Dissertations / Theses: 'Platelet response'

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Barbosa, Alzira Maria de Castro. "Chronic immune thrombocytopenic purpura and infection Helicobacter pylori: platelet response to the bacteria elimination of treatment." Universidade Federal do CearÃ, 2015. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=16378.

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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico The Chronic Immune Thrombocytopenic Purpura (ITPc) is a condition caused by autoimmune response resulting awareness of platelets by self antiplatelet antibodies, causing lysis of platelets. Infection with H. pylori has been shown to likely factor for the development of PTIc, with possible platelet response relationship in PTIc after treatment of bacterial eradication. The objective was to evaluate possible effects of eradication of Helicobacter pylori in the number of platelets of patients with PTIC patients at the University Hospital Walter CantÃdio. Were invited to participate in the study 29 patients with PTIc, 15 remained and all were treated for H. pylori and were followed for a period of 6 months to a year for clinical evaluation and platelet count. All patients underwent endoscopy for diagnosis of infection and, after treatment, held breath test to confirm eradication. PCR was performed for the presence of H. pylori cagA gene. Of the 15 patients 01 (6.6%) were male and 14 (93.3%) were female, the mean age was 47.7 years (27-68), the mean disease duration was 7.43 years (1-25). After the treatment, 13 patients (86.7%) eradicated H. pylori 04 (30.7%) had clinical response; and 03 (75.0%) complete response and 01 (25.0%) partial response to PTIc. It was possible to evaluate the presence of H. pylori CagA gene in 09 patients strains, 06 of these (54.5%) had CagA-positive strains. Of the 04 patients of the group who responded to treatment, 03 (75.0%) were cagA-positive. The treatment for eradication of Helicobacter pylori increased the number of platelets in 30% of patients with PTIc after six months of follow-up of these patients. A PÃrpura TrombocitopÃnica ImunolÃgica CrÃnica (PTIc) Ã uma afecÃÃo causada por resposta auto-imune decorrente da sensibilizaÃÃo das plaquetas por auto anticorpos antiplaquetÃrios, causando lise das plaquetas. A infecÃÃo pelo H. pylori tem sido mostrada como provÃvel fator para o desenvolvimento de PTIc, com possÃvel relaÃÃo de resposta plaquetÃria na PTIc apÃs o tratamento de erradicaÃÃo da bactÃria. O objetivo foi avaliar possÃveis efeitos da erradicaÃÃo do Helicobacter pylori no nÃmero de plaquetas dos pacientes com PTIc atendidos no Hospital UniversitÃrio Walter CantÃdio. Foram convidados a participar do estudo 29 pacientes com PTIc, 15 permaneceram e todos foram tratados para o H. pylori, sendo acompanhados por um perÃodo de 6 meses a um ano para a avaliaÃÃo clÃnica e contagem de plaquetas. Todos realizaram endoscopia digestiva para diagnÃstico da infecÃÃo e, apÃs o tratamento, realizaram teste respiratÃrio para confirmaÃÃo da erradicaÃÃo. Foi realizado PCR para averiguar a presenÃa do gene cagA do H. pylori. Dos 15 pacientes tratados 01 (6,6%) era do gÃnero masculino e 14 (93,3%) foram do gÃnero feminino, a mÃdia de idade foi de 47,7 anos (27-68), O tempo mÃdio de doenÃa foi de 7,43 anos (1-25). ApÃs o tratamento, 13 pacientes (86,7%), erradicaram o H. pylori, 04 (30,7%) obtiveram reposta clÃnica; sendo 03 (75,0%) resposta completa e 01 (25,0%) resposta parcial Ã PTIc. Foi possÃvel avaliar a presenÃa do gene cagA do H. pylori em cepas de 09 pacientes, desses 06 (54,5%) apresentaram cepas cagA-positivas. Dos 04 pacientes do grupo que responderam ao tratamento, 03 (75,0%) foram cagA-positivos. O tratamento para erradicaÃÃo do H.pylori aumentou de forma sustentada, mais de seis meses de seguimento, o nÃmero de plaquetas dos pacientes com PTIc, em trinta por cento dos pacientes avaliados. NÃo houve associaÃÃo estatÃstica significativa com nenhum dos fatores de risco avaliados, tais como, idade, gÃnero e tempo de doenÃa dos portadores e presenÃa do gene cagA.

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Narayanan, Padmini. "Interleukin 1 Receptor1 signaling in Platelet Inflammatory responses Interleukin-1ß processing and secretion." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1425911007.

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Nijm, Johnny. "Inflammation and cortisol response in coronary artery disease /." Linköping : Univ, 2007. http://www.bibl.liu.se/liupubl/disp/disp2007/med1037s.pdf.

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Balasubramaniam, Karthik. "Platelet dependent thrombosis, blood thrombogenicity and response to antiplatelet therapy in health, ageing and type 2 diabetes mellitus." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3499.

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Elderly and type 2 diabetes mellitus (T2DM) patients with stable coronary artery disease (CAD) have increased risk of atherothrombotic events despite recommended secondary prevention therapy. High platelet reactivity drives this risk. Novel approaches to antiplatelet therapy are needed. Objectives: To:  determine the effect of age and T2DM on blood thrombogenicity and response to dual antiplatelet therapy in stable CAD  assess the effect of changes in platelet count on thrombus quantity and quality with Rafigrelide Methods: Study 1: Patients with stable CAD, 4 groups: age < 75 non-DM, age≥75 T2DM, age≥75 non-DM and age<75 T2DM studied at baseline and one week after clopidogrel. I performed Badimon chamber study, thromboelastography, VerifyNow® and Multiplate® aggregometry, coagulation and inflammatory biomarkers and scanning electron microscopy. Study 2: Twelve volunteers took Rafigrelide (novel platelet lowering agent) singly and then with aspirin. I performed Badimon chamber study and thromboelastography at pre-defined intervals. Results: Study 1: At baseline and after clopidogrel therapy, there was no difference in thrombus area between the four groups. Serum TNFα levels were higher in elderly T2DM patients. Other coagulation and inflammatory markers were similar between the groups. Clopidogrel reduced thrombus area, lowered platelet content of thrombus and increased fibrin diameter and density in all four groups. Elderly and T2DM patients demonstrated high platelet reactivity and hyporesponsiveness to clopidogrel. Significant reduction in thrombus area was demonstrated both in good- and hypo-responders to clopidogrel. Point of care tests and thrombus area showed no correlation. Post chamber blood confirmed release of P selectin, CD40 ligand and PAI-1 from activated platelets. ii Study 2: Rafigrelide reduced platelet count and thrombus area, delayed initiation of clot formation and reduced over all clot strength. Platelet count positively correlated with thrombus area. Conclusion: Elderly and T2DM patients had similar over all blood thrombogenicity but higher platelet reactivity when compared to young and non-diabetic patients. Addition of clopidogrel reduced thrombus area with ultrastructural changes in fibrin favouring fibrinolysis. Reduction in platelet count with Rafigrelide reduced thrombus formation and lowered viscoelastic strength. Dual antiplatelet therapy and novel therapeutic strategies may reduce future thrombotic risk in these high risk populations.

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Wong, Shen. "The measurement of platelet function in response to 3 common antiplatelet regimens in patients with peripheral occlusive arterial disease." Thesis, The University of Sydney, 2004. https://hdl.handle.net/2123/27942.

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Background: Anti-platelet therapy reduces vascular complications in patients with peripheral occlusive arterial disease (POAD) with aspirin the most commonly prescribed agent. However, aspirin resistance can be observed in patients who suffer clinical thromboembolic events, or have persistent platelet activity despite regular aspirin treatment. The clinical benefits of clopidogrel or combination aspirin and clopidogrel therapy may be due to superior platelet inhibition or the inhibition of platelets in aspirin resistant patients. Aim: To investigate the effects of aspirin, clopidogrel, and combination therapy on platelet inhibition in patients with POAD, and to test the response of laboratory defined aspirin resistant patients to alternative antiplatelet therapies. Methods: 50 patients were recruited from the vascular outpatient clinic at Royal North Shore hospital, at the consulting rooms of Royal North Shore Hospital vascular surgeons and the associated vascular imaging laboratories. Patients with confirmed symptomatic peripheral vascular disease were randomised to receive either aspirin or clopidogrel for 2 weeks, followed by 2 weeks of combined aspirin and clopidogrel therapy. Patients were then asked to “crossover” to the alternative antiplatelet monotherapy for the final two weeks of the trial. After each 2 week course of antiplatelet therapy, platelet activation was flow cytometrically determined by detecting platelet membrane expression of the activation markers CD62P, PACl, fibrinogen receptor and platelet-leukocyte aggregates. Measurements were performed after the addition of PGE, (for resting activation levels), and after platelet activation by low and high dose (0.5&5uM) ADP. Global platelet function was assessed using the Platelet Function Analyser-100 (PFA-lOO) with the Collagen/Epinephrine and the Collagen/ADP cartridges. Results: By flow cytometry, no significant differences in activation marker expression between aspirin, clopidogrel and combination treated patients were detected in the PGE, treated control groups. There were statistically significant differences in levels of all platelet activation markers expressed between the three antiplatelet therapies (ANOVA, p<0.001), with clopidogrel and combination therapy significantly reducing expression after both low and high dose ADP compared to aspirin (Wilcoxon p<0.05). No significant differences in marker expression were observed between clopidogrel and combination therapies. With the PFA-lOO, 9 of 50 (18%) patients were aspirin resistant by the Coll/Epi cartridge. Six of 9 aspirin resistant patients became sensitive to aspirin after combination antiplatelet therapy. Both PFA-lOO cartridges were insensitive to clopidogrel monotherapy. Statistically significant differences in Coll/ADP closure times were seen between combination therapy and aspirin (Wilcoxon p=0.0102). There was no significant difference in median levels of flow cytometric platelet activation between aspirin resistant and sensitive patients (Mann-Whitney p>0.05). Conclusions: Clopidogrel and combination therapy significantly inhibit platelet activation compared to aspirin in patients with POAD, but no significant difference in platelet inhibition was observed between clopidogrel and combination therapy. A significant proportion of POAD patients were resistant to aspirin by PFA-l 00. The majority of these patients became sensitive to aspirin with combined aspirin and clopidogrel therapy.

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Gandhi, Neha Sureshchandra. "Molecular modelling of platelet endothelial cell adhesion molecule 1 and its interaction with glycosaminoglycans." Thesis, Curtin University, 2007. http://hdl.handle.net/20.500.11937/1513.

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The Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) has many functions including its roles in leukocyte extravasation as part of the inflammatory response, and in the maintenance of vascular integrity through its contribution to endothelial cell-cell adhesion. Various heterophilic ligands of PECAM-1 have been proposed. The possible interaction of PECAM-1 with glycosaminoglycans (GAGs) is the focus of this thesis. The three dimensional structure of the extracellular immunoglobulin (Ig)-domains of PECAM-1 was constructed using homology modelling and threading methods. Potential heparin/heparan sulfate binding sites were predicted on the basis of their amino acid consensus sequences and a comparison with known structures of sulfate binding proteins. Heparin and other GAG fragments have been docked to investigate the structural determinants of their protein binding specificity and selectivity. It is predicted that two regions in PECAM-1 appear to bind heparin oligosaccharides. A high affinity binding region was located in Ig-domains 2 and 3 and a low affinity region was located in Ig-domains 5 and 6.These GAG binding regions are distinct from regions involved in PECAM-1 homophilic interactions. Docking of heparin fragments of different size revealed that fragments as small as a pentasaccharide appear to be able to bind to domains 2 and 3 with high affinity. Binding of longer heparin fragments suggests that key interactions can occur between six sulfates in a hexasaccharide with no further increase in binding affinity for longer fragments. Molecular dynamics simulations were also used to characterise and quantify the interactions of heparin fragments with PECAM-1. These simulations confirmed the existence of regions of high and low affinity for GAG binding and revealed that both electrostatic and van der Waals interactions determine the specificity and binding affinity of GAG fragments to PECAM-1. The simulations also suggested the existence of ‘open’ and ‘closed’ conformations of PECAM-1 around domains 2 and 3.

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Varenhorst, Christoph. "Platelet Inhibition in Coronary Artery Disease – Mechanisms and Clinical Importance : Studies with Focus on P2Y12 Inhibition." Doctoral thesis, Uppsala universitet, Medicin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-131154.

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Despite the currently recommended dual antiplatelet treatment (DAT) with aspirin and P2Y12 inhibition in patients with coronary artery disease (CAD) there is a risk of adverse clinical outcome. Pharmacodynamic (PD) poor response to clopidogrel occurs in ~ 30% of clopidogrel-treated patients and is associated with an increased risk of recurrent thrombotic events. The aims of this thesis were to compare the PD and pharmacokinetic effects of clopidogrel 600 mg loading dose (LD)/ 75 mg standard maintenance dose (MD) with the novel P2Y12 inhibitor prasugrel 60 mg LD/10 mg MD, in 110 patients with CAD. The mechanisms behind clopidogrel poor response were investigated by assessing the pharmacodynamics after adding clopidogrel active metabolite (AM) and genotyping for variation in CYP-genes involved in thienopyridine metabolism. In another study, we compared the on-clopidogrel platelet reactivity of patients with stent thrombosis (ST) (n=48) or myocardial infarction (MI) (n=30) while on DAT and their matched controls (n=50 + 28). Prasugrel achieved a faster and greater P2Y12-mediated platelet inhibition than clopidogrel measured with light transmission aggregometry, VASP and VerifyNow® P2Y12. Prasugrel’s greater platelet inhibition was associated with higher exposure of AM. The addition of clopidogrel AM led to maximal platelet inhibition in all subjects, suggesting that prasugrel’s greater antiplatelet effect was related to more efficient AM generation compared to that of clopidogrel. Lower levels of AM as well as less platelet inhibition were seen in clopidogrel-treated patients with reduced-metabolizer genotype CYP2C19 compared to those with normal genotype. Patients with ST while on DAT showed higher on-clopidogrel platelet reactivity compared to matched stented controls. Patients with spontaneous MI after stenting did not. In conclusion, these results showed a high rate PD poor response to a high bolus dose of clopidogrel because of a partly genetically caused lower generation of AM which could be overcome by prasugrel treatment. In patients after coronary stenting, clopidogrel poor response was related to ST but not to spontaneous MI, illustrating difficulties in optimizing treatment with clopidogrel based on platelet function or genetic testing in individual patients.

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Smith, Simon Matthew Giles. "Investigations into the genetic basis of platelet responsiveness to adenosine diphosphate and thrombin receptor activating peptide, and the variable response to clopidogrel therapy." Thesis, University of Sheffield, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444830.

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Christian, Lea Rajeshkumar. "Xeroderma Pigmentosum A Deficiency Results in Increased Generation of Microvesicle Particles in Response to Ultraviolet B Radiation." Wright State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=wright1621875551264658.

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Kroegel, Claus. "Molecular mechanisms of stimulus-response coupling in human and guinea pig eosinophils : transduction pathways utilized by platelet activating factor and their relationship to cellular effector functions." Thesis, Imperial College London, 1991. http://hdl.handle.net/10044/1/46876.

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Buitrago, Murcia Claudia Lorena. "Cbl proteins in platelet functional responses." Diss., Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/198139.

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Physiology Ph.D. c-Cbl protein functions as an E3 ligase and scaffolding protein, where three residues, Y700, Y731, and Y774, upon phosphorylation, have been shown to initiate several signaling cascades. In this study, we investigated the role of these phospho-tyrosine residues in the platelet functional responses upon integrin engagement. We observed that c-Cbl Y700, Y731 and Y774 undergo phosphorylation upon platelet adhesion to immobilized fibrinogen, which was inhibited in the presence of PP2, a pan-src family kinase (SFK) inhibitor, suggesting that c-Cbl is phosphorylated downstream of SFKs. However, OXSI-2, a Syk inhibitor, significantly reduced c-Cbl phosphorylation at residues Y774 and Y700, without affecting Y731 phosphorylation. Interestingly, PP2 inhibited both platelet spreading on fibrinogen as well as clot retraction, whereas OXSI-2 blocked only platelet spreading, suggesting a differential role of these tyrosine residues. The physiological role of c-Cbl and Y731 was studied using platelets from c-Cbl KO and c-CblYF/YF knock-in mice. c-Cbl KO and c-Cbl YF/YF platelets had a significantly reduced spreading over immobilized fibrinogen. Furthermore, clot retraction with c-Cbl KO and c-Cbl YF/YF platelets was drastically delayed. These results indicate that c-Cbl and particularly its phosphorylated residue Y731 plays an important role in platelet outside-in signaling contributing to platelet spreading and clot retraction Temple University--Theses

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Shaw, A. M. "Cytosolic free calcium and platelet responses to putative lipid mediators of platelet activation." Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.378176.

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Sage, Stewart O. "Stimulus-response coupling in human blood platelets." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236016.

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Bosnic, Anthony Martin. "Human antibody responses to a chlamydia-secreted protease factor : a thesis /." San Antonio : UTHSC, 2005. http://learningobjects.library.uthscsa.edu/cdm4/item%5Fviewer.php?CISOROOT=/theses&CISOPTR=14&REC=5.

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Cardoso, Andréia Machado. "Efeitos do exercício físico sobre a atividade de enzimas dos sistemas purinérgico e colinérgico em sangue de ratos hipertensos." Universidade Federal de Santa Maria, 2014. http://repositorio.ufsm.br/handle/1/4482.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Hypertension is a multifactor clinical condition, which is accompanied by a low-grade inflammation and alterations in platelet function. These modifications may be related to an imbalance in the regulation of adenine nucleotides (ATP, ADP and AMP), adenosine and acetylcholine (ACh) levels. This regulation is performed by purinergic [NTPDases, ecto-5 - nucleotidase and adenosine deaminase (ADA)] and cholinergic [Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE)] system enzymes, present in blood, respectively. These enzymes can be modulated by regular practice of physical exercise, which has been recommended for the treatment of hypertension. Thus, the aim of this study was to investigate the effect of six swimming training weeks on blood pressure, on purinergic and cholinergic systems enzymes activities in blood as well as on platelet aggregation and classic inflammatory markers in rats with hypertension induced by methyl Nω-nitro-L-arginine ester hydrochloride (L-NAME) administration. In order to better understand chronic changes, we also evaluated the effect of a single acute bout of exercise on the activity of the enzymes already mentioned. The animals were divided into four groups (n = 10): control, exercise, LNAME and exercise L-NAME. After 60 days of treatment, animals were euthanized and platelets, lymphocytes, whole blood and serum were used for experimental determinations. The results showed that swimming training was able to reduce blood pressure in hypertensive rats, and to prevent the increase in NTPDase, ecto-5'-nucleotidase and ADA activities in lymphocytes and platelets. This probably contributed in preventing platelet aggregation. Chronically, swimming was also effective in preventing the increase in AChE (in lymphocytes and whole blood) and BuChE (in serum) activities. Regarding to the expression of NPTDase1, exercise per se triggered a reduction in the expression of this enzyme, but had no significant effects in hypertensive rats. The prevention of the increase in cholesterol, triglycerides, C-reactive protein levels and myeloperoxidase activity generated by swimming practice reinforces the fact that exercise reduced inflammation in hypertensive rats. In response to a single acute bout of exercise, was observed an increase in the activity of cholinergic system enzymes in whole blood, lymphocytes and serum, and purinergic system enzymes in platelets. However, there was a decrease in the activity of NTPDase and ADA in lymphocytes. It can be concluded that this study allowed us to unveil, in part, the mechanisms related to the protective processes arising from regular physical exercise on hypertension related to inflammation and platelet aggregation. The results also reinforce the importance of measuring the purinergic and cholinergic systems enzymes as parameters of inflammatory response. Also, it is concluded that regular physical exercise has antithrombotic and anti-inflammatory effects by modulating the activity purinergic and cholinergic systems enzymes in hypertension. It is suggested that these responses have been derived from the adaptations that occur in the body due to each acute stimulus that promotes enough impact to break homeostasis and promote beneficial adaptations. Thus, moderate aerobic exercise has a key role in acting as an adjuvant in the treatment of hypertension. A hipertensão é uma condição clínica multifatorial que, na maioria dos casos, está acompanhada de um quadro inflamatório de baixo grau e alterações nas funções plaquetárias. Essas modificações podem estar relacionadas a um desequilíbrio na regulação dos níveis de nucleotídeos de adenina (ADP, ADP e AMP), da adenosina e da molécula acetilcolinesterase (ACh), que é realizada pelas enzimas do sistemas purinérgico [NTPDases, ecto-5 -nucleotidase e adenosina desaminase (ADA)] e colinérgico [Acetilcolinesterase (AChE) e Butirilcolinesterase (BuChE)] presentes no sangue, respectivamente. A atividade dessas enzimas pode ser modulada pela prática regular de exercícios físicos, a qual tem sido recomendada para o tratamento da hipertensão. Sendo assim, o objetivo deste estudo foi verificar o efeito de seis semanas de natação sobre a pressão arterial, a atividade de enzimas dos sistemas purinérgico e colinérgico em sangue, bem como sobre a agregação plaquetária e marcadores inflamatórios clássicos em ratos com hipertensão induzida através de administração de metila Nω-Nitro-L-arginina cloridrato de éster (L-NAME). Com o objetivo de melhor compreender as alterações crônicas, avaliouse, também, o efeito de uma única sessão aguda de exercício sobre a atividade das enzimas já mencionadas. Os animais foram divididos em quatro grupos (n = 10): Controle, Exercício, L-NAME e L-NAME Exercício. Após 60 dias de tratamento, os animais foram submetidos à eutanásia e as plaquetas, os linfócitos, o sangue total e o soro foram usados para as determinações experimentais. Os resultados obtidos mostraram que o treinamento com natação foi capaz de reduzir a pressão sanguínea em ratos hipertensos, além de prevenir o aumento da atividade das enzimas NTPDase, ecto-5 -nucleotidase e ADA em linfócitos e plaquetas, o que provavelmente contribuiu para prevenir a agregação plaquetária. Cronicamente, a natação também foi eficaz na prevenção do aumento da atividade das enzimas AChE em linfócitos e sangue total e BuChE em soro. Com relação à expressão da NPTDase1, o exercício per se gerou a redução da expressão desta enzima, mas não apresentou efeitos significativos nos ratos hipertensos. A prevenção do aumento dos níveis de colesterol, triglicerídeos, proteína C-reativa e mieloperoxidase gerada pela prática da natação reforça o fato de que o exercício reduziu a inflamação em ratos hipertensos. Como resposta a uma única sessão aguda de exercício, verificou-se o aumento da atividade das enzimas dos sistemas colinérgico em sangue total, linfócitos e soro e do sistema purinérgico em plaquetas. Entretanto, ocorreu a diminuição da atividade da NTPDase e da ADA em linfócitos. Pode-se concluir que este estudo permitiu desvendar em parte os mecanismos relacionados aos processos protetores advindos da prática regular de exercício físicos na hipertensão relativos aos processos inflamatórios e à agregação plaquetária. Os resultados ainda reforçam a importância da dosagem das enzimas dos sistemas purinérgico e colinérgico como parâmetros da resposta inflamatória. Conclui-se, também, que a prática regular de exercício físico possui efeitos antitrombóticos e antiinflamatórios através da modulação da atividade das enzimas dos sistemas purinérgico e colinérgico na hipertensão. Sugere-se que estas respostas tenham sido provenientes das adaptações ocorridas no organismo decorrentes de cada estímulo agudo, que gerou estímulos suficientes para quebrar a homeostase do organismo e promover adaptações benéficas. Desta forma, o exercício físico aeróbico moderado possui um papel fundamental na atuação como coadjuvante no tratamento da hipertensão.

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Bhavanasi, Dheeraj. "Role of Protein Kinase C delta in regulating platelet functional responses." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/283099.

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Physiology Ph.D. Platelets upon activation change their shape, aggregate and secrete alpha and dense granule contents among which ADP acts as a feedback activator. Different Protein Kinase C (PKCδ) isoforms have specific non-redundant roles in mediating platelet responses including secretion and thrombus formation. Protein Kinase C delta (PKCδ), a novel class of PKC isoform requiring diacyl glycerol but not calcium for its activation, has been shown to play an important role in several pathological processes. The aims of our current study are 1) to identify possible PKCδ specific substrates in platelets, 2) evaluate a novel PKCδ selective inhibitor and 3) to investigate the role of PKCδ in ADP-induced platelet activation. We show that Protein kinase D2 (PKD2) is the major isoform of PKD that is expressed in human as well as murine platelets and is a specific substrate for PKCδ in platelets. CGX1037 was identified and characterized as a selective small molecule inhibitor of PKCδ in platelets. Furthermore, by using PKCδ knock out murine platelets, we showed that PKCδ plays a functional role in mediating ADP-induced thromboxane generation and classical PKC isoforms α/β regulate tyrosine phosphorylation on PKCδ and subsequent thromboxane generation through a tyrosine kinase, Lyn and a tyrosine phosphatase, Shp1 suggesting an important role of PKCδ to agonist-induced platelet activation. Temple University--Theses

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Albrecht, Madlin [Verfasser], and Ingo [Akademischer Betreuer] Ahrens. "The role of platelet immuno-receptors in patients with acute coronary syndrome and C-reactive protein induced pro-inflammatory gene response in early endothelial progenitor cells = Die Rolle von Plättchen Immuno-Rezeptoren bei Patienten mit akutem Koronarsyndrom und Einfluss von C-reaktivem Protein auf endotheliale Progenitorzellen." Freiburg : Universität, 2014. http://d-nb.info/1123481938/34.

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Scase, Timothy John. "Blood platelet responses induced by adenosine 5'-diphosphate : functional and molecular studies." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624899.

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Poole, Alastair W. "Responses of equine blood platelets induced by adenosine 5'-diphosphate." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260575.

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Wright, Joy Rhiannon. "Variation in the haemostatic response and thrombotic risk : interplay between haemostatic factors, platelets and monocytes." Thesis, University of Leicester, 2010. http://hdl.handle.net/2381/10075.

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The haemostatic response comprises the interaction of coagulation factors and peripheral blood cells which play a vital role in maintaining vascular integrity. This study begins with the finding that plasma from premature MI subjects has increased endogenous thrombotic potential linked to higher levels of circulating Tissue Factor (TF), suggesting these individuals may have a hypercoagulable phenotype. This study seeks to further understand how cellular interaction, in particular platelet-monocyte interaction, modulates the haemostatic response. Throughout the study, TF and Tissue Factor Pathway Inhibitor (TFPI) were studied as representing the procoagulant and anticoagulant response, respectively. Study of the effects of activated platelets on monocytes found that whereas direct platelet or platelet-microparticle adhesion to monocytes, and release of platelet soluble mediators induced monocyte gene expression of TF, induction of TFPI was driven solely by platelet soluble mediators. Extension of these studies using gene expression microarray technology found that whereas activation of monocytes via PSGL-1 generates a pro-angiogenic expression profile, platelet soluble mediators significantly enhanced this profile, enabling monocytes to interact with ECM components involved in the wound healing environment of the thrombus, and additionally induced anti-inflammatory, and anti-atherothrombotic genes. Whether cells within a thrombus act simply as structural and secretory components, or play a more active role involving gene expression is unclear, therefore gene expression array analysis was carried out on thrombi generated in vitro. Genes demonstrating significant time-dependent increases included those encoding chemotactic proteins (IL8, CCL2, CXCL1, CXCL2), cell adhesion (ITGAV, ITGA5, ITGB1), regulation of coagulation (THBD, PLAU, SERPINE1), wound-healing (ENDG, SPP1, LAMB3), and regulatory transcription factors (FOS, EGR1, PPARG). Whereas initiation of thrombosis is driven by plasma proteins and facilitated by the platelet surface, this study provides evidence that thrombus resolution may be driven by changes in gene expression within the thrombus that regulate the haemostatic response, thrombus growth, and facilitate wound-healing. These findings could have implications for individuals at risk of plaque rupture, where variation in gene expression may affect not just the formation of an occlusive thrombus but also the rate of resolution.

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Plant, Stuart D. "The response of human umbilical vein endothelial cells and blood platelets to modified NiTi surfaces." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275630.

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Salehe, Bajuna Rashid. "Predictive tools for the study of variations in ADP platelet responses : implications for personalised CVD risk and prevention strategies." Thesis, University of Reading, 2017. http://centaur.reading.ac.uk/74255/.

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The major aim of this project is to develop novel computational approaches for rapid identification of key omic variations, particularly SNPs that are likely to be associated with the variability of the ADP (Adenosine diphosphate) activated platelet responses. The ADP platelet response was chosen as a model system due to its distinct role during the platelet amplification and aggregation, and it is the main therapeutic target for cardiovascular disease (CVD) antiplatelet drug treatments. Based on recent studies, CVD is currently the second lethal noncommunicable disease after cancer in both developed and developing countries. Interindividual variability of the ADP platelet responses was previously reported in genetic association studies, and susceptible SNPs were identified. However, most of the standard biostatistical methods that were previously employed were found to be suboptimal, and it is assumed that other crucial SNPs might have been potentially missed. In genetics, this phenomenon is known as ‘missing heritability’ problem. Therefore, to address this issue, this study aims to employ alternative computational approaches in an integrated manner in order to identify previously unidentified key SNPs, which may underlie the ADP platelet responses variability. Additionally, the project aims to develop predictive approaches to unveil the molecular mechanisms of the identified key SNPs, which are likely to underpin the interindividual variability in the ADP platelet responses and aggregation. The molecular mechanisms underpinning these SNPs, or ‘omic variations are rarely addressed in standard genetic mapping or association studies. This may be due to the experimental hurdles related to the costs and labour that are required in pursuing such undertakings, hence our predictive approach seeks to address such inefficiencies in closing these knowledge gaps. Moreover, the project culminates in the development of a method for predicting an individuals’ ADP platelet response levels with a focus on determining the extreme cases, i.e., individuals showing high and low responses to ADP platelet activation. Predicting ADP responses levels might be suitable for determining which allelic features will contribute most to the extreme ADP platelet responses. This understanding may be useful for suggesting new drug targets or individualised treatments in the targeted CVD therapeutics or personalised medical settings for the next generation of medical practice.

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Field, Cara Lisa. "A biophysical characterization of northern elephant seal (Mirounga angustirostris) blood platelets and response to temperature and pressure changes /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2005. http://uclibs.org/PID/11984.

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Ferraz, Natalia. "Effect of Surface Nanotopography on Blood-Biomaterial Interactions." Doctoral thesis, Uppsala universitet, Institutionen för fysikalisk och analytisk kemi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110614.

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Biologically inspired materials are being developed with the aim of improving the integration of medical implants and minimizing non-desirable host reactions. A promising strategy is the design of topographically patterned surfaces that resemble those found in the extracellular environment. Nanoporous alumina has been recognized as a potential biomaterial and as an important template for the fabrication of nanostructures. In this thesis in vitro studies were done to elucidate the role of alumina nanoporosity on the inflammatory response. Specifically, by comparing alumina membranes with two pore sizes (20 and 200 nm in diameter). Complement and platelet activation were evaluated as well as monocyte/macrophage behaviour. Whole blood was incubated with the alumina membranes and thereafter the biomaterial surfaces were evaluated in terms of protein and platelet adhesion as well as procoagulant properties. The fluid phase was analyzed for complement activation products and platelet activation markers. Besides, human mononuclear cells were cultured on the alumina membranes and cell adhesion, viability, morphology and release of pro-inflammatory cytokines were evaluated. The results indicated that nanoporous alumina with 200 nm pores promotes higher complement activation than alumina with 20 nm pores. In addition, platelet response to nanoporous alumina was found to be highly dependent on the material porosity, as reflected by differences in adhesion, PMP generation and procoagulant characteristics. A clear difference in monocyte/macrophage adhesion and activation was found between the two pore size alumina membranes. Few but highly activated cells adhered to the 200 nm membrane in contrast to many but less activated monocytes/macrophages on the 20 nm surface. The outcome of this work emphasizes that nanotopography plays an important role in the host response to biomaterials. Better understanding of molecular interactions on nano-level will undoubtedly play a significant role in biomaterial implant development and will contribute to design strategies for controlling specific biological events.

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Larsson, Jimmy. "Neural stem and progenitor cells cellular responses to known and novel factors /." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110722.

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Nosul, Matylda [Verfasser], and Gerald [Akademischer Betreuer] Kolb. "Erfassung von Acetylsalicylsäure Non-Responder mittels Platelet Function Analyser (PFA-100) und Risikofaktoren nach ischämischem Insult bei geriatrischen Patienten / Matylda Nosul. Betreuer: Gerald Kolb." Marburg : Philipps-Universität Marburg, 2013. http://d-nb.info/1038786576/34.

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Imperiali, Rosario Claudia. "Evaluación de la fracción de plaquetas inmaduras y de otros biomarcadores asociados a complicaciones inflamatorias en el postoperatorio de cirugía cardíaca." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/671171.

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Gràcies als avenços en la disciplina i a causa del canvi en l’estil de vida de la població, el nombre de cirurgies cardíaques s’ha vist incrementat amb el temps. Donades les característiques de la cirurgia i dels pacients que es sotmeten a elles; cada vegada més longeus i amb un major nombre de comorbiditats, existeix un important risc d’aparició de complicacions postoperatòries que poden arribar a comprometre l’èxit de la intervenció. La complexitat de la cirurgia i dels procediments dels quals d’ella deriven, donen lloc a una resposta inflamatòria reactiva que, en certs casos, pot veure’s exacerbada i originar complicacions majors. Diferenciar entre una resposta inflamatòria que succeeix de forma fisiològica al trauma quirúrgic i una resposta exacerbada, que pot comportar efectes perjudicials per al pacient, suposa un repte pels clínics amb les eines actuals disponibles. L’estudi de nous biomarcadors implicats en la fisiopatologia de la resposta inflamatòria (l’objectiu principal de la present tesi doctoral) ajudarien al clínic a l’hora d’establir el diagnòstic de forma objectiva i a valorar de forma precoç l’evolució del pacient durant el postoperatori. Durant el 2015 i 2017 es van incloure 327 pacients que van ingressar a la Unitat de Cures Intensives (UCI) de l’Hospital Universitari de Bellvitge després d’haver estat sotmesos a una cirurgia cardíaca major. Durant el període d’ingrés dels pacients a la UCI es van mesurar diferents biomarcadors seleccionats prèviament atenent a la seva implicació en la resposta inflamatòria. Aquests biomarcadors van ser la fracció de plaquetes immadures, la concentració d’interleucina-6, procalcitonina, proteïna C reactiva i de troponina T, aquest últim, com a biomarcador de dany miocàrdic. Durant el període d’ingrés a la UCI, a cada pacient se li van calcular diferents scores pronòstics i es van registrar les complicacions que van presentar. A través de tres publicacions en revistes científiques es va demostrar que la diferència entre dos resultats consecutius de la fracció de plaquetes immadures (delta) s’associa a una resposta inflamatòria clínicament significativa i és un predictor independent del risc de desenvolupament d’aquesta. Així mateix, la seva combinació al score APACHE II, millora la capacitat predictora de la resposta inflamatòria. D’altra banda, i juntament amb el delta de troponina T, tots dos biomarcadors s’associen al desenvolupament d’esdeveniments cardiovasculars majors postcirurgia cardíaca. Els resultats obtinguts en aquesta tesi doctoral demostren, per primera vegada, que la incorporació del mesurament de la fracció de plaquetes immadures en el seguiment del postoperatori dels pacients sotmesos a cirurgia cardíaca, és una eina d’utilitat per a la detecció d’aquells pacients que desenvolupen una resposta inflamatòria exacerbada que pot donar lloc a complicacions majors. Gracias a los avances en la disciplina y debido a los cambios en el estilo de vida de la población, el número de cirugías cardíacas ha ido incrementando con el tiempo. Dadas las características propias de la cirugía y de los pacientes cada vez más longevos y con mayores comorbilidades que se someten a ellas, existe un riesgo importante de aparición de complicaciones postoperatorias que pueden llegar a comprometer el éxito de la intervención. La complejidad de la propia cirugía y de los procedimientos de los que de ella derivan, dan lugar a una respuesta inflamatoria reactiva, que en ciertos casos, puede verse exacerbada y originar complicaciones mayores. Diferenciar entre una respuesta inflamatoria que sucede de forma fisiológica al trauma quirúrgico y una respuesta exacerbada, que puede comportar efectos perjudiciales para el paciente, supone un desafío para los clínicos, teniendo en cuenta las herramientas actuales disponibles. El estudio de nuevos biomarcadores implicados en la fisiopatología de la respuesta inflamatoria, objetivo principal de la presente tesis doctoral, ayudarían al clínico a la hora de establecer el diagnóstico de forma objetiva y a valorar de forma precoz la evolución del paciente durante el postoperatorio. Durante el 2015 y 2017 se incluyeron 327 pacientes que ingresaron en la Unidad de Cuidados Intensivos (UCI) del Hospital Universitari de Bellvitge tras ser sometidos a una cirugía cardíaca mayor. Durante la estancia en UCI se midieron diferentes biomarcadores previamente seleccionados atendiendo a su implicación en la respuesta inflamatoria. Dichos biomarcadores fueron la fracción de plaquetas inmaduras, concentración de interleucina-6, procalcitonina, proteína C reactiva y de troponina T, este último, como biomarcador de daño miocárdico. Durante el periodo de ingreso en UCI, a cada paciente se le calcularon diferentes scores pronósticos y se registraron las complicaciones que presentaron. A través de tres publicaciones en revistas científicas, se ha demostrado que la diferencia entre dos resultados consecutivos de la fracción de plaquetas inmaduras (delta) se asocia a una respuesta inflamatoria clínicamente significativa y es un predictor independiente del riesgo de desarrollo de la misma. Asimismo, su combinación al score APACHE II, mejora la capacidad predictora de la respuesta inflamatoria. Por otro lado, y juntamente con el delta de troponina T, ambos biomarcadores se asocian al desarrollo de eventos cardiovasculares mayores postcirugía cardíaca. Los resultados obtenidos en esta tesis doctoral demuestran, por primera vez, que la incorporación de la medición de la fracción de plaquetas inmaduras en el seguimiento del postoperatorio de los pacientes sometidos a cirugía cardíaca, es una herramienta útil para detectar aquellos pacientes que desarrollan una respuesta inflamatoria exacerbada, que puede dar lugar a complicaciones mayores. Thanks to the technological advances in the discipline and due to the changes in the population lifestyle, the number of cardiac surgery has been increased over time. Given the specific characteristics of the surgery and since the greater longevity and major comorbidities of patients, there is an important risk of having postoperative complications. These complications might compromise the surgery success rates. The complexity of the surgery and its derived procedures lead to a reactive inflammatory response. This inflammatory response may be exacerbated and it can cause major complications. The differentiation between an inflammatory response that occurred physiologically after surgical trauma and an exacerbated inflammatory response (that it can lead adverse effects in the patient), it is still a challenge for the physicians with the current tools. The research in new biomarkers involved in the physiopathology of the inflammatory response, which is the principal aim of this thesis, can help the clinicians to establish an objective diagnosis and to the early assessment of the postoperative evolution of the patient. From 2015 to 2017, 327 patients who were admitted at the Intensive Care Unit (ICU) of the Bellvitge University Hospital after major cardiac surgery, were enrolled in the study. Some previous selected inflammatory biomarkers were measured during the ICU stay. That biomarkers were: immature platelet fraction, interleukin-6, procalcitonin, C reactive protein, and troponin T, the last one was included as myocardial injury biomarker. Moreover, at the ICU stay, different prognostic scores were calculated and complications were recorded. Through three publications in scientific journals, it has been shown that the difference between two consecutive results of immature platelet fraction (delta) is associated with clinically significant inflammatory response and it is an independent predictor of the risk of their development. Likewise, the combination of the delta of immature platelet with an APACHE II score, it improves their predictive capacity for inflammatory response. Furthermore, the delta of immature platelets and troponin T are associated with the development of major adverse cardiovascular events after surgery. The obtained results in this thesis show, for the first time, that immature platelet fraction measurement during the postoperative period of cardiac surgery would be helpful to detect those patients who will develop an exacerbated inflammatory response that may lead to major complications.

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Huber-Petersen, Lisa. "Häufigkeit und Auswirkungen der ASS Non-Response bei kardiochirurgischen Patienten." Doctoral thesis, 2018. http://hdl.handle.net/11858/00-1735-0000-002E-E313-1.

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Ross, Julia Myers. "Platelet interactions with subendothelial surfaces under physiological shear conditions: Response to type VI collagen and an endothelial cell wound model." Thesis, 1995. http://hdl.handle.net/1911/16874.

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The elucidation of the molecular mechanisms of platelet adhesion and aggregation in response to naturally occurring subendothelial surfaces under flow conditions is important medically in atherosclerosis and mural thrombosis. Type VI collagen is a subendothelial constituent that binds vWF and platelets. The interaction of platelets with type VI collagen and the roles of platelet glycoprotein receptors and vWF were studied under flow conditions using epi-fluorescent video microscopy coupled with digital image processing. We found that surface coverage was less than 6% on collagen VI at a high wall shear rate (1000s$\sp{-1}$), and approximately 60% at a low wall shear rate (100s$\sp{-1}$). The molecular mechanisms involved in low shear platelet binding were studied using monoclonal antibodies to platelet GPIb and GPIIb-IIIa, and polymeric ATA. Anti-GPIIb-IIIa was the most effective in eliminating adhesion (surface coverage, 0.8%), followed by anti-GPIb (4.3%), and ATA (12.6%). Experiments with vWD blood indicated that vWF is involved in platelet adhesion to collagen VI at 100s$\sp{-1}$. Our results suggest a possible role for collagen VI and vWF in platelet adhesion and aggregation in vascular regions with low shear rates. The endothelial cells lining the vasculature present the ultimate biocompatible surface to flowing blood. Upon blood vessel injury the endothelial cells exhibit an acute response by releasing compounds that mediate the local tissue response. Endothelial derived PGI$\sb2$ and NO act as local modulators of platelet function. To incorporate this aspect of a vascular wound into our model of a damaged blood vessel, monolayers of human umbilical vein endothelial cells were cultured on collagen I coated coverslips and subjected to microinjury prior to exposure to flowing blood. To determine the effect of PGI$\sb2$ on platelet function, monolayers of HUVECs were incubated with aspirin to inhibit PGI$\sb2$ formation. The effect of NO on platelet function was also investigated by using L-NMMA to block NO production. Treatment with aspirin resulted in increased platelet adhesion within the wound site, while treatment with L-NMMA did not. This indicates that endothelial PGI$\sb2$ but not NO may act to reduce platelet reactivity within a wound.

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Lin, Yu-An, and 林祐安. "Immune and Osteogenic Response to Zirconia Surface Immobilized with Bone Morphogenetic Protein-2 and Platelet-rich Plasma Released Cytokines through a Natural Cross-linker." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/ap6vcj.

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Lauener, Ronald William. "Role of phosphoinositide 3-kinase in platelet responses to platelet-activating factor." Thesis, 1997. http://hdl.handle.net/2429/6652.

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Platelets are necessary for hemostasis but are also involved in a broad range of pathophysiologic processes such as atherosclerosis and thrombosis. Platelet activating factor (PAF), an inflammatory mediator, is an important physiological regulator of platelet function. The major objective of this work was to determine the role of phosphoinositide 3-kinase (PI 3-kinase) in platelet responses to platelet activating factor. We show, for the first time in platelets, that PAF activates PI 3-kinase over a rapid time course that correlates closely with the aggregation response. The potent PI 3-kinase inhibitors, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (LY294002) were used to probe the dependence of PAF-induced aggregation and dense granule release on PI 3-kinase. Both compounds markedly inhibited PAF-induced aggregation; however, only at low activation states giving reversible aggregation (primary phase) did this correlate with PI 3-kinase inhibition. Secretion, measured as release of 3Hhydroxytryptamine, was inhibited to a maximum of 30 % and only at low concentrations of PAF. We suggest that PI 3-kinase activation is important for reversible (primary) aggregation of platelets in response to PAF, perhaps by contributing to the 'inside-out' activation of platelet glycoprotein Ilbllla, the fibrinogen receptor. PI 3-kinase only plays a minor role in PAF induced dense granule release at low activation states. Both responses are dramatically less dependent on PI 3-kinase activity when high concentrations of PAF are used, suggesting greater contribution from other pathways. Tyrosine kinases appear to be important regulators of PI 3-kinase at high PAF levels as stimulation results in a greater than 10 fold increase in PI 3-kinase activity associated with tyrosine-phosphorylated proteins. The p85 regulatory subunit of PI 3-kinase is not tyrosine-phosphorylated. Rather, the enzyme associates rapidly with a major tyrosinephosphorylated 115 kDa protein, a potential regulator of PI 3-kinase activation in platelets. This protein was not immunoreactive with several antibodies to proteins in this molecular weight range known to be tyrosine phosphorylated and to associate with PI 3- kinase on cell activation.

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Lordkipanidzé, Marie. "Étude de l’effet des médicaments antiplaquettaires sur la fonction plaquettaire : de la variabilité de réponse à l’effet rebond." Thèse, 2009. http://hdl.handle.net/1866/3953.

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En inhibant la formation de caillots dans le sang, les médicaments antiplaquettaires diminuent de façon importante le risque d’événements ischémiques aigus. Cependant, une sous-population de patients souffrant de maladie coronarienne présente une inhibition inadéquate de la fonction plaquettaire malgré la prise quotidienne d’acide acétylsalicylique (AAS). Le premier volet de cette thèse démontre qu’une régénération plaquettaire accélérée pourrait expliquer en partie la variabilité dans la persistance de l’effet antiplaquettaire de l’AAS chez certains sujets souffrant de maladie coronarienne. Ces données suggèrent qu’une augmentation de la fréquence d’administration d’AAS d’une à deux fois par jour pourrait être bénéfique chez ces sujets. Des méta-analyses ont suggéré qu’une réponse plaquettaire inadéquate à l’AAS pourrait augmenter le risque d’événements ischémiques récurrents. La nature rétrospective de ces analyses ne permet pas d’établir la causalité. Dans le deuxième volet de cette thèse, les résultats d’une étude prospective visant à comparer la pertinence clinique de 6 tests de fonction plaquettaire fréquemment utilisés pour évaluer la réponse plaquettaire à l’AAS est présentée. Les résultats démontrent qu’aucun des tests de fonction plaquettaire couramment employés ne prédit la survenue d’événements ischémiques aigus chez des patients souffrant de maladie coronarienne stable. Toutefois, la cessation de la prise d’AAS est un prédicteur important d’événements thrombotiques. La cessation de médicaments antiplaquettaires a souvent été associée à la survenue d’événements thrombotiques dans les jours suivant l’interruption. À savoir si la survenue de ces événements est attribuable uniquement au retrait d’un médicament protecteur ou plutôt à une sensibilisation plaquettaire, constitue un débat d’actualité. Dans le troisième volet de cette thèse, des données sont présentées démontrant que la cessation de clopidogrel après la période recommandée par les lignes directrices actuelles provoque une sensibilisation des plaquettes nouvellement formées aux stimuli plaquettaires physiologiques. Ces résultats encouragent la recherche sur différentes modalités pour atténuer le risque thrombotique accru chez ces patients souffrant de maladie coronarienne. En conclusion, cet ouvrage présente des études visant à identifier les sous-populations de patients qui sont plus à risque de complications cardiovasculaires récurrentes. Dans ce contexte, la personnalisation de traitement est une avenue thérapeutique prometteuse, où chaque patient pourra recevoir un traitement ciblé en fonction de ses besoins et de ses contre-indications. Ce changement de paradigme d’une thérapie empirique issue d’études de grande envergure sur des données populationnelles à une thérapie ajustée aux besoins individuels représente un vaste champ de recherche, où la majorité des découvertes sont à faire. By inhibiting the formation of blood clots, antiplatelet drugs significantly reduce the risk of acute ischemic events. However, a subpopulation of patients suffering from coronary artery disease presents with an inadequate inhibition of platelet function despite taking acetylsalicylic acid (ASA) daily. The first part of this thesis demonstrates that accelerated platelet turnover could partly explain the variability in the persistence of the antiplatelet effect of ASA in some coronary artery disease patients. These results suggest that increasing the frequency of administration of ASA from once to twice daily may be beneficial in selected patients. Meta-analyses have suggested that an inadequate platelet response to ASA may increase the risk of recurrent ischemic events. The retrospective nature of these analyses forbids the inference of causality. In the second part of this thesis, the results of a prospective study comparing the clinical relevance of 6 platelet function tests commonly used to assess platelet response to ASA are presented. The results show that none of the commonly used platelet function tests predict the occurrence of acute ischemic events in stable coronary artery disease patients. However, discontinuation of ASA is an important predictor of thrombotic events. Discontinuation of antiplatelet drugs has often been associated with thrombotic events in the days following cessation. If the occurrence of these events is due solely to the withdrawal of a protective drug or rather platelet sensitization is a topic of some debate. In the third part of this thesis, data are presented demonstrating that clopidogrel discontinuation, after the period recommended by current guidelines, leads to sensitization of newly formed platelets to physiological platelet stimuli. These results encourage research on different ways to mitigate the increased risk of thrombosis in coronary artery disease patients scheduled to discontinue clopidogrel therapy. In conclusion, this dissertation presents studies aiming to identify subpopulations of patients who are at increased risk of recurrent cardiovascular events. In this context, the personalization of treatment is a promising therapeutic avenue, where each patient can receive a targeted therapy according to his needs and contraindications. This shift in paradigm from empirical therapy based on population data retrieved from large clinical studies to therapy tailored to individual needs opens a vast field of research, where the majority of discoveries remain to be made.

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Konstantopoulos, Konstantinos. "Flow cytometric studies of platelet responses to shear stress." Thesis, 1995. http://hdl.handle.net/1911/16842.

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The objective of this study was to improve our understanding of platelet involvement in vascular disease. A cone-and-plate viscometer was used to simulate the fluid mechanical conditions in narrowed arteries. Platelet responses induced by shear stress were quantitated by flow cytometry. This methodology allows the study of platelets in whole blood rather than in platelet suspensions in buffer or plasma, a situation that reflects more closely the physiologic status of platelets circulating in vivo. Using this technique, platelets and platelet aggregates were distinguished from the other blood cells by a fluorescently-labeled monoclonal antibody (MoAb), 6D1, specific for the platelet glycoprotein (GP) Ib. Use of the MoAb anti-CD62, directed against the granule membrane protein-140, yielded sensitive determinations of platelet activation. This methodology was applied to test the efficacy of two novel antiplatelet drugs infused in patients undergoing angioplasty, in preventing the ex vivo shear-induced platelet aggregation (SIPA). Both of these drugs, c7E3-Fab and Integrelin, are GPIIb-IIIa antagonists, and were found to be potent inhibitors of SIPA. In contrast, aspirin, a widely used antiplatelet agent, does not affect SIPA. The same methodology was used to evaluate platelet responses to shear stress in groups of stroke patients and normal subjects. Activated platelets and neutrophil-platelet aggregates were found to circulate in patients' blood in numbers significantly higher than those of normal subjects'. Patients' blood was also more susceptible to SIPA. These enhanced platelet responses were also observed in the patients many days after the onset of stroke suggesting that they are not consequences of ischemia. Flow cytometry was also applied to quantitate shear-induced vWf binding to platelets. The results demonstrate that vWf binding is specific, and although it involves both GPIb and GPIIb-IIIa, it has an absolute requirement for GPIb. This study is the first to directly show that "large" vWf multimers bind to platelets in response to shear more readily than "small" vWf fractions. These findings may contribute to our understanding of mechanisms involved in the pathogenesis of thrombotic disorders, and provide insights for the development of new therapies for vascular diseases.

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Cheng, Hui-ju, and 鄭慧茹. "The mechanism underlying the response of platelets to Streptococcus pyogenes bacteria." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/76628057505852548259.

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碩士 慈濟大學 藥理暨毒理學研究所 94 Circulating platelets play an important role in the pathogenesis of infectious endocarditis, a severe disease caused mostly by the infection of Gram-positive bacteria. Platelets may help bacteria attach to endocardium, initiating endocarial infection, followed by facilitating the formation of macroscopic vegetation which may disperse away from valves, resulting in systemic embolization. Given the interaction of bacteria with platelets is a critical virulent mechanism for bacteria to induce infectious endocarditis, a better understanding of the processes involved in bacterium-platelet interaction would be meaningful in the design of more efficacious therapeutic strategy for the prevention and treatment of infectious endocarditis. Our previous study revealed that plasma fibrinogen mediates Staphylococcus aureus (S. aureus)-platelet interaction by acting as a bridging molecule, leading to the activation and aggregation of platelets. Streptococcus pyogenes (S. pyogenes) is one of the clinically important pathogens that can cause platelet activation and aggregation. Although a variety of studies have been devoted to elucidate the mechanism underlying S. pyogenes-platelet interaction, the precise mechanism by which S. pyogenes triggers platelet activation and aggregation remains controversial. In order to unravel the mystery regarding the S. pyogenes-platelet interaction, this study was undertaken to elucidate the mechanism underlying the response of platelets to S. pyogenes. It was found that both S. pyogenes M29588 and S. pyogenes 78M6 caused platelet activation and aggregation in platelet-rich plasma with a lag of several minutes and their platelet reactivity could be abrogated either by the platelet GP IIb/IIIa antagonist tirofiban (Aggrastat®) or ClfA221-550, which binds to the γ chain C-terminus of fibrinogen, leading to the inhibition of fibrinogen-mediated platelets aggregation. This platelet reactivity of S. pyogenes appears to be similar to that of S. aureus 30326. We also found that fibrinogen supplement enables S. aureus 30326 to induce activation and aggregation of washed human platelets, which was not observed with S. pyogenes bacteria. All the results indicate that although fibrinogen plays an indispensable role in causing aggregation of platelets by S. pyogenes bacteria, some other plasma factor(s) might be also required for S. pyogenes bacteria to induce platelet activation and the subsequent aggregation. In this study, we also develop a convenient method for the purification of plasma fibrinogen using a ClfA221-550-based affinity column. Highly purified fibrinogen was obtained with this method as examined by SDS-PAGE and it was shown able to support platelet adhesion, aggregation and form fibrin clot in response to thrombin.

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Worthley, Matthew I. "Tissue responses to nitric oxide donors: studies in platelets and in myocardium." Thesis, 2004. http://hdl.handle.net/2440/37979.

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The nitric oxide molecule (NO ·) is without doubt one of the most influential on the pathophysiology of the cardiovascular system. Its effects are broad ranging in this system influencing almost all of its components, particularly the vasculature, platelets and the myocardium. The beneficial effects of this molecule not only in inhibiting the development of cardiovascular disease (CVD) but in minimizing the risk of its acute thrombotic complications makes it an obvious target for therapies designed to enhance its effects. Assessing the tissue effects of NO · in platelets and the myocardium has been the main focus of this thesis. Determinants of platelet responsiveness to nitric oxide in diabetic patients with acute coronary syndromes: Effects of glycaemic control Background: We chose to perform our initial experiments in diabetic patients admitted with an acute coronary syndrome (ACS). This cohort offered us a unique opportunity to assess NO · bioavailability in a group with one of the highest cardiovascular morbidity and mortality rates. We assessed this via platelet NO · responsiveness, which has been shown from our laboratory to be impaired in ACS but to date had not been assessed specifically in a diabetic group. As hyperglycaemia is a known independent predictor of mortality in this group we chose in our first set of experiments to primarily assess the effects of glycaemic control (acute and chronic) on platelet NO · responsiveness. Study: In diabetic patients admitted with an ACS the relationship between glycaemic control and the main determinants of platelet NO · responsiveness, superoxide (O2-)generation and guanylate cyclase activity were assessed. Secondary hypotheses assessed the effects of acute glycaemic control on other potential modulators of NO · responsiveness such as asymmetric dimethylarginine (ADMA), L-arginine, Larginine/ADMA ratio, platelet activated O2- release and C-reactive protein (CRP). Other values assessed included CK rise, non-esterified fatty acid (NEFA) levels, ADP induced platelet aggregation and neutrophil count. We also assessed the determinants of both platelet SNP response and of O2- levels by a stepwise multivariate analysis; parameters assessed were age, sex, blood sugar level (BSL), statin therapy, insulin therapy, ACE-inhibitor therapy and CK elevation. Conclusions: In diabetic patients admitted with an ACS; 1. Admission BSL was inversely correlated with platelet SNP responsiveness and directly correlated with O2- generation, but not with guanylate cyclase activity. 2. Admission BSL also correlated with CK rise, CRP, neutrophil count and ADP enhanced O2- generation. Admission BSL was inversely correlated with ADMA and L-arginine levels. 3. On multivariate analysis, admission BSL was a significant determinant of O2- levels and an inverse determinant of SNP response; with increasing age also a significant inverse determinant of SNP response. Acute Resolution of hyperglycaemia normalizes platelet responsiveness to nitric oxide in diabetics with acute coronary syndromes Background: We then explored whether improving glycaemic control had any effect on platelet NO · responsiveness. This was performed by randomizing diabetics with ACS to either intravenous infusions or subcutaneous injections of insulin. This experiment was designed to determine possible mechanisms to explain the results of the DIGAMI study, which showed that tight glycaemic control decreased mortality in diabetics admitted with an acute myocardial infarction (AMI). Study: Sixty diabetic patients admitted with an ACS were randomized to aggressive IV insulin therapy or standard subcutaneous insulin therapy over 12 hours. The primary objective of this study, was to assess the acute effects of tight glycaemic control on platelet NO · responsiveness, O2- generation and guanylate cyclase activity. To explore all possible mechanisms of any observed effect δ ADMA,L- arginine and Larginine/ADMA ratio, CRP, non esterified fatty acids (NEFA) and platelet aggregation were assessed. Conclusions: In diabetic patients admitted with an ACS; 1. Aggressive glycaemic control resulted in significantly enhanced platelet responsiveness to SNP, related to a reduction in O2- generation. No effect on guanylate cyclase activity was seen. 2. A significant reduction in ADMA and L-arginine levels were observed with intravenous compared to subcutaneous insulin therapy. Effects of an oral glucose load on platelet responsiveness to nitric oxide Background: Elevated BSLs are associated with adverse cardiovascular outcomes in ACS in both diabetic and non-diabetic subjects. Hyperglycaemia is no longer considered an ‘ innocent bystander ’ however, having detrimental mechanistic implications on a number of protective biological systems. Indeed, harmful effects of sudden glucose loads such as post-prandial hyperglycaemia on the cardiovascular system are becoming apparent. While our previous experiments had focused on the impact of hyperglycaemia and its subsequent correction, on NO · bioavailability, our follow up experiments assessed the effect of an oral glucose load in normal subjects and patients with known cardiovascular disease. In light of the previous findings, we assessed the effects of an acute glucose load on platelet NO · responsiveness and vascular reactivity as assessed by applanation tonometry. Study: 8 healthy and 10 ‘ high-risk ’ cardiovascular subjects were enrolled into this study. A 75 gm glucose load was administered and baseline and 2 hour data were assessed. Platelet SNP responsiveness and O2- generation along with augmentation index (AIx) and ADP-induced platelet aggregation were assessed in all subjects. In the ‘ high-risk ’ cohort cGMP generation and insulin levels were also evaluated. Conclusions: In the healthy volunteers; 1. No significant change occurred in any of the variables assessed In the ‘ high-risk ’ cohort 1. 80 % of patients had undiagnosed impaired glucose handling 2. A significant increase in soluble guanylate cyclase activity was associated with an oral glucose load possibly related to an increase in insulin levels Lack of inotropic effect of nitric oxide in rat papillary muscle. Background: Our final set of experiments moved away from platelet studies to the assessment of myocardial contractility. Differing methodologies and animal models have resulted in variable results in the assessment of the inotropic effects of NO · . While the consensus is that NO · donors have a positive inotropic effect in low doses and are negatively inotropic at high doses, this has been difficult to show in the papillary muscle of most animal models. We addressed this issue in the papillary muscle of the Sprague-Dawley rat. Study: The experimental protocol involved the assessment of NO · effects on contractility on the left ventricular muscle of the Sprague-Dawley rat. These studies initially involved assessing the most stable preparation, comparing a 10bpm with a 35bpm protocol. The effect of the NO · donor SNP was then assessed not only on the isolated LV papillary muscle but also in the presence of β -adrenoceptor stimulation and an ischaemic/reperfusion model (15mins of anoxia/ 30 mins of reperfusion). Conclusions: In the left ventricular papillary muscle of the Sprague-Dawley rat 1. A stimulation frequency of 10bpm resulted in a more stable preparation over a 60 minute protocol, compared to 35bpm. 2. The isolated rat papillary muscle had no measurable response to exogenous NO · donors. The inotropic effects of β -adrenoceptor stimulation and ischaemia-reperfusion were NO · -independent in this model. While the field of NO · research is rapidly expanding, we forget that it is only just over 20 years since we were first aware of its existence. From Furchgott and Zawadski ' s ( Furchgott and Zawadzki, 1980 ) initial observation of an endotheliumderived relaxing factor ( EDRF ) to the subsequent studies by Palmer et al. ( Palmer et al., 1987 ) and Ignarro et al. ( Ignarro et al., 1987 ) showing that EDRF was indeed NO ·, many questions remain unanswered in relation to the 1992 ‘ molecule of the year ’. This thesis contributes to our understanding of NO · and its associated bioavalability in a number of tissues, particularly in relation to a high-risk cohort, the hyperglycaemic diabetic with an ACS. Thesis (Ph.D.)--Medical School, 2004.

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42

Worthley, Matthew I. "Tissue responses to nitric oxide donors: studies in platelets and in myocardium." 2004. http://hdl.handle.net/2440/37979.

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The nitric oxide molecule (NO ·) is without doubt one of the most influential on the pathophysiology of the cardiovascular system. Its effects are broad ranging in this system influencing almost all of its components, particularly the vasculature, platelets and the myocardium. The beneficial effects of this molecule not only in inhibiting the development of cardiovascular disease (CVD) but in minimizing the risk of its acute thrombotic complications makes it an obvious target for therapies designed to enhance its effects. Assessing the tissue effects of NO · in platelets and the myocardium has been the main focus of this thesis. Determinants of platelet responsiveness to nitric oxide in diabetic patients with acute coronary syndromes: Effects of glycaemic control Background: We chose to perform our initial experiments in diabetic patients admitted with an acute coronary syndrome (ACS). This cohort offered us a unique opportunity to assess NO · bioavailability in a group with one of the highest cardiovascular morbidity and mortality rates. We assessed this via platelet NO · responsiveness, which has been shown from our laboratory to be impaired in ACS but to date had not been assessed specifically in a diabetic group. As hyperglycaemia is a known independent predictor of mortality in this group we chose in our first set of experiments to primarily assess the effects of glycaemic control (acute and chronic) on platelet NO · responsiveness. Study: In diabetic patients admitted with an ACS the relationship between glycaemic control and the main determinants of platelet NO · responsiveness, superoxide (O2-)generation and guanylate cyclase activity were assessed. Secondary hypotheses assessed the effects of acute glycaemic control on other potential modulators of NO · responsiveness such as asymmetric dimethylarginine (ADMA), L-arginine, Larginine/ADMA ratio, platelet activated O2- release and C-reactive protein (CRP). Other values assessed included CK rise, non-esterified fatty acid (NEFA) levels, ADP induced platelet aggregation and neutrophil count. We also assessed the determinants of both platelet SNP response and of O2- levels by a stepwise multivariate analysis; parameters assessed were age, sex, blood sugar level (BSL), statin therapy, insulin therapy, ACE-inhibitor therapy and CK elevation. Conclusions: In diabetic patients admitted with an ACS; 1. Admission BSL was inversely correlated with platelet SNP responsiveness and directly correlated with O2- generation, but not with guanylate cyclase activity. 2. Admission BSL also correlated with CK rise, CRP, neutrophil count and ADP enhanced O2- generation. Admission BSL was inversely correlated with ADMA and L-arginine levels. 3. On multivariate analysis, admission BSL was a significant determinant of O2- levels and an inverse determinant of SNP response; with increasing age also a significant inverse determinant of SNP response. Acute Resolution of hyperglycaemia normalizes platelet responsiveness to nitric oxide in diabetics with acute coronary syndromes Background: We then explored whether improving glycaemic control had any effect on platelet NO · responsiveness. This was performed by randomizing diabetics with ACS to either intravenous infusions or subcutaneous injections of insulin. This experiment was designed to determine possible mechanisms to explain the results of the DIGAMI study, which showed that tight glycaemic control decreased mortality in diabetics admitted with an acute myocardial infarction (AMI). Study: Sixty diabetic patients admitted with an ACS were randomized to aggressive IV insulin therapy or standard subcutaneous insulin therapy over 12 hours. The primary objective of this study, was to assess the acute effects of tight glycaemic control on platelet NO · responsiveness, O2- generation and guanylate cyclase activity. To explore all possible mechanisms of any observed effect δ ADMA,L- arginine and Larginine/ADMA ratio, CRP, non esterified fatty acids (NEFA) and platelet aggregation were assessed. Conclusions: In diabetic patients admitted with an ACS; 1. Aggressive glycaemic control resulted in significantly enhanced platelet responsiveness to SNP, related to a reduction in O2- generation. No effect on guanylate cyclase activity was seen. 2. A significant reduction in ADMA and L-arginine levels were observed with intravenous compared to subcutaneous insulin therapy. Effects of an oral glucose load on platelet responsiveness to nitric oxide Background: Elevated BSLs are associated with adverse cardiovascular outcomes in ACS in both diabetic and non-diabetic subjects. Hyperglycaemia is no longer considered an ‘ innocent bystander ’ however, having detrimental mechanistic implications on a number of protective biological systems. Indeed, harmful effects of sudden glucose loads such as post-prandial hyperglycaemia on the cardiovascular system are becoming apparent. While our previous experiments had focused on the impact of hyperglycaemia and its subsequent correction, on NO · bioavailability, our follow up experiments assessed the effect of an oral glucose load in normal subjects and patients with known cardiovascular disease. In light of the previous findings, we assessed the effects of an acute glucose load on platelet NO · responsiveness and vascular reactivity as assessed by applanation tonometry. Study: 8 healthy and 10 ‘ high-risk ’ cardiovascular subjects were enrolled into this study. A 75 gm glucose load was administered and baseline and 2 hour data were assessed. Platelet SNP responsiveness and O2- generation along with augmentation index (AIx) and ADP-induced platelet aggregation were assessed in all subjects. In the ‘ high-risk ’ cohort cGMP generation and insulin levels were also evaluated. Conclusions: In the healthy volunteers; 1. No significant change occurred in any of the variables assessed In the ‘ high-risk ’ cohort 1. 80 % of patients had undiagnosed impaired glucose handling 2. A significant increase in soluble guanylate cyclase activity was associated with an oral glucose load possibly related to an increase in insulin levels Lack of inotropic effect of nitric oxide in rat papillary muscle. Background: Our final set of experiments moved away from platelet studies to the assessment of myocardial contractility. Differing methodologies and animal models have resulted in variable results in the assessment of the inotropic effects of NO · . While the consensus is that NO · donors have a positive inotropic effect in low doses and are negatively inotropic at high doses, this has been difficult to show in the papillary muscle of most animal models. We addressed this issue in the papillary muscle of the Sprague-Dawley rat. Study: The experimental protocol involved the assessment of NO · effects on contractility on the left ventricular muscle of the Sprague-Dawley rat. These studies initially involved assessing the most stable preparation, comparing a 10bpm with a 35bpm protocol. The effect of the NO · donor SNP was then assessed not only on the isolated LV papillary muscle but also in the presence of β -adrenoceptor stimulation and an ischaemic/reperfusion model (15mins of anoxia/ 30 mins of reperfusion). Conclusions: In the left ventricular papillary muscle of the Sprague-Dawley rat 1. A stimulation frequency of 10bpm resulted in a more stable preparation over a 60 minute protocol, compared to 35bpm. 2. The isolated rat papillary muscle had no measurable response to exogenous NO · donors. The inotropic effects of β -adrenoceptor stimulation and ischaemia-reperfusion were NO · -independent in this model. While the field of NO · research is rapidly expanding, we forget that it is only just over 20 years since we were first aware of its existence. From Furchgott and Zawadski ' s ( Furchgott and Zawadzki, 1980 ) initial observation of an endotheliumderived relaxing factor ( EDRF ) to the subsequent studies by Palmer et al. ( Palmer et al., 1987 ) and Ignarro et al. ( Ignarro et al., 1987 ) showing that EDRF was indeed NO ·, many questions remain unanswered in relation to the 1992 ‘ molecule of the year ’. This thesis contributes to our understanding of NO · and its associated bioavalability in a number of tissues, particularly in relation to a high-risk cohort, the hyperglycaemic diabetic with an ACS. Thesis (Ph.D.)--Medical School, 2004.

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43

McCrary, Jeffrey Kirk. "Receptor-specific binding of von Willebrand factor to platelets in response to shear stress." Thesis, 1994. http://hdl.handle.net/1911/16757.

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Physical and biochemical forces convert platelets in human blood in vivo from the quiescent state as freely moving, discoid, singlets to aggregates adhering to subendothelial surfaces and secreting a wide variety of bioactive substances. Platelet aggregation, one of the essential components of hemostasis, can be caused in vitro by several chemical agonists, and by shear stress, as is found in flowing blood. Platelet aggregation at high shear stress is a receptor-mediated process requiring the binding of the plasma protein von Willebrand factor (vWf) to platelets. This study was undertaken to detect and characterize by direct measurement the binding of vWf to platelets under shear stress. Three different binding assays were developed. Two utilize radioassays for detection of vWf-platelet binding, one using radioiodinated, plasma-derived vWf multimers, the other using a novel technique which produces radiolabeled, unusually large vWf multimers from human umbilical vein cell cultures. The third assay utilizes an immunoassay technique to measure extracellular vWf concentration. Each experimental technique was verified using the platelet agonist, ristocetin. The measurements reported here constitute the first direct determination of vWf multimer binding to platelets in response to shear stress. Binding of exogenous vWf multimers to platelets is detected over the entire ranges of shear stresses and times of exposure tested (15-180 dynes/cm$\sp2$ and 15-300 seconds, respectively). It is receptor-specific, involving both platelet receptors GPIb and GPIIb/IIIa without apparent interdependence. Binding of the exogenous forms persists after long periods of shear, where platelet secretion of vWf can exceed the extent of binding of exogenous vWf, resulting in a net increase in extracellular vWf concentration. Shear stress-induced binding requires large vWf multimers, and involves the secretion of adenosine diphosphate from intraplatelet granules. These results demonstrate that vWf binds to platelet receptors GPIb and GPIIb/IIIa under levels of shear stress which cause platelet aggregation in vitro, and which correspond to arterial thrombosis occurrence in vivo. The findings discussed herein thus contribute to our understanding of the role of platelets in thrombotic disorders, and may be useful in development of methods for therapy and/or prophylaxis.

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44

Plein, Helene. "The platelet as a peripheral marker of the (receptor regulated calcium) second messenger responses in psychiatric illness." Thesis, 2014.

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This thesis examines the use of the platelet as a peripheral marker of receptor regulated calcium second messenger responses of neuronal cells in major depression, subsyndromal depression, panic disorder and schizophrenia. These psychiatric disorders have substantia] overlap in clinical symptomatology. Identification of a peripheral marker that might differentiate the disease conditions in terms of the underlying pathophysiology of the illness would greatly benefit the diagnosis and treatment o f the psychiatric illnesses.Platelet intracellular calcium in response to neurotransmitter stimulation was measured using the fluorescent dye fura-2. This study has shown that in major depression, treated with electro-convulsive therapy (to control for a drug effect), the augmented intracellular calcium response to serotonin stimulation changes with treatment. The response is correlated with clinical improvement and suggests the platelet response as a state marker in major depression. This platelet response is specific for major depression, since no abnormality in second messenger transduction to serotonin stimulation was seen in patients with subsyndromal depression. Furthermore, the platelet response demonstrates selectivity; in patients with panic disorder, no difference in the calcium response is seen between patients and controls, lending further proof that major depression and panic disorder may ha ve differences in terms of serotonergic dysregulation. The role calcium influx has in the augmented intracellular calcium response was measured by manganese influx and radiolabelled calcium uptake experiments. Calcium influx in response to serotonin stimulation is augmented in major depressive patients compared to normal controls. An interesting finding is that the uptake response is biphasic which may substantiate the two-pool model of calcium oscillations within cells that was proposed by Berridge, 1991. Although many peripheral markers for depression have been suggested,there is a paucity of information concerning peripheral markers of schizophrenia.Serotonin and dopamine have not shown encouraging results as agonists in this disorder.Glutamate is an excitatory amino acid that has been implicated in the pathogenesis of schizophrenia. On stimulation, the platelet glutamate receptoi activates divalent cation channels which cause intracellular calcium release, so in truth it is not a second messenger response. Schizophrenic patients show augmented intracellular calcium responses to glutamate stimulation in comparison to controls. This study supports the use o f the platelet as a peripheral marker in schizophrenia. The last analysis looked at the intracellular calcium response to thrombin in the various psychiatric illnesses. Panic disorder and major depression have the highest intracellular calcium responses to thrombin stimulation. Electroconvulsive therapy does not alter this response, suggesting that it is a trait of the illness. Schizophrenia and subsyndromal depression have no altered intracellular response to thrombin. These results support the growing evidence suggesting that major depression and panic disorder are associated with significant cardiovascular complications, yet whether this is a question of association or causality must still be investigated. I feel that the thesis supports the use of the platelet as a peripheral marker of the receptor regulated calcium second messenger response of the neuronal cell, and the findings may provide some utility in the diagnosis and treatment of the psychiatric disorders.

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45

Sterling, Katherine. "The role of CD8+ T cells in the regulation of recipient immune responses induced by allogeneic platelet transfusions." 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=81000&T=F.

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46

Simpson, Elisa. "Mechanisms of Action and Relative Efficacy of Glucocorticosteroid Treatment in Ameliorating Immune Thrombocytopenia Induced by Anti-platelet GPIbα Versus GPIIbIIIa Immune Responses". Thesis, 2012. http://hdl.handle.net/1807/42899.

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Immune thrombocytopenia (ITP) is an autoimmune disorder, mediated mainly by autoantibodies against platelet glycoprotein GPIIbIIIa and GPIbα resulting in enhanced platelet destruction. Decreased platelet production and cellular immunity also contribute to ITP. GPIIbIIIa and GPIbα are distinct platelet receptors. Previous studies suggested that anti-GPIbα (versus anti-GPIIbIIIa)-mediated ITP is less responsive to IVIG therapy. However, little information is available whether antibody specificities also dictate efficacy of Glucocorticosteroids (GC), which are the first-line ITP treatment. Here, I first induced ITP in mice by passive administration of anti-GPIbα or anti-GPIIbIIIa antibodies. Results suggest GCs were more effective at amelioration of anti-GPIIbIIIa-mediated thrombocytopenia. I repeated this observation in an active ITP model, in which splenocytes from wild-type platelet immunized GPIbα-/- or GPIIIa-/- mice were engrafted into wild-type mice, which developed ITP. Thus, I established new murine models of ITP for GC therapy and demonstrated that anti-GPIbα-mediated thrombocytopenia may be less responsive to GC therapy.

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47

Su, Chen-Yi, and 蘇珍儀. "The effects of ganodermic acid S on the responses of human platelets to the thromboxane A2 analogue U46619, collagen and prostaglandin E1." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/81462574792308182493.

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博士 國立清華大學 生命科學系 87 Ganodermic acid S (GAS) [lanosta-7,9(11),24-triene-3beta,15alpha-diacetoxy-26-oic acid], a triterpene isolated from the Chinese medicinal fungus Ganoderma lucidum (Fr.) Karst (Polyporaceae), exerts multiple effects on human platelet responses to various aggregating agonists. The thesis investigated how GAS less than 16 microM may affect the responses of human gel-filtered platelets (GFP) to (1) thromboxane (TX) A2 mimetic U46619, (2) collagen, and (3) prostaglandin (PG) E1. In platelet response to U46619, GAS inhibited Ca2+ mobilization, phosphorylation of myosin light chain and pleckstrin, alpha-granule secretion, and cell aggregation. GAS at 7.5 microM also strongly inhibited U46619-induced diacylglycerol formation, arachidonic acid release, and TXB2 formation. Immunoblotting study of protein-tyrosine phosphorylation showed that GAS inhibited the phosphotyrosine proteins at the steps involving the engagement of integrin alphaIIbbeta3 and aggregation. However, GAS did not inhibit U46619-induced platelet shape change, nor the inhibitory effect of U46619 on PGE1-evoked cyclic AMP level in GFP. It is concluded that GAS inhibits platelet response to TXA2 on the receptor-Gq-phospholipase Cbeta1 pathway, but not on the receptor-Gi pathway. In platelet response to collagen, GAS inhibited cell aggregation by prolonging lag and shape change periods and decreasing the initial cell aggregation rate. However, the inhibitory efficiency was less than its inhibition on GFP response to U46619. In the agent-effect on biochemical events, GAS effectively inhibited Ca2+ mobilization, phosphorylation of myosin light chain, dense granule secretion and TXB2 generation. The inhibition might be originated from blocking Ca2+ mobilization of the TXA2-dependent pathway. GAS partially decreased the phosphorylation of most phosphotyrosine proteins from early activation to the integrin alphaIIbbeta3-regulated steps. The agent did not affect the phosphorylation of four proteins at the steps regulated by integrin alphaIIbbeta3. These results suggest that GAS inhibits the collagen response predominantly on the TXA2-dependent signaling, and the tyrosine kinase-dependent pathway in collagen response plays a major role in cell aggregation. In platelet response to PGE1, GAS at < 20 microM did not affect the basal cyclic AMP level. However, GAS potentiated the PGE1-evoked cyclic AMP level in a bell-shaped, concentration-dependent manner. The agent at 7.5 microM enhanced the level up to 1.8 fold of that evoked by PGE1 alone. Collagen did not inhibit the PGE1-induced cyclic AMP level in platelets pretreated with GAS of 6 to 7.5 microM. Besides, the agent at 7.5 microM enhanced the inhibition of PGE1 on platelet response to collagen in: phosphorylation of myosin light chain and pleckstrin, alpha-granule secretion, cell aggregation and protein-tyrosine phosphorylation. In addition, the agent along with PGE1 almost abolished the dense granule secretion and TXB2 formation. The results suggest that GAS potentiated the PGE1-induced cyclic AMP synthesis. The elevated cyclic AMP level might contribute to part of the enhancement of GAS in PGE1-inhibition of platelet response to collagen. These studies indicate that the insertion of GAS less than 7.5 microM into human platelet plasma membrane exhibits multiple effects on platelet functions. It may be due that the lipid environments surrounding the receptors of various agonists are different. The thesis establishes the inhibitory mechanisms of GAS on platelet response to TXA2 mimetic U46619 and collagen, and distinguishes the effects of GAS on both two agonists. Besides, the study shows that GAS plays another role on platelets by potentiation of PGE1-induced cyclic AMP synthesis and PGE1-inhibition of collagen response.

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