelets to adhere to surface-adsorbed Fg, while the RGD sequences we similarly not required. A receptor induced binding site (RIBS), the Fg RIBS-I site (gamma373--385), on Fg either bound to its GPIIbIIIa-receptor or on a surface, is not directly involved in interactions between platelet GPIIbIIIa and immobilized Fg. The inhibitory effects of the anti-Fg-RIBS-I antibody are due to steric hindrance of the accessibility of the AGDV site to platelet GPIIbIIIa. Thus, the extreme carboxyl terminus of the gamma chain is the only site in both fluid and solid phase Fg that is involved in platelet GPIIbIIIa-Fg interactions.Though resting platelets are able to adhere to surface-bound Fg, this adhesion efficiency is much lower than that of the adhesion of the activated platelets. The adhesion efficiency of both resting and activated platelets to surface-adsorbed Fg decreases with increasing shear rate from 100 s -1 to 2,000 s-1. However, the decrease of the adhesion efficiency of the resting platelets is more marked than the decrease of the adhesion efficiency of the activated ones. Thus, the higher the shear rates, the larger the difference in the adhesion efficiencies between resting and activated platelets. However, due to the higher collision frequencies at higher shear rates, the adhesion of resting platelets was maintained at a similar level from shear rates of 300--2,000 s-1, while the adhesion of activated platelets kept increasing from 100 s -1 to 2,000 s-1. These data indicate that platelet activation is an efficient regulation pathway for platelet adhesion to surfaces.
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Plesser, Kristin [Verfasser]. "Protease-activated receptor 4-deficiency reduces inflammation-associated neutrophil-platelet aggregation / Kristin Plesser." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/1153196697/34.
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Fraser, Joanne Louise. "Influence of synthetic progestogens on platelet aggregation and arrhythmias associated with myocardial ischaemia." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343753.
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Hagger, Madison Barbara Allerton. "The synergy of adenosine and ibrutinib on platelet aggregation in chronic lymphocytic leukemia." Thesis, Hagger, Madison Barbara Allerton (2021) The synergy of adenosine and ibrutinib on platelet aggregation in chronic lymphocytic leukemia. Honours thesis, Murdoch University, 2021. https://researchrepository.murdoch.edu.au/id/eprint/61681/.
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Introduction:
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults caused by a gradual clonal expansion of B-cells in the bone marrow. Bruton’s Tyrosine Kinase (BTK) plays a role in the signalling of immune cells such as B-cells and platelets and has been implicated in the survival pathways of cancer. The BTK inhibitors, ibrutinib and acalabrutinib, are used to treat CLL; however, a significant bleeding risk has been observed in patients taking these inhibitors that is not seen in people with BTK-mutation (X-lined agammaglobulinemia (XLA)). CLL patients using ibrutinib and acalabrutinib have platelet dysfunction characterised by impaired response to collagen-related peptide (CRP; a specific glycoprotein VI (GPVI) agonist) and collagen. A disease factor may potentiate the antiplatelet effects of BTK inhibitors to cause significant bleeding issues in CLL patients. The CLL microenvironment is characterised by high levels of CD73-generated adenosine, which plays a role in suppressing immune responses such as platelet aggregation. Thus, it is hypothesized that adenosine amplifies the effect of ibrutinib and acalabrutinib to inhibit platelet function, which would explain the associated increased bleeding risk.
Methods:
Plasma was collected from stable, untreated CLL patients (n = 24) and age-matched healthy controls (n = 10). Using ELISA and the Malachite green assay, soluble CD73 levels and activity were determined. For ex vivo platelet activation studies, blood was collected from healthy volunteers into sodium citrate for whole blood assays (n=2), or ACD anticoagulant (n=6) for washed platelet tests. Flow cytometry, light transmission aggregometry, and Western blotting were used to delineate the impact of adenosine on the antiplatelet activities of ibrutinib and acalabrutinib.
Results:
Soluble CD73 was detected in the plasma of CLL patients, and its activity was confirmed by measuring phosphate generation from AMP using the Malachite green assay and a selective CD73 inhibitor. In whole blood platelet activation assays, adenosine potentiated the antiplatelet effect of ibrutinib and acalabrutinib. In washed platelets, using clinically relevant concentrations, ibrutinib and acalabrutinib inhibited CRP (P < 0.0001) but not collagen-induced platelet aggregation as single agents (P > 0.05). When combined with the adenosine derivative, 2-Hexynyladenosine-5'-N-ethylcarboxamide (HENECA), both inhibitors managed to reduce collagen-induced platelet aggregation, although Ibrutinib’s effect was stronger (P < 0.0001). The combination of HENECA with ibrutinib or acalabrutinib broadens the antiplatelet activity of these inhibitors as evidenced by changes in collagen-mediated phosphorylation of the downstream kinases: ERK, AKT, VASP, BTK and SYK.
Conclusion:
The results of this study provide initial evidence that increased bleeding risk present in the CLL microenvironment might be caused by the synergy between the BTK inhibitors and high levels of adenosine. Furthermore, the synergistic effect was more pronounced with ibrutinib rather than acalabrutinib. Future studies should focus on examining the association between plasma adenosine levels, CD73 and platelet activation in CLL patients.
31
Bartholomew, Ashley Elizabeth. "Enhancement of platelet activation and aggregation by erytrocytes: role of red cells in thrombosis." Thesis, The University of Arizona, 2009. http://hdl.handle.net/10150/192286.
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Wilson, Alasdair. "The effects of combination antiplatelet therapy on smooth muscle mitogenesis after angioplasty for claudication." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=165239.
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peripheral arterial disease (PAD), a limiting factor in the success of percutaneous transluminal angioplasty (PTA) is the development of restenosis secondary to vascular smooth muscle cell (SMC) proliferation. The aim of this study was to determine the effect of combination antiplatelet therapy on the ability of plasma, from patients undergoing PTA, to stimulate SMCs in vitro. We aimed to investigate the effect of combination treatment on levels of circulating adhesion molecules and factors which mediate SMC proliferation in experimental models. We also sought to demonstrate any association between changes in measured markers and the development of restenosis or vascular events. Methods Fifty patients were randomised to receive clopidogrel or placebo, for thirty days, in addition to their daily 75mg aspirin. To measure proliferative capacity, diluted plasma was incubated with 24h-growth-arrested rat vascular SMCs, and Extracellular-regulated-kinase (ERK)1/2 activation was analysed by Western blotting at baseline, 1-hour pre-PTA, and at 1-hour, 24-hours and 30-days post-PTA. Plasma platelet-derived growth factor (PDGF-BB), soluble (s)E-selectin, sICAM-1 (intracellular adhesion molecule-1) and von Willebrand factor (vWF) were measured by ELISA (Enzyme-linked immunosorbent assay), at the same time-points. Platelet activation was measured by flow cytometry of ADP-stimulated platelet fibrinogen binding at baseline and 1-hour post-PTA. Patients’ notes and all investigations were reviewed for 2 years post-PTA to record restenosis or vascular events. Results Samples were available for all 50 patients at baseline, 1-hour pre-PTA and 1-hour post-PTA timepoints. In this cohort ERK1/2 activation was significantly increased post-PTA in both the aspirin/clopidogrel and aspirin/placebo groups. Those who developed a symptomatic restenosis had a significantly higher level of SMC activation at the 1-hour post-PTA time-point. There was a statistically significant decrease in PDGF-BB, and increase in vWF, following loading with clopidogrel. sICAM-1 levels significantly decreased in the aspirin/placebo group following PTA. ADP-stimulated platelet fibrinogen binding was significantly inhibited by clopidogrel therapy post-PTA. Conclusions This is the first study to show in-vitro ERK1/2 activation (a marker of SMC proliferation) increases post-PTA. Patients developing a symptomatic restenosis had a significantly higher level of SMC activation at the 1-hour post-PTA time-point. Clopidogrel therapy had no significant effect on ERK1/2 activation, although it did reduce PDGF-BB in the larger cohort of patients. Further work is required to evaluate potential therapeutic treatments which may reduce peripheral PTA-induced smooth muscle cell activation.
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Coimbra, Leila Santana [UNESP]. "Influência de drogas antiplaquetárias na reparação da doença periodontal experimental em ratos." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/95389.
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O objetivo deste trabalho foi avaliar o efeito da administracao da aspirina (Asp), do clopidogrel (Clo) e da ticlopidina (Tic) sobre o processo de reparacao dos tecidos periodontais apos inducao experimental de periodontite em ratos. Primeiramente avaliou-se a acao destas drogas sobre a expressao das citocinas pro-inflamatorias: TNF-α, IL-6 e TXA2 no tecido gengival de 25 ratos subdivididos em 5 grupos (n=5), 15 dias apos a instalacao da ligadura ao redor do primeiro molar inferior. Para avaliacao do reparo dos tecidos periodontais, setenta e dois ratos (Rattus norvegicus albinus, Holtzman) foram distribuídos aleatoriamente em 6 grupos (n=12), sendo 1 controle e 5 submetidos a periodontite atraves da instalacao de ligadura bilateral na regiao de primeiro molar inferior. Apos 15 dias, o grupo controle e um grupo com periodontite foram sacrificados. Para a inducao do reparo dos tecidos periodontais, as ligaduras dos animais dos outros 4 grupos foram removidas e os ratos foram tratados com solucao de NaCl 0.9%, Asp (30mg/kg), Clo (75 mg/kg) e Tic (300 mg/kg), diariamente, via gavagem. Apos 15 dias de tratamento, os animais foram sacrificados, as hemi- mandibulas do lado direito removidas para analise histologica e as do lado esquerdo para avaliacao macroscopica, microtomografia computadorizada e analise da expressao, atividade especifica e co-localizacao das metaloproteinases de matriz (MMPs) -2 e -9 atraves de zimograma e zimografia in situ. Apos a retirada da ligadura, houve reparacao do osso alveolar e reparacao do tecido gengival representado pela recomposicao da arquitetura tecidual do epitélio e do tecido conjuntivo. O tratamento com Asp comprometeu a reparacao óssea alveolar na face mesial e acelerou na area de furca, ao passo que nao influenciou na recomposicao da arquitetura do tecido epitelial e...
The aim of this study was to evaluate the effect of administration of aspirin (Asp), clopidogrel (Clo) and ticlopidine (Tic) in the process of periodontal tissue repair after induction of experimental periodontitis in rats. First, we evaluated the action of these drugs on the expression of pro-inflammatory cytokines: TNF-α, IL-6 and TXA2 in the gingival tissue of 25 rats randomly distributed in five equal groups (n=5), 15 days after ligature placement around lower first molars. For periodontal tissue evaluation, seventy-two rats (Rattus norvegicus albinus, Holtzman) were randomly distributed in 6 equal groups (n=12). One control and 5 submitted to a ligature-induced periodontitis model in the region of lower first molar bilaterally. After 15 days, the control group and a group with periodontitis were sacrificed. To induce periodontal tissue repair, ligatures from the other 4 groups were removed and the rats treated with NaCl 0.9%, Asp (30 mg/kg), Clo (75 mg/kg) and Tic (300 mg/kg) daily by gavage. After 15 days of treatment, animals were killed, the right mandibles were removed for histological analysis and the left side to macroscopic, microtomography evaluation and expression, activity and colocalization of matrix metalloproteinases (MMPs) -2 and -9 by zymogram and in situ zymography. After removal of the ligature, there was repair of the alveolar bone and gingival tissue represented by the restoration of tissue architecture of the epithelium and connective tissue. Treatment with Asp undertook the repair of the mesial alveolar bone and accelerated the repair of furcation area, while not influenced the restoration of tissue architecture and epithelial tissue. Treatment with Tic undertook the repair of mesial alveolar bone and furcation the area, as well as the repair of gingival epithelial... (Complete abstract, click electronic access below)
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Lopes-Pires, Maria Elisa 1980. "Estudo das vias de sinalização envolvidas na ativação da NADPH oxidase e na inibição da agregação plaquetária na sepse experimental." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308118.
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Orientador: Sisi Marcondes PaschoalTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A sepse e ainda causa de muitos óbitos em hospitais do mundo todo. A gravidade da sepse esta relacionada ao estado de ativação de plaquetas. Trabalho prévio do nosso grupo mostrou que o tratamento de ratos com lipopolissacarideo (LPS) leva a inibição da agregação plaquetaria e aumento da formação de espécies reativas de oxigênio (EROs) via NADPH oxidase. Entretanto, o efeito inibitório do LPS na agregação não e dependente da liberação de EROs. Portanto, o objetivo do presente trabalho foi investigar as vias de sinalização envolvidas na inibição da agregação e na ativação da NADPH oxidase em plaquetas de ratos tratados com LPS. Para tanto, ratos Wistar machos foram injetados com LPS (1 mg/kg, i.p.) e apos 6h ou 48h o sangue foi coletado. A agregação plaquetaria foi induzida por ADP (10 ?M) na ausência e na presença de diferentes inibidores enzimáticos. A formação de EROs em plaquetas foi determinada por citometria de fluxo utilizando a sonda fluorescente DCFH-DA e a concentração intraplaquetaria de GMPc por imunoensaio. Também foram realizados ensaios de western blotting para a analise da ativação das enzimas c-Src, AKT e NADPH oxidase, bem como para a detecção de proteínas contendo resíduos de nitrotirosina. A analise do western blotting mostrou que a fosforização da c-Src quinase no resíduo Tyr 416, que indica ativação da enzima, foi semelhante em plaquetas de ratos injetados com salina ou LPS em 6h ou 48h. Alem disso, a inibição de Src com PP2 (10 ?M) não modificou a agregação plaquetaria de ratos tratados com LPS. Nos verificamos que a inibição da agregação foi acompanhada por um aumento significativo dos níveis de GMPc, bem como da nitracao de proteínas, em plaquetas de ratos 6h ou 48h apos o tratamento com LPS. A incubação das plaquetas com o sequestrador de peroxinitrito -(-) epigalocatequina gallato (10 ?M) aumentou significativamente a agregação de ratos injetados com LPS em 48h, mas não alterou a agregação em 6h. Entretanto, a inibição da agregação plaquetaria em ratos tratados com LPS em 6h foi revertida pelo inibidor da enzima guanilil ciclase ODQ (25 ?M) ou pelo inibidor de PKG Rp-8-Br (25 ?M). De forma semelhante, o inibidor nao seletivo de PKC GF109203X (10 ?M) reverteu o efeito inibitório do LPS em 6h na agregação e reduziu os niveis de GMPc em plaquetas. Nos mostramos que a fosforização da AKT no resíduo Thr308 foi significativamente maior em plaquetas de ratos tratados com LPS quando comparado com ratos injetados com salina. A incubacao das plaquetas de ratos tratados com LPS com o inibidor de PI3K wortmannin (100 nM) nao modificou a agregação. Entretanto, o inibidor da AKT PPI-1 (20 ?M) aumentou a agregação para níveis semelhantes aos observados nos ratos injetados com salina. A agregação plaquetaria de ratos 48h apos o tratamento com LPS não foi afetada por nenhum dos inibidores enzimáticos utilizados neste trabalho. O aumento da geração de EROs em plaquetas de ratos tratados com LPS em 6h ou 48h foi acompanhado pelo aumento significativo da fosforização do resíduo Ser345 na subunidade p47-phox da NADPH oxidase. A incubação de plaquetas de ratos tratados com LPS com GF109203X inibiu a fosforização da p47-phox bem como reduziu a geração de EROS. A produção aumentada de EROs em plaquetas de ratos tratados com LPS em 6h também foi reduzida em 42% por PP2. A inibição de PI3K ou AKT não modificou a produção de EROS em plaquetas de ratos tratados com LPS. A incubação de plaquetas com ODQ ou com Rp-8-Br (5?M) reduziu significativamente a produção de EROS somente em plaquetas de ratos 48h apos o tratamento com LPS. Portanto, no presente trabalho podemos concluir que a inibição da agregação plaquetaria observada 6h apos a injeção de LPS e mediada pela via NO/GMPc/PKG e também e modulada pela PKC e AKT, enquanto que, o efeito inibitório do LPS em 48h e essencialmente dependente da formação de peroxinitrito. A produção aumentada de EROs em plaquetas de ratos tratados com LPS envolve a fosforização da subunidade p47-phox da NADPH oxidase pela PKC. Alem da PKC, são importantes no aumento da liberação de EROs em plaquetas a Src em 6h e a via GMPc/PKG em 48h apos a injeção de LPS
Abstract: Sepsis is still a cause of high mortality in hospitals all over the world and its severity is directly related to platelet activity. A previous work of our group showed that the treatment of rats with lipopolysaccharide (LPS) inhibited platelet aggregation and also increased reactive oxygen species (ROS) production which was mediated especially by NADPH oxidase. However, the inhibitory effect of LPS on platelet aggregation is independent of ROS formation. Therefore, in the present work we investigated the signaling pathways involved in the aggregation inhibition as well as in the increased ROS formation in platelets of LPS-treated rats. Male Wistar rats were injected with LPS (1 mg/kg, i.p.) and blood was collected after 6h or 48h. Platelet aggregation was induced by ADP (10 ?M) in the absence or in the presence of different enzymatic inhibitors. ROS formation in platelets was determined through flow cytometry using 2',7'-dichlorofluorescein diacetate (DCFHDA) and cGMP intraplatelet levels by enzyme immunoassay kit. Western blotting assays were carried out to analyze AKT and NADPH oxidase activation and the presence of nitrated proteins in platelets. In the present work, we observed that the inhibition of aggregation was accompanied by a significant increase of cGMP levels as well as protein nitration in platelets of LPS-treated rats. Incubation of platelets with the peroxynitrite scavenger -(-) epigallocatechingallate (10 ?M) significantly increased aggregation of LPS-treated rats at 48h, but did not modify it at 6h. However, the inhibitory effect of LPS at 6h on platelet aggregation was reversed by the guanylyl cyclase (sGC) inhibitor ODQ (25 ?M) or by the PKG inhibitor Rp-8-Br (25 ?M). Likewise, the PKC inhibitor GF109203X (10 ?M) reversed the inhibition of aggregation and the increased cGMP levels in platelets of LPS-treated rats at 6h. We demonstrated that AKT phosphorylation at Thr308 was significantly higher in platelets of LPS-injected rats than in the saline group. The AKT inhibitor PPI-1 (20 ?M) increased platelet aggregation of rats 6h after LPS-injection to the levels comparable to the saline group, despite of the PI3K inhibitor wortmannin (100 nM) has had no effect. Platelet aggregation of rats 48h after LPS injection was not affected by any enzymatic inhibitors used in this work. Increased ROS formation in platelets of LPS injected rats at 6h or 48h was followed by a marked increase of the NADPH oxidase subunit p47-phox phosphorylation at Ser345. Incubation of platelets of LPS-injected rats with GF109203X inhibited the p47-phox phosphorylation as well as ROS generation. The increased ROS production in platelets of rats 6h after LPS-injection was reduced 42% by PP2. Inhibition of both PI3K and AKT did not change ROS production in platelets of LPS-injected rats. Incubation of either ODQ or Rp-8-Br (5 ?M) reduced significantly the ROS production just in platelets of rats 48h after LPS-injection. Therefore, our results show that the inhibition of ADP-induced platelet aggregation of rats 6h after LPS injection is mediated by NO/cGMP/PKG-dependent mechanisms, and PKC and AKT probably act upstream upregulating this pathway. On the other hand, the inhibitory effect of LPS at 48h on platelet aggregation is essentially dependent on ONOO- production. In addition, our results show that the augmented ROS production in platelets of LPS-treated rats is mediated by PKCdependent phosphorylation of p47-phox. Besides PKC, the increased ROS formation in platelets is also modulated by Src at 6h after LPS injection, while NO/cGMP/PKG pathway takes part of this effect at 48h
Doutorado
Farmacologia
Doutora em Farmacologia
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Nylander, Sven. "Thrombin/ADP-induced platelet activation and drug intervention /." Linköping : Univ, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med885s.pdf.
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Kasirer-Friede, Ana. "Dynamics of von Willebrand factor-mediated platelet aggregation in laminar flow : physical and molecular determinants." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0020/NQ55344.pdf.
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Wang, Ying Jie. "Effects of advanced glycation end products and haemodialysis on platelet phosphatidylserine externalisation and micro-aggregation." Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443997.
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Shearer, Jennifer. "Effects of endocannabinoids in acute cerebal ischaemia and whole blood platelet aggregation in the rat." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18221.
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Cerebral ischaemia causes an increase in the endocannabinoid anandamide and expression of cannabinoid receptors in the brain. Endocannabinoids are known to exert anti-inflammatory effects and may reduce injury in cerebral ischaemia through modulation of the immune response. The aims of this study were to examine the effect of endocannabinoids, anandamide and 2-AG, in acute cerebral ischaemia and investigate the mechanisms involved, including characterising the microglia response. Endocannabinoids exert pro-aggregatory effects in human platelets and may affect cerebral ischaemia through actions on platelets. As such, it was decided to characterise the effects of endocannabinoids on platelet aggregation in rat whole blood. Anaesthetised rats underwent 4 hour permanent middle cerebral artery occlusion and received either: anandamide (10mg/kg, s.c.); 2-AG (6mg/kg, i.v.); metabolism inhibitors, URB597 (0.3mg/kg, s.c.) or JZL184 (10mg/kg, i.v.); or appropriate vehicle. Whole blood aggreg ometry was performed to examine the aggregatory effect of 2-AG (19-300(So(BM) alone and in the presence of cannabinoid receptor antagonists and metabolism inhibitors. Anandamide and URB597 did not affect total injury volume but modified injury topography with reduced cortical and increased subcortical injury. In contrast, 2-AG and JZL184 increased cortical injury volume (111.7±9.4mm³ and 121.3±10.1mm³ vs. 82.3±3.5mm³) and JZL184 increased total injury (167.9±13.5mm³ vs. 134.7±5.7mm³). Neither anandamide nor 2-AG significantly affected microglia number or activation. The detrimental effect of 2-AG and JZL184 may be related to a reduction in cerebral blood flow (20.2±8.8% and 22.7±6.4 at 4 hours vs. 56.4±12.1% with vehicle). In rat whole blood 2-AG produced agregation at micromolar concentrations through CB2 receptors and COX metabolism to form thromboxane A2. Addition of 2-AG and ADP in combination potentiated the ADP response. Endocannabinoids modified injury development. Endocannabinoids modified injury development inacute cerebral ischaemia but did not affect the microglia response. The effects of 2-AG on injury may be related to changes in cerebral blood flow and platelet aggregation.
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Fan, Jung, and 樊蓉. "The mechanical study of platelet-derived microparticles-stimulated platelets aggregation." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/40002767474287227782.
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碩士國立陽明大學
藥理學研究所
99
Blood contains many microparticles (MPs) derived from different cell types, mainly from platelets. Recently, the elevation of platelet-derived microparticles (PMPs) levels has been related to various physiological and pathological conditions such as cell adhesion, apoptosis, haemostasis, thrombosis, cardiovascular diseases, and cancer. Some studies have explored the action mechanisms of PMP formation. In addition to the known thrombin and collagen, my study found that various agents such as arachidonic acid, ADP, IBOP, PAF and A23187 all can induce PMPs formation. To study the biological function of PMPs, the present study prepared PMPs from A23187-stimulated platelets and characterized them by CD41 and annexin V double staining and Megamix beads standardization using flow cytometry. Since the isolated PMPs can induce platelet aggregation, the underlying action mechanisms were studied. As some inhibitors such as SQ-29548 (a TXA2 antagonist), CV3988 (a PAF antagonist) and aspirin were applied, the PMPs-stimulated platelet aggregation can be inhibited by CV3988 or SQ-29548, but not by aspirin. And ginkgolide B, the other known PAF antagonist, also could suppress the PMPs-induced platelet aggregation. The results indicated that PAF may be produced and distributed into PMPs’ membrane which could induce platelet aggregation. Trying to change the PAF metabolism to affect PAF content of PMPs, both SB203580 and dexamethasone pretreatment could not affect the action of induced PMPs on platelet aggregation. However, PAF content in the membrane surface of PMPs couldn’t be detected by PAF ELISA kit but PMPs’ supernatant could be detected. So, the actual mechanisms of PMPs induce platelet aggregation need to further study.
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Fang, Chiao-Ling, and 方喬玲. "Mechanisms of morphine potentiated agonist-induced platelet aggregation in human platelets." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/10384534537796013427.
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碩士台北醫學院
醫學研究所
88
The discovery of pharmacological activity of morphine early in the 19th century and the demonstration of its potent analgesic properties. Morphine had been used to relax the pain of cancer patients on the last phase , and dealed with some serious diseases、trauma and surgery was needed. However, how the influence of morphine on wash human platelets, and what are the mechanisms involved in this influence, it still remains unclear. Recently the subject had not been discussed widely. The aim of this thesis is to further investigate the detailed mechanisms of morphine on human platelets. In our studies, we found that morphine (1, 5 M) dose—dependently potentiated platelet aggeregation and ATP release by collagen (1 g/ml) and U46619 (0.5 in human platelet suspensions. Morphine (5 M) potentiated [3Hinositol monophosphate formation stimulated by collagen (5 g/ml) in [3Hmyoinositol loaded platelets. Furthermore, morphine also potentiated [Ca2+]i mobilization in human platelet suspensions stimulated by collagen (1 g/ml). At the same dose, morphine significantly potentiated thromboxane B2 formation of collagen-activated platelets. Consequently, we measured prostagladinE2 formation as an index of cyclooxygenase activity. We found that morphine had no significant effect on cyclooxygenase activity, and found it did not potentiate collagen-induced platelet aggregation in the presence of yohimbine. According to these results, we found the effect of morphine on human platelets may be mediated via activation of adrenoceptors. On the other hand, morphine (1, 5 ) inhibited prostaglandin E1 (10 induced cyclic AMP increase in human platelets. We examined this potentiation involved in platelet signal transduction system such as Na/H pump in human platelet suspensions. In contrast, morphine did not significantly increase nitrate formation in human platelets. Moreover, we found morphine did not influence the binding of FITC-triflavin to platelet glycoprotein IIb/IIIa complex. Triflavin, an Arg-Gly-Asp-containing antiplatelet peptide, was purified from Trimeresurus flavoviridis snake venom. Measurement of the platelet membrane fluidity, we found that morphine did not significantly affect the platelet membrane fluidity diphenylhexatriene (DPH)-loaded platelets . Based on the above observations, we suggested that morphine may bind to adrenoceptors in human platelets, resulting in inhibition of cyclic AMP formation and concurrently increased intracellular Ca2+, resulting in activation of phospholipase A2 , and increased formation of thromboxane A2 formation, and potentiation of platelet aggregation.
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Lin, Chien-Liang, and 林建良. "Anti-platelet aggregation of Scutellaria baicaleinsis." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/61784048923192672725.
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碩士台北醫學院
生藥學研究所
88
Scutellariae Radix, the roots of Scutellaria baicalensis Georgi (Labiatae) has been demonstrated that the therapeutic effects on treatment of bloodless in Chinese medicinal books. However, the action mechanism of Scutellariae Radix on blood function is undefined. Therefore, study the functions of Scutellariae Radix on platelet aggregation was performed in this project. Baicalin、baicalein、oroxylin A and wogonin are the major compounds of Scuteiilaire Radix and several biological activities have been demonstrated in these compounds including antioxidant activity and anti-inflammation. In order to study the activities from Scutellariae Radix on platelet aggregation, these four compounds isolated from Scutellariae Radix were used to investigate their inhibitory effects on platelet aggregation induced by collagen, U46619 or ADP in human platelet-rich plasma. The results showed that these four polyphenolic compounds showed the significant inhibition on collagen-, U46619- or ADP-induced aggregation. The IC50 values of baicalin, baicalein and wogonin are 74.5, 34.5, >100, 59.1 μg/ml in the collagen-induced aggregation, and 35.2, 37.7, 45, 45 μg/ml in the U46619-induced aggregation, respectively. As the same part of experiment, both baicalin and baicalein also showed the obvious dose-dependent inhibition of ADP-induced platelet aggregation, and the IC50 values are 61.5 and 65.8 μg/ml, respectively. These data provided evidences that Scutellariae radix inhibits stimulators induced platelet aggregation. Nitric oxide (NO) and TxB2 have been implicated to play as modulators in the process of platelet aggregation. Upon oroxylin A and wogonin treated platelet, NO production was significantly increased to 8.5 ± 0.4 and 15.5 ± 1.2 μM, respectively, as compared with the controlled group (2.6 ± 0.1 μM). A binding site for TxA2 antagonist wogonin to PRP was studied. Wogonin competitively antagonized aggregation of PRP by the TxA2 mimetic U46619. A Schild analysis of the pharmacology study revealed a pA2 of 3.90 and pA10 of 5.01. It suggests that this high-affinity binding sites is the site responsible for inhibition of aggregation induced by U46619. These data provided evidences that Scutellariae Radix inhibits stimulators induced platelet aggregation.
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Vanags, Daina M. "Adrenergic and serotonergic potentiation of platelet aggregation / Daina M. Vanags." Thesis, 1993. http://hdl.handle.net/2440/21466.
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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.
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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Yang, Wen-Chia, and 楊文嘉. "Inhibition of platelet aggregation in rabbit platelets by essential oils of herbs." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/38093217561766281371.
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碩士國立陽明大學
生物化學研究所
93
Platelet-activating factor (PAF) is an important pro-inflammatory mediator produced by various cells. It possesses potent activity for inducing aggregation and a series of inflammatory responses, and may be involved in serious pathological situations such as thrombosis, myocardial infraction and embolismic stroke. There are a number of herbs which were traditionally used to remove thrombi and promote circulation. However, there have been no reports concerning the pharmacological mechanism. Therefore, it is important to find out the components of essential oils isolated from traditional herbs, which have the activity to prevent the platelet aggregation induced by PAF. In the present study, from approximately 210 kinds of essential oils of herbs we found 25 candidates with the inhibitory effect on platelet aggregation induced by 5 nM PAF. The essential oil from P. cablin showed the excellent inhibitory effect, and the active compound, α-bulnesene, isolated from the oil of P. cablin was identified with GC / MS and NMR. According to the results, it showed that α-bulnesene inhibited platelet aggregation induced by PAF with the IC50 value of 24.47 ± 2.45 μM, and then the cytotoxic effect of α-bulnesene was excluded by LDH activity assay. Furthermore, α-bulnesene competitively inhibited [3H] PAF (0.2 nM) binding to PAF receptors on washed platelets with the IC50 value of 17.62 ± 5.68 μM. Moreover, it also concentration-dependently inhibited the PAF-induced intracellular Ca2+ release with the IC50 of 19.62 ± 1.32 μM. On the other hand, the inhibition of MDA biosynthesis revealed that α-bulnesene could interrupt AA metabolic pathway. The inhibition of TXB2 and PGE2 formation also indicated that α-bulnesene interfered with TXA2 production through inhibiting COX activity. Consequently, the above results indicated that α-bulnesene, the active compound isolated from the essential oil of P. cablin, exerted the inhibitory effect on PAF-induced platelet aggregation by competitively inhibiting PAF binding to PAF receptors, inhibited further intracellular Ca2+ mobilization, and inhibited TXA2 formation by interfering with the AA metabolism.
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Guo, Xuan-Zhong, and 郭軒中. "Inhibition of Platelet Aggregation by Morinda citrifolia Extracts." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/dhjv94.
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碩士元培科學技術學院
生物技術研究所
94
The present study was conducted to evaluate the antiplatelet activity of extracts from different parts of Noni (Morinda citrifolia L.), including leaf, fruit and stem. Ethanol and distilled water were used as solvents and antiplatelet effects measured by a platelet aggregation test. Rabbit platelets were prepared and incubated in vitro with different concentrations of the tested extracts and aggregation was induced by different agonists including collagen (10μg/ml), arachidonic acid (100μM), thrombin (0.1U/ml), PAF (2ng/ml) and U46619 (1μM). The aqueous extract of Noni leaf selectively and concentration dependently inhibited platelets aggregation caused by arachidonic acid and collagen without affecting the aggregation caused by thrombin, PAF and U46619. The IC50 value (drug concentration inhibiting maximum response by 50%) of the crude aqueous extract for aggregation induced by collagen and arachidonic acid was 7.9, 1.2 mg/ml, respectively. The aqueous extract of Noni leaf was time dependent. Furthermore, the extract inhibited thromboxane B2 and prostaglandin D2 formation provoked by collagen and arachidonic acid. Based on these observations, the data indicated that the extract potently inhibited rabbit platelet aggregation mainly via the inhibition of the cyclooxygenase-1 activity. On the other hand, the aqueous extract of Noni fruit selectively and concentration dependently inhibited platelets aggregation caused by collagen and U46619. The IC50 value of the crude aqueous extract for aggregation induced by collagen and U46619 was 7.6, 7.3 mg/ml, respectively. The ethanolic extract of Noni leaf produced an inhibitory effect on collagen, arachidonic acid and U46619-induced platelet aggregation with an IC50 of 0.18, 0.97, 0.58 mg/mL. The ethanolic extract of Noni fruit produced a inhibitory effect on collagen, arachidonic acid and U46619-induced platelet aggregation with an IC50 of 1.3, 2.7, 2.5 mg/mL. The ethanolic extract of Noni stem produced an inhibitory effect on collagen, arachidonic acid, U46619 and PAF-induced platelet aggregation with an IC50 of 1.45, 0.64, 0.98, 1.12 mg/mL. These results support the traditional use of Noni in the treatment and/or prevention of cardiovascular disease.
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CAI, XING-ZHANG, and 蔡星章. "Synthesis and activity of anti-platelet aggregation agents." Thesis, 1992. http://ndltd.ncl.edu.tw/handle/43696793326076902070.
Full text
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"Modeling of platelet aggregation via a continuum approach." Tulane University, 2001.
Find full textAbstract:
Using a modified form of Fogelson's continuum model of platelet aggregation, this work investigated relationships between platelet aggregation and the Reynolds number of the flow, the ratio of the formation of interplatelet links to the destruction of interplatelet links, and the platelet activation rate. Numerical simulations were performed via the finite element method using the FreeFem+ programming environment, and the flow domain was a straight vessel with a portion of the wall transiently releasing ADP into the flow to stimulate aggregation. The growth of an aggregate was found to be inversely related to the inlet Reynolds number. As the inlet Reynolds number increased, the overall profile of the aggregate decreased along with the concentration of platelets within the aggregate. For a given inlet Reynolds number, an upper limit was found for the ratio of link formation to link destruction, beyond which a stable aggregate could not be formed. A similar trend was observed for the rate of platelet activation, with a maximum rate of platelet activation for each inlet Reynolds number. Collectively, a region of stability was determined for the parameter values of the model, and the results compared well with experimental dataacase@tulane.edu
47
Lee, Ming-Kun, and 李銘坤. "Hemostatic and Anti-Platelet Aggregation Activities of Natural Sources." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/06091402250761264463.
Full textAbstract:
碩士台北醫學院
生藥學研究所
87
Hemostatic Abnormalities including the hemorrhage and thrombosis are the common diseases in human.There are still many sede effects in therapy drugs up to the present day. So this research uses the traditionalchinese hemostatic herbs and natural occurring furocoumarins and evaluates the hemostatic and anti-platelet activities of them.And the paper is divided into two parts. Part one. Bletillae tuber is the dried stem of the Orchidaceae plant Bletilla striata Thunb. It is used in traditional Chinese medicine with clinical application for lung, nose, and stomach hemorrhageing as well as for ameliorating post-operative bleeding, burns, and dermal splitting caused by aridity. At present research of the Bletillae tuber is limited to antibiotic applications and none has yet been conducted into hemostasis. The Dictionary of Traditional Chinese Medicine records that oral intake of the entire peanut (minus the shell) is effective in slowing bleeding in hemophiliacs. According to the dictionary, the potency of the skin is 50 times that of the nut . We still do not understand the principles behind this. This research project employs the delivery method of traditional chinese method and mixes powered Bletilla tuber into a 1.25%, 2.5%, and 5% gel solutions and peanut skinof Arachis hypogaea into 15.2mg/ml, 7.6mg/ml and 3.8mg/ml. Oral administration is given to both normal mice and heparin-induced pathological bleeding animal model of ICR mice to determine coagulation time, bleeding time, and changes in platelet count to assess the hemostatic activity of the bletillae tuber and arachis hypogaea. The resul The platelet aggregation of water extract, 50% methanol extract and 70% acetone extract of bletillae tuber and 96% Alcohol extract of peanut skinof Arachis hypogaea to collagen and ADP induced platelet aggregation in platelet rich plasma (PRP) from healthy blood donors. The results exhibited that the water extract of bletilla striata and 96% alcohol extract of Arachis hypogaea promoted the induced platelet aggregation . Part two.The anti-platelet aggregation of 14 furocoumarins including 2 angelicin type and 12 psoralen type to Collagen, ADP, arachidonic acid, Thrombin and PAF induced platelet aggregation in platelet rich plasma (PRP) from the healthy blood donors (without taking any medicine 2 week before) by the turbidimetric method. Aspirin is used as the positive control group. The results exhibited that Bergapten to the collagen, Phellopterin to the ADP, Psoralen to the Arachidonic acid, and Sphondin to the Thrombin a Psoralen (C5-H and C8-H ) is the most potency compound to the A.A induced platelet aggregation. If the side chain of C5 and C8 position are replaced with others , the anti-platelet activities will be decreased. Angelicin type show more potency than psoralen type in Thrombin and PAF induced platelet aggregation.The Sphondin (C5-H and C8-OCH3) shows the best anti-platelet activities to the thrombin and PAF induced platelet aggregation. When the side chain of C5 and C8 positions are exchanged ,it shows almost
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KUO, YI-CHUNG, and 郭義忠. "Synthesis, anti -platelet aggregation and vasorelaxation of adenine derivatives." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/99509535636967408362.
Full textAbstract:
碩士高雄醫學大學
天然藥物研究所
90
Numerous studies have shown that the Ganoderma lucidum can improve human immune-system, anti-hypertension, prevent blood coagulation, and anticancer effect, etc. Adenosine is one of the main compounds of the Ganoderma lucidum to have the anti-platelet aggregation activities. Adenosine derivatives, Adeno-1, Adeno-2, and Adeno-3 were designed and competited with YC-1 about their anti-platelet aggregation activities and vasorelaxant effects. Evidences indicated that Adeno-1, Adeno-2, and Adeno-3 (from 0.2 ~ 200 M) had concentration-dependently inhibited arachidonic acid (AA)-, collagen-, epinephrine-, ADP-, thrombin-, serotonin (5-HT)-, and PAF-induced platelet aggregation. In phenylephrine- preconstricted endothelium-intact or denuded rat aortic rings, Adeno-3 produced concentration-dependent relaxations. The relaxation was reduced by endothelium removal or by the presence of L-NAME (100 μM), a nitric oxide synthase inhibitor. In addition, the vasorelaxant effect of Adeno-3 was inhibited by pretreatment with a soluble guanylate cyclase inhibitors ODQ (1 μM), a K+ channels blocker TEA (10 mM), a voltage-dependent potassium channels blocker 4-aminopyridine (4-AP, 100 μM), and charybdotoxin (ChTX, 0.1 μM), while not significantly different with a KATP channels blocker glibenclamide (1 μM). Moreover, increased extracellular potassium levels (80 mM high potassium solution) resulted in an attenuation of the concentration-dependent vasodilator effects of Adeno-3. Preincubation with Adeno-3 could enhance the vasodilator response to the exogenous NO-donor SNP. In isolated rat atria, Adeno-3 didn’t produce inotropic or chronotropic activities. While the depressive effect was revealed at concentration above 10-5 M. Adeno-3 (with 0.1, 1, 10, 100 μM) induced concentration-dependently increases in intracellular cyclic GMP levels in rat aortic smooth muscle cells (RASMC). When pretreated with L-NAME (100 μM), methylene blue (100 μM) or ODQ (10 μM) before Adeno-3 (100 μM) , the contents of cyclic GMP was decreased. In phosphodiesterase inhibitor assay, Adeno-1, Adeno-2, and Adeno-3 were inhibited about 50%, 13%, and 71% activities related to the IBMX inhibited activities. It is suggested that the smooth muscle relaxant effects of Adeno-3 might be mediated by the stimulation of NO / sGC / cGMP pathway, the opening activity of the K+ channel and PDE5 inhibited effents. In human platelet, the Adeno-3 is able to inhibit the platelet aggregation activities might be mediated by the PDE5 inhibited effents.
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Almaghrabi, SY. "The Effects of vanilloid-like agents on platelet aggregation." Thesis, 2012. https://eprints.utas.edu.au/15891/2/whole-almaghrabi-exc-pub-mat.pdf.
Full textAbstract:
Capsaicin, the ‘hot’ principle found in chilli, and other vanilloids exert their effects on neuronal cells through activation of transient receptor potential vanilloid 1 (TRPV1). TRPV1 is widely distributed in neuronal and non-neuronal cells. It has been proposed that consumption of vanilloid-like agents, including capsaicinoids, inhibits platelet aggregation and may protect against the development of cardiovascular disease. The aim of this study was to investigate the effects of a range of vanilloid-like agents on in vitro platelet aggregation.
Venous blood was collected from healthy subjects who avoided antiplatelet medications and dietary chilli for at least 10 and 2 days, respectively. Collagen (4 and 8 μg/mL), ADP (10 and 5 μM) and arachidonic acid (AA) (300 and 400 mg/mL) -induced platelet aggregation was determined using platelet rich plasma (PRP; \(250x10^9L\)) in the absence and presence of the capsaicinoids [capsaicin and dihydrocapsaicin (DHC)] and the endocannabinoid/endovanilloid agents [Noleoyldopamine (OLDA) and N-arachidonoyl-dopamine e (NADA)]. %Maximum aggregation (%Max), % area under curve (%AUC) and slope of platelet aggregation were determined. Platelet lactate dehydrogenase (LDH), which is released rapidly after cell membrane damage, was investigated to determine the direct toxic effects of these agents on platelets. Platelet factor 4 (PF4) and β-thromboglobulin (β-TG) release were examined to determine the effects of vanilloids on alpha granule release. Finally, the effects of TRPV1 antagonist (SB-452533) on capsaicin- and OLDA-mediated inhibition of ADP-induced platelet aggregation were investigated.
ADP-induced (5 μM) platelet aggregation was inhibited in a concentration-dependent manner by capsaicin (%Max, mean ±SEM; 0 vs 100 μM, 83.8±0.9% vs 45.2±2.4%, n=6, p>0.001); OLDA (0 vs 100 μM, 71.6±8.2% vs 9.4±1.4%, n=4, p<0.001); and NADA (0 vs 100 μM, 71.5±5.9% vs 38.2±1.4%, n=4, p<0.008). Similar results were observed using 10 μM ADP. OLDA and NADA, but not capsaicin and DHC, inhibited platelet aggregation induced by 4μg/mL collagen: OLDA (Max%, 0 vs 100 μM, 89.3±1.4% vs 45.5±12.5%, p<0.001); and NADA (0 vs 100 μM, 87.7±0.8% vs 28.5±8.2%, p<0.001). AA-induced (300 mg/mL) aggregation was inhibited in a concentration-dependent manner by capsaicin (Max%, 0 vs 100 μM, 89.6±0.9% vs 11±0.8%, p<0.001); DHC (0 vs 100 μM, 88.3±2.1% vs 18.7±6.9%, p<0.001); and NADA (0 vs 100 μM, 84±1.8% vs 21.9±4.7%, p<0.001). Similar results were observed using 400mg/mL AA. The inhibition of platelet aggregation by all agents was not due to direct toxic effects as LDH release from platelets was unaffected by any of the vanilloids. SB-452533 did not inhibit the effects of OLDA (SB-45253; Max 0 vs 10μM, 55.9±2.1% vs 58.4±1.37%) and capsaicin (SB-45253; Max 0 vs 10μM, 65.15±0.44% vs 65.55±1%) on platelet aggregation, suggesting that inhibition of ADP-induced aggregation is not TRPV1 mediated. ADP-stimulated PF4 release from platelets was impaired by capsaicin, DHC and OLDA whereas NADA enhanced ADP-stimulated PF4 release. Furthermore, OLDA and capsaicin impaired the release of β-TG from ADP-stimulated platelets.
The present study using human platelet shows that capsaicin, DHC, OLDA and NADA inhibit in vitro aggregation. The inhibitory effects of vanilloids are not TRPV1 mediated and not due to a direct toxic effect on platelets. Vanilloids may inhibit platelet aggregation by interfering with granule release, although further investigation of this possibility is warranted.
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Stevens, Christiaan Simeon Michael. "A role for phosphatidylinositol 3-kinase in platelet aggregation." Thesis, 1999. http://hdl.handle.net/2429/9341.
Full textAbstract:
The aggregation of human platelets is an important physiological hemostatic event
contingent upon receptor-dependent activation of the surface integrin GPIIb-IIIa and
subsequent binding of fibrinogen. Previous studies have demonstrated that
phosphatidylinositol 3-kinase (PI 3-kinase) is activated both prior to, and following,
activation of GPIIb-IIIa in human platelets, but the role of PI 3-kinase in platelets has not
been elucidated. The objective of the work contained in this thesis was to better understand
the function of PI 3-kinase in platelets. I showed that the p85 subunit of PI 3-kinase
associates with a tyrosine-phosphorylated 105 kDa protein. This association was dependent
on GPIIb-IIIa activation and was not inhibited by PI 3-kinase inhibitors. Furthermore, the
protein was not immunoreactive with several antibodies to known proteins in this weight
range. PI 3-kinase inhibitors were also used to probe the dependence of thrombin-induced
aggregation on PI 3-kinase. It was found that when platelets were stimulated with high
concentrations of thrombin in the presence of LY294002, a competitive inhibitor of PI 3-
kinase, the inhibitors had no affect on aggregation nor GPIIb-IIIa activation. However,
with lower concentrations of thrombin, aggregation and GPIIb-IIIa activation were almost
completely inhibited by LY294002. These results indicate that aggregation and GPIIb-IIIa
activation is less dependent on PI 3-kinase activity when high concentrations of agonist are
used, indicating that there are PI 3-kinase-independent pathways that can function under
these conditions. Finally, the role of the SH2 domain containing inositol 5-phosphatase
(SHIP) in regulating the products of PI 3-kinase in platelets was investigated using mice
with a targeted gene disruption. It was found that the level of phosphatidylinositol 3,4,5-
trisphosphate [PI(3,4,5)P3] was increased in SHIP"7" platelets in response to Collagen
Related Peptide (CRP) whereas formation of phosphatidylinositol 3,4-bisphosphate
[PI(3,4)P2] was reduced demonstrating a role for the 5-phosphatase in the metabolism of
PI(3,4,5)P3 . I also demonstrated that the elevation of PI(3,4,5)P3 was insufficient to
activate phospholipase C but it enhanced the elevation of the protein tyrosine kinase, Btk,
and calcium influx.