Дисертації з теми "Thrombu"
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1
Mutch, Nicola J. "Thrombin activity in human thrombi and the vessel wall." Thesis, University of Aberdeen, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340809.
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2
Moir, Elaine. "The pro- and anti-fibrinolytic properties of human leucocytes." Thesis, University of Aberdeen, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340602.
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3
Petersen, Helen J. "Streptococcus-induced thrombus formation." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.541609.
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4
Machi, Paolo. "Evaluation expérimentale des propriétés mécaniques et de l'efficacité d'enlèvement des thrombus des stent retrievers." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT263/document.
Повний текст джерелаАнотація:
Un certain nombre d'essais cliniques contrôlés, randomisés et publiés récemment en littérature a démontré que la thrombectomie mécanique, offerte aux patients présentant un AVC ischémique aigu, est liée à une meilleure évolution clinique en comparaison au traitement standard de fibrinolyse intraveineuse. Les stents retriever ont été reconnus dans ces essais comme les dispositifs les plus efficaces pour la thrombectomie intracrânienne. Actuellement, toutes les industries produisant des dispositifs neuro-interventionnels lancent sur le marché un nombre croissant de stents retriever. Chaque nouveau dispositif proposé est censé avoir une particularité permettant de meilleures performances par rapport aux dispositifs déjà disponibles sur le marché. Néanmoins, aucune étude clinique n’a démontré, jusqu'à présent, la supériorité en termes de résultats anatomiques et cliniques d'un stent retriever donné. En outre, le mécanisme d'interaction entre les stents retriever et le thrombus n'a pas été évalué jusqu'ici de façon exhaustive. Dans la présente étude, nous avons analysé expérimentalement les performances de tous les stents retriever disponibles sur le marché français jusqu'à juin 2015. Le but de cette étude était d'identifier toutes les caractéristiques des dispositifs fonctionnels à la capture du thrombus. Chaque dispositif a été évalué par des tests mécaniques et fonctionnels : les tests mécaniques ont été effectués afin d'étudier la force radiale des dispositifs. L'objectif était d'évaluer la force radiale exercée par le stent dans deux conditions spécifiques : lors du déploiement et pendant le retrait.Les tests fonctionnels ont visé à évaluer visuellement la capacité du stent à rester en apposition sur la paroi des vaisseaux et à maintenir le thrombus à l'intérieur de ses mailles au cours du retrait. Nous avons évalué l'interaction des dispositifs avec thrombus de taille et de caractéristiques différentes que nous avons générées en utilisant du sang humain afin d'obtenir deux types de caillot : un souple « de type rouge » composé par tous les éléments du sang et un dur « de type blanc» qui a été principalement composé de plasma riche en plaquettes. Ces essais ont été effectués en utilisant un modèle vasculaire rigide reproduisant la circulation cérébrale antérieure. Deux neuro-interventionnels ayant une expérience dans les procédures de thrombectomie ont effectué les tests fonctionnels. Chaque expérience a été filmée et deux auteurs par la suite ont effectué une analyse visuelle des résultats.Les essais mécaniques ont montré un comportement différent en termes de variation de pression radiale au cours du retrait pour chaque stent. Une pression radiale constante pendant le retrait est liée à une cohésion constante sur la paroi artérielle pendant le retrait, avec un taux plus important de retrait du caillot. Tous les stents retriever glissent sur le caillot blanc de grande taille (diamètre>6 mm) ayant un très bas taux d’efficacité en termes de retraitA number of randomized controlled trials recently appeared in literature demonstrated that early mechanical thrombectomy offered to patients presenting with acute ischemic stroke is related to improved functional outcome in comparison to standard care intravenous fibrinolysis. Stent retrievers have been recognized in these trials as the most effective devices for intracranial thrombectomy. Currently, all industries producing neuro-interventional devices are launching into the market an increasing number of stent-based retriever tools. Each new device proposed for clinical use is supposed to have peculiar features allowing better performances in comparison to devices already available for clinical practice. Nevertheless, none clinical study has demonstrated so far the superiority, in terms of anatomical and clinical results, of a given stent retriever device. Furthermore, the mechanism of interaction between stent retrievers and thrombi has not exhaustively evaluated so far. In the present study we experimentally analyzed performances of all stent retrievers available into the French market up to Juin 2015. The aim of this study was to identify any device feature that was functional to the thrombus removal.Stent retrievers were evaluated by mechanical and functional test: mechanical tests were performed in order to investigate devices radial force, the aim was to evaluate the radial force exerted by the stent in two specific conditions: upon deployment and during the retrieval.Functional tests were aimed to visually evaluate the stent retriever’s ability in remaining in close apposition to the vessels wall and to maintain the thrombus engaged within its struts during the retrieval. We evaluated the interaction of the devices with thrombi of different features and sizes that we generated using human blood in order to obtain two types of clot: one softer “red type” that was composed by all elements of the whole blood and one stiffer “white type” that was mainly composed by platelet-rich plasma. Such tests were conducted using a rigid 3D printed vascular model reproducing the brain anterior circulation. Two neuro-interventionalists with experience in thrombectomy procedures performed functional tests, each experiment was filmed and two authors thereafter conducted visual analysis of the results.Mechanical tests showed different behavior in terms of radial pressure variation during retrieval for each stent. Constant radial pressure during retrieval was related to constant cohesion over the vessel wall during retrieval and higher rate of clot removal efficacy. All stent retrievers slide over the clot failing in clot removal when interact with white large thrombi (diameter>6 mm)
5
Ramaiola, Ilaria. "Thrombus composition in acute coronary syndrome." Doctoral thesis, Universitat Pompeu Fabra, 2015. http://hdl.handle.net/10803/456681.
Повний текст джерелаАнотація:
Atherothrombosis and, specifically intracoronary thrombosis is a major cause of acute coronary syndromes (ACS) and consequently of morbidity and mortality throughout the world. While management of acute ST-elevation myocardial infarction (STEMI) has dramatically improved over the last years, there is still a need to find thrombosis-related biomarkers for an early identification of ischemic processes and a better stratification of patients that have suffered an ACS. In fact, the ischemia time, defined as the time from the onset of symptoms to reperfusion, has been recently suggested as the “New Gold Standard for STEMI-Care”. This thesis mainly focuses on the protein composition of the occluding coronary thrombus, occurring both in the native coronary arteries and in the commonly implanted coronary stents. The study based on the proteomic analysis of coronary thrombi, obtained after percutaneous coronary intervention (PCI), has provided consistent evidence of the dynamic composition of the coronary thrombi in relation with the time of ischemia, and has resulted in the identification of novel biomarkers of potential use to be translated to the clinical practice. Furthermore, the comparison of native and in-stent-thrombosis has allowed the identification of proteins that might serve as interesting therapeutic targets to prevent thrombosis in patients who undergo PCI with stent-implantation.La enfermedad aterotrombotica y concretamente la trombosis intracoronaria es la mayor causa de los síndromes coronarios agudos (SCA), y consecuentemente de morbilidad y mortalidad en el mundo. El manejo de los pacientes con infarto agudo de miocardio con elevación del segmento ST ha mejorado considerablemente en los últimos años, a pesar de esto sigue siendo necesario encontrar biomarcadores para la detección temprana de los procesos isquémicos y que permitan una estratificación más eficiente de los pacientes que han sufrido un evento isquémico agudo. De hecho, el tiempo de isquemia, definido como el tiempo entre el inicio del dolor y la revascularización, ha sido recientemente definido como el parámetro fundamental en el tratamiento de los pacientes con STEMI. Este trabajo de tesis está enfocado a elucidar la composición proteica de los trombos coronarios oclusivos que se forman tanto en las arterias coronarias nativas como en aquellas con stent. El estudio se basa en el análisis proteómico de trombos coronarios en relación al tiempo de isquemia, con la finalidad de encontrar nuevos biomarcadores para trasladar a la práctica clínica. Además, la comparación entre trombos nativos y trombos desarrollados sobre el stent permite la identificación de proteínas diferenciales que podrían ser futuras dianas terapéuticas para prevenir la formación del trombo en pacientes sometidos a angioplastia coronaria transluminal percutánea (ACTP) con implantación de un stent coronario.
6
Bowker, Timothy J. "A computational model for thrombus prediction." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558527.
Повний текст джерелаАнотація:
The haemostatic system stops the loss of blood, thereby maintaining the integrity of the circulatory network. Whilst haemostasis is necessary for survival, thrombosis - haemostasis in the wrong place - is the most common cause of mortality in the West. The presence of a thrombus is governed by the triad of endothelial injury, blood constitution and flow. The central protein involved in this process is thrombin which is formed through a reaction network known as the coagulation cascade. Cerebral saccular aneurysms are balloon like dilations of the cerebral vasculature that are estimated to be present in 2-6% of the population. The currently preferred treatment method for such aneurysms is the deliberate initiation of thrombus formation (leading to occlusion) through the placement of platinum coils within the aneurysm. An emerging alternative is the use of a stent which is deployed across the aneurysm neck, reducing the rate at which flow enters the aneurysm, leading again to the controlled formation of a thrombus. A comprehensive model of thrombus formation within cerebral aneurysms should simulate the reduction to flow as the thrombus grows within the aneurysm. The model must capture the spatial and temporal regulators of thrombus formation - incorporating both biological and mechanical factors. This first part of this thesis examines the sensitivity of flow conditions within cerebral aneurysms to changes in boundary conditions (simulated exercise) and geometrical changes (stent placement). The main contribution of this thesis is the development of frameworks which enable examination of thrombus formation. First, an idealised arteriole is used to examine the impact of flow upon two approaches to computational modelling of thrombin generation. The second framework uses the Level Set technique to track the position of a thrombus surface within a patient specific aneurysmal geometry.
7
Glossop, Paul. "Thrombin inhibition." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244533.
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8
Levade, Marie. "Mécanismes moléculaires de la production et des fonctions plaquettaires : rôle de Vps34 et impact des inhibiteurs ciblés de kinases." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30036.
Повний текст джерелаАнотація:
Les plaquettes sanguines jouent un rôle essentiel dans le maintien de l'intégrité des vaisseaux sanguins. En cas de brèche vasculaire, elles conduisent à la formation d'un clou hémostatique via des étapes successives d'adhésion, sécrétion et agrégation finement régulées et préviennent alors un saignement excessif. Les plaquettes jouent également un rôle critique dans les pathologies thrombotiques comme l'athérothrombose, ce qui en fait des cibles pharmacologiques majeures dans ces situations. Au cours de ma thèse, deux axes de recherche ont été abordés : (i) l'étude du rôle de la PI3-kinase de classe III (Vps34) dans la formation et l'activation des plaquettes et (ii) l'étude de l'impact de nouvelles drogues ciblant les kinases en thérapie anti-cancéreuse sur les fonctions plaquettaires et l'hémostase. Dans un premier temps, je me suis concentrée sur la caractérisation du rôle de Vps34 et de son produit lipidique, le phosphatidylinositol 3 monophosphate (PtdIns3P), dans la physiologie plaquettaire à l'aide d'un modèle de souris présentant une délétion de Vps34 spécifiquement dans la lignée mégacaryocyte/plaquette (PF4-Cre/Vps34lox/lox). Nous avons observé une microthrombopénie modérée associée à un défaut de migration des mégacaryocytes ainsi que des anomalies morphologiques des granules de sécrétion. Ce phénotype apparaît lié à une diminution de taux de PtdIns3P associé à un trafic vésiculaire perturbé. De plus, nous avons mis en évidence une altération des fonctions prothrombotiques des plaquettes, ex vivo en conditions de flux mais aussi in vivo en conférant aux souris une protection contre la thrombose induite à la carotide par lésion au chlorure ferrique. La contribution de Vps34 dans les mécanismes d'activation plaquettaire, indépendamment de son rôle dans le mégacaryocyte, a été montrée ex vivo via l'utilisation de nouveaux inhibiteurs spécifiques de Vps34 (SAR405 et INH1) récemment développés pour une application en oncologie, notamment pour réduire la résistance de certains cancers aux chimiothérapies. Dans un second temps, je me suis intéressée à l'impact des nouvelles thérapies ciblées anticancéreuses sur les plaquettes afin de comprendre la majoration du risque hémorragique associée à ces molécules. Nous avons étudié l'effet de l'ibrutinib, un inhibiteur des tyrosine-kinases de la famille BTK activées en aval des PI3-kinases de classe I, utilisé en clinique dans le traitement des hémopathies lymphoïdes B (lymphomes et leucémie lymphoïde chronique). L'exploration des fonctions plaquettaires au sein d'une cohorte de patients du service d'hématologie du CHU-Toulouse a permis de corréler les signes hémorragiques de certains patients traités par ibrutinib avec un défaut de signalisation plaquettaire en aval des récepteurs GPVI et GPIb, se traduisant par une diminution de l'agrégation au collagène et au CRP et par un défaut d'adhésion sur matrice de facteur von Willebrand en conditions de flux. En conclusion, mes travaux de thèse (i) apportent de nouvelles données fondamentales sur la participation de Vps34 dans les mécanismes de production et d'activation plaquettaires et (ii) ont permis de proposer des recommandations quant à l'utilisation clinique des nouvelles thérapies ciblées anti-cancéreusesBlood platelets play an essential role in the maintenance of vascular integrity. They prevent excessive blood loss after vessel injury by orchestrating haemostatic clot formation through successive steps of adhesion, secretion and aggregation. Platelets are also major pharmacologic targets as they participate in thrombotic pathologies such as atherosclerosis. My thesis work was focused on two axis: (i) the role of class III PI3-kinase (Vps34) in platelet formation and activation and (ii) the impact of new anticancer drugs targeting kinases on platelet functions and haemostasis. First, I studied the role of Vps34 and its lipid product, phosphatidylinositol 3 monophosphate (PtdIns3P), in platelet physiology using a unique mouse model of Vps34 deletion specifically in megakaryocyte lineage (PF4-Cre/Vps34lox/lox). We observed a moderate microthrombocytopenia associated to a defect in megakaryocyte migration and morphologic abnormalities in secretion granules. This phenotype is linked to a decrease in PtdIns3P level associated with defective vesicular trafficking. Moreover, PF4-Cre/Vps34lox/lox mice exhibit altered prothrombotic functions, ex vivo in shear conditions and in vivo by conferring a protection against ferric chloride-induced carotid thrombosis. A role for Vps34 in platelet activation, independently from its role in megakaryocyte, was shown ex vivo using two specific Vps34 inhibitors (SAR405 and INH1) recently developed to reduce autophagy-mediated resistance to chemotherapy. Secondly, I assessed the impact of new targeted drugs used in cancer therapy on platelets in order to understand the increased bleeding risk associated to these molecules. We studied the effect of ibrutinib, a specific inhibitor of BTK family tyrosine kinases recently approved for the treatment of B malignancies (mantle cell lymphoma, chronic lymphocytic leukemia). By exploring platelet functions of ibrutinib-treated patients treated from Hematology department of Toulouse, we correlated bleeding symptoms to a defective platelet signaling downstream GPVI and GPIb receptors as shown by a strongly reduced platelet aggregation in response to collagen and CRP and by a defect in platelet adhesion on von Willebrand matrix under flow conditions. In conclusion, my thesis work (i) brings fundamental insights about Vps34 contribution in mechanisms of platelet production and functions and (ii) allows recommendations about clinical use of new targeted molecules in cancer therapy
9
Cardillo, Giulia. "Fluid Dynamic Modeling of Biological Fluids : From the Cerebrospinal Fluid to Blood Thrombosis." Thesis, Institut polytechnique de Paris, 2020. http://www.theses.fr/2020IPPAX110.
Повний текст джерелаАнотація:
Dans cette thèse, trois modèles mathématiques ont été proposés, avec l’objectif de modéliser autant d’aspects complexes de la biomédecine, dans lesquels la dynamique des fluides du système joue un rôle fondamental: i) les interactions fluide-structure entre la pulsatilité du liquide céphalo-rachidien et la moelle épinière (modélisation analytique); ii) dispersion efficace d’un médicament dans l’espace sous-arachnoïdien (modélisation numérique); et iii) la formation et l’évolution d’un thrombus au sein du système cardiovasculaire (modélisation numérique).Le liquide céphalorachidien est un fluide aqueux qui entoure le cerveau et la moelle épinière afin de les protéger. Une connaissance détaillée de la circulation du liquide céphalorachidien et de son interaction avec les tissus peut être importante dans l’étude de la pathogenèse de maladies neurologiques graves, telles que la syringomyélie, un trouble qui implique la formation de cavités remplies de liquide (seringues) dans la moelle épinière.Par ailleurs, dans certains cas, des analgésiques - ainsi que des médicaments pour le traitement de maladies graves telles que les tumeurs et les infections du liquide céphalorachidien - doivent être administrés directement dans le liquide céphalorachidien. L’importance de connaître et de décrire l’écoulement du liquide céphalorachidien, ses interactions avec les tissus environnants et les phénomènes de transport qui y sont liés devient claire. Dans ce contexte, nous avons proposé: un modèle capable de décrire les interactions du liquide céphalo-rachidien avec la moelle épinière, considérant cela, pour la première fois, comme un milieu poreux imprégné de différents fluides (sang capillaire et veineux et liquide céphalo-rachidien); et un modèle capable d’évaluer le transport d’un médicament dans l’espace sousarachnoïdien, une cavité annulaire remplie de liquide céphalo-rachidien qui entoure la moelle épinière.Avec le troisième modèle proposé, nous entrons dans le système cardiovasculaire.Dans le monde entière, les maladies cardiovasculaires sont la cause principale de mortalité. Parmi ceux-ci, nous trouvons la thrombose, une condition qui implique la formation d’un caillot à l’intérieur d’un vaisseau sanguin, qui peut causer sa occlusion. À cet égard, un modèle numérique a été développé qui étudie la formation et l’évolution des thrombus, en considérant simultanément les aspects chimico-biomécaniques et dynamiques des fluides du problème. Dans le modèle proposé pour la première fois, l'importance du rôle joué par les gradients de contrainte de cisaillement dans le processus de thrombogenèse est pris en compte.Les modèles sélectionnés ont fourni des résultats intéressants. Tout d’abord, l’étude des interactions fluide-structure entre le liquide céphalo-rachidien et la moelle épinière a mis en évidence es conditions pouvant induire l’apparition de la syringomyélie. Il a été observé comment la déviation des valeurs physiologiques du module d’Young de la moelle épinière, les pressions capillaires dans l’interface moelle-espace sousarachnoïdien et la perméabilité des compartiments capillaire et veineux, conduisent à la formation de seringues.Le modèle de calcul pour l’évaluation de la dispersion pharmacologique dans l’espace sousarachnoïdien a permis une estimation quantitatif de la diffusivité effective du médicament, une quantité qui peut aider à l’optimisation des protocoles d’injections intrathécales.Le modèle de thrombogenèse a fourni un instrument capable d’étudier quantitativement l’évolution des dépôts de plaquettes dans la circulation sanguine. En particulier, les résultats ont fourni des informations importantes sur la nécessité de considérer le rôle de l’activation mécanique et de l’agrégation des plaquettes aux côtés de la substance chimiqueIn the present thesis, three mathematical models are described. Three different biomedical issues, where fluid dynamical aspects are of paramount importance, are modeled: i) Fluid-structure interactions between cerebro-spinal fluid pulsatility and the spinal cord (analytical modeling); ii) Enhanced dispersion of a drug in the subarachnoid space (numerical modeling); and iii) Thrombus formation and evolution in the cardiovascular system (numerical modeling).The cerebrospinal fluid (CSF) is a liquid that surrounds and protects the brain and the spinal cord. Insights into the functioning of cerebrospinal fluid are expected to reveal the pathogenesis of severe neurological diseases, such as syringomyelia that involves the formation of fluid-filled cavities (syrinxes) in the spinal cord.Furthermore, in some cases, analgesic drugs -- as well drugs for treatments of serious diseases such as cancers and cerebrospinal fluid infections -- need to be delivered directly into the cerebrospinal fluid. This underscores the importance of knowing and describing cerebrospinal fluid flow, its interactions with the surrounding tissues and the transport phenomena related to it. In this framework, we have proposed: a model that describes the interactions of the cerebrospinal fluid with the spinal cord that is considered, for the first time, as a porous medium permeated by different fluids (capillary and venous blood and cerebrospinal fluid); and a model that evaluates drug transport within the cerebrospinal fluid-filled space around the spinal cord --namely the subarachnoid space--.The third model deals with the cardiovascular system. Cardiovascular diseases are the leading cause of death worldwide, among these diseases, thrombosis is a condition that involves the formation of a blood clot inside a blood vessel. A computational model that studies thrombus formation and evolution is developed, considering the chemical, bio-mechanical and fluid dynamical aspects of the problem in the same computational framework. In this model, the primary novelty is the introduction of the role of shear micro-gradients into the process of thrombogenesis.The developed models have provided several outcomes. First, the study of the fluid-structure interactions between cerebro-spinal fluid and the spinal cord has shed light on scenarios that may induce the occurrence of Syringomyelia. It was seen how the deviation from the physiological values of the Young modulus of the spinal cord, the capillary pressures at the SC-SAS interface and the permeability of blood networks can lead to syrinx formation.The computational model of the drug dispersion has allowed to quantitatively estimate the drug effective diffusivity, a feature that can aid the tuning of intrathecal delivery protocols.The comprehensive thrombus formation model has provided a quantification tool of the thrombotic deposition evolution in a blood vessel. In particular, the results have given insight into the importance of considering both mechanical and chemical activation and aggregation of platelets
10
Chalayer, Emilie. "Myélome multiple et maladie thrombo-embolique veineuse : aspects épidémiologiques, économiques, physiopathologiques et pharmacologiques." Thesis, Saint-Etienne, 2015. http://www.theses.fr/2015STET007T/document.
Повний текст джерелаАнотація:
Comme dans tout cancer, l'association entre myélome multiple et maladie thrombo-embolique veineuse est bien établie. Son incidence au cours du myélome est en moyenne de 10 à 20%. Elle semble plus élevée en cas de myélome de novo et lors de l’utilisation de traitements immunomodulateurs comme le thalidomide. Pourtant, la part de surcroît du risque de thrombose dû à ce traitement n’est pas encore très bien définie. Tout d’abord, nous avons réalisé un bilan de ces pathologies afin de délimiter le champ d’étude grâce à une revue de la littérature. Nous avons ensuite évalué l’incidence de la maladie thrombo-embolique veineuse, identifié les facteurs de risque thrombotique et évalué le classement en groupe de risque des patients présentant un myélome et traités par immunomodulateur grâce à une étude observationnelle, multicentrique, prospective, de la prise en charge des myélomes par les hématologues en France. Par la suite, nous avons réalisé l’analyse médico-économique du seul essai randomisé réalisé à ce jour sur la thrombophylaxie chez les malades présentant un myélome multiple traités par thalidomide en première ligne. Cette étude montre un gain de qualité de vie associé à des économies majeures lors de la prévention de la thrombose par aspirine plutôt que par héparine. Enfin nous avons réalisé 2 études médicales utilisant la génération de thrombine, test biologique de recherche. La première a été effectuée afin d’essayer de prédire les patients qui vont présenter une thrombose. La deuxième a pour but de rechercher l’existence d’une résistance à l’héparine aux doses habituelles utilisées dans cette pathologieThe association between multiple myeloma and venous thromboembolic disease is well established. This incidence in myeloma is on average from 10 to 20%. It appears to be higher in newly diagnosed myeloma and immunomodulatory drugs such as thalidomide might significantly increase the risk. However, the risk of thrombosis due to these treatments is not yet well defined. First, we performed a review of these diseases in order to delimit the field of this study through a literature review. Then, we evaluated the incidence of venous thromboembolic disease in patients with myeloma and treated with immunomodulatory, identified the thrombotic risk factors and evaluated the thrombotic risk assessment based on the physicians choice, through an observational, multicenter, prospective French study. Moreover, we performed the medico-economic analysis of the only randomized trial conducted to date on the thrombophylaxis in patients with multiple myeloma treated with thalidomide in the first line of chemotherapy. This analysis showed a gain in quality of life associated with significant cost savings in the prevention of thrombosis by aspirin rather than heparin. Finally we performed two medical studies using thrombin generation test, a global assay that measures the overall tendency of a plasma sample to form thrombin. The first study was conducted to predict patients who will have thrombosis. The second is performed to know if a heparin resistance with the usual doses in this pathology, exists
11
Koikkalainen, Janne Santeri. "Role of transglutaminases in model thrombus stability." Thesis, University of Aberdeen, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424957.
Повний текст джерелаАнотація:
The effect of transglutaminases in fibrin stability was studied in model thrombus system. Model thrombi were formed under flow from whole blood and FITC-fibrinogen was incorporated. A specific inhibitor of transglutaminases, R283, was included in some thrombi. Lysis was monitored as fluorescence release. The rate of lysis by tPA or uPA present at pharmacological concentrations was significantly increased when transglutaminases were inhibited. Effect was more pronounced with uPA lysis. The model thrombi were divided into cell-rich head and fibrin-rich tail. The effect of transglutaminases was mainly observed in tail, where lysis was increased significantly. It has been previously shown that endogenous lysis is due to uPA and localised in to the head. Inhibition of transglutaminases caused minor increase in rate of endogenous lysis. A patient deficient in FXIII was also studied and model thrombi were found to be markedly less stable. FXIII therapy increased stability of thrombus. These data show that transglutaminases are important in stabilization of thrombi to thrombolysis, but that endogenous fibrinolytic activity is not affected by the degree of cross-linking. Potential role for TG2 in thrombus was also studied. TG2 was found to be present in model and arterial thrombi by immunohistochemistry and also by western blotting. Addition of purified TG2 from guinea pig to forming thrombi stabilised model thrombi, whereas additional FXIII had no effect using normal blood. Inhibition of TG2 in model thrombi was attempted using neutralising antibody and allosteric inhibitor of TG2, the GTPγS. FXIIa is the main transglutaminase responsible for stabilisation of fibrin in model thrombus system.
12
Rouzet, François. "Développement de l'imagerie moléculaire du thrombus artériel." Thesis, Paris Est, 2011. http://www.theses.fr/2011PEST1116.
Повний текст джерелаАнотація:
Le thrombus artériel, ou thrombus intra-luminal (ILT), est impliqué à des degrés divers dans la majorité des pathologies cardiovasculaires dégénératives. Actuellement, sa détection et sa caractérisation repose sur des techniques d'imagerie morphologique qui ne renseignent pas sur l'évolution possible du thrombus en relation avec son profil d'activités biologiques. Dans ce contexte, l'imagerie moléculaire du thrombus a 3 objectifs principaux : (1) la détection du thrombus initial et la recherche de localisations secondaires, (2) l'évaluation du potentiel évolutif du thrombus et de son impact sur les tissus environnants en relation avec son activité biologique, (3) l'évaluation précoce de l'efficacité thérapeutique (avant une modification morphologique). L'objectif de ce travail a été de développer des agents d'imagerie moléculaire des activités biologiques de l'ILT. En ce qui concerne l'activité proagrégante du thrombus artériel, nous avons mis en évidence le lien existant entre l'intensité du signal en Annexine A5 radiomarquée détecté in vivo et l'intensité de l'activité proagrégante dans un modèle d'endocardite infectieuse. Nous avons développé un nouveau traceur élaboré sur la base d'un ligand naturel et de haute affinité (le fucoïdan) de la P-sélectine exprimée par les plaquettes activées, puis validé sa capacité à détecter in vivo le thrombus artériel. En ce qui concerne l'activité plasminergique du thrombus artériel, nous avons utilisé l'aprotinine radiomarquée pour détecter la plasmine dans le thrombus anévrysmal humain ex vivo, puis entamé une collaboration pour optimiser son radiomarquage en utilisant un tag peptidique sans cystéine en position N-terminale. Parallèlement nous avons développé une nouvelle approche basée sur un inhibiteur peptidique conjugué à un agent chélateur bifonctionnelArteriel or intra-luminal thrombus (ILT) is involved to various degrees in most of the degenerative cardiovascular diseases. Its detection and characterization is currently based on morphological imaging techniques that do not provide information about its possible evolution in relation to biological activities profile. In this context, molecular imaging of thrombus has three main objectives: (1) detection of the initial thrombus and of secondary locations, (2) evaluation of the thrombus evolutive potential and its impact on surrounding tissues in relationship with its biological activity, and (3) early assessment of therapeutic efficacy (before morphological changes). The aim of this work was to develop molecular imaging agents of biological activities of ILT. Regarding the proaggregant activity, we demonstrated a relationship between annexin A5 signal intensity and vegetation proaggregant activity in a model of infective endocarditis. We also developed a novel P-selectin imaging agent based on a natural high affinity ligand (fucoidan), and validated its ability to detect ILT in vivo. Regarding the plasminergic activity of ILT, we used radiolabelled aprotinin to detect plasmin in human aneurysmal thrombus ex vivo; we also initiated a collaboration to optimize its radiolabelling using a cystein-free tag peptide in N-terminal position. In parallel we developed a new approach based on a peptide inhibitor conjugated with a bifunctional chelating agent
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Chinswangwatanakul, Vitoon. "The role of thrombin and thrombin receptor in pancreatic cancer." Thesis, Imperial College London, 1999. http://hdl.handle.net/10044/1/7660.
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Richardson, John Lee. "Structural and kinetic characterization of the leech derived inhibitor haemadin in complex with human [alpha]-thrombin [alpha-thrombin] structural analysis of the tsetse thrombin inhibitor in complex with bovine [alpha]-thrombin [alpha-thrombin] /." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965976335.
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15
Giuliano, Simon 1975. "Calcium signalling regulating platelet adhesion and thrombus growth." Monash University, Dept. of Medicine, 2002. http://arrow.monash.edu.au/hdl/1959.1/7875.
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Kuijpers, Marijke Johanna Elfrieda. "Platelet receptors and procoagulant activity in thrombus formation." [Maastricht] : Maastricht : UPM, Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 2006. http://arno.unimaas.nl/show.cgi?fid=7651.
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Wadoodi, Ashar. "The role of bone marrow in thrombus resolution." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-bone-marrow-in-thrombus-resolution(2983faec-0618-4c4f-8897-7816419c55bd).html.
Повний текст джерелаАнотація:
Deep vein thrombosis (DVT) is a common condition affecting 1-2% of the population. It can be further complicated by serious sequelae such as life threatening pulmonary embolus and the chronically debilitating post-thrombotic syndrome. The main treatment modalities available for DVT are only able to limit disease progression, with resolution occurring physiologically. Natural resolution of DVT occurs through a process of thrombus retraction and recanalisation which is comparable to progenitor mediated neovascularisation. The focus of this project was to examine the circulating progenitor cell response to venous thrombosis and to profile the underlying cytokine response. This data was ultimately used, to manipulate the number of circulating progenitor cells and expression of cytokines to enhance the recanalisation process. The presence of venous thrombus produced a bimodal circulating haematopoietic progenitor cell response whilst in the bone marrow compartment progenitor cells were simultaneously depleted. GCSF, GMCSF, VEGF, PIGF and SDF1 were expressed differentially in thrombus, vein wall and plasma, with the laparotomy wound mirroring the cytokine profile of the resolving thrombus. The expression pattern of PIGF in the resolving thrombus was however, unusually specific and not seen in the healing laparotomy wound.
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Grover, Steven Philip. "Prolyl hydroxylase domain proteins in venous thrombus resolution." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/prolyl-hydroxylase-domain-proteins-in-venous-thrombus-resolution(ff255bc6-858a-4155-88fc-963fe740f240).html.
Повний текст джерелаАнотація:
The prolyl hydroxylase domain (PHD) proteins serve as critical regulators of the cellular response to tissue hypoxia, like that present in the early venous thrombus, through regulation of hypoxia-inducible factor 1α (HIF1α) stability. This study sought to determine: (i) the expression of PHD1, PHD2 and PHD3 at the gene and protein level during natural thrombus resolution; (ii) the effect of gene specific deletion of Phd2 on thrombus resolution; (iii) the effect of pan- PHD inhibition on thrombus resolution; and (iv) the contribution of endogenous VEGFR signalling to thrombus resolution. All three PHD isoforms were expressed in the naturally resolving thrombus at the gene and protein level. Gene expression of Phd1 remained invariant while Phd2 and Phd3 expression demonstrated distinct temporal patterns. PHD isoforms were localised to the cellular component of the thrombus, with morphological analysis suggesting expression in both neutrophils and macrophages. Constitutive heterozygous Phd2 gene deletion failed to increase HIF1α stabilisation as was not associated with increased thrombus resolution. Inducible homozygous Phd2 gene deletion significantly enhanced HIF1α nuclear accumulation and transcriptional activity but thrombus resolution was unchanged. Pharmacological inhibition of PHD isoforms with novel small molecule inhibitor, AKB-4924 and JNJ-42041935, signficantly increased HIF1α nuclear accumulation and transcriptional activity. Treatment with these inhibitors significantly increased thrombus neovascularisation but thrombus resolution was unaffected. Blocking of endogenous VEGFR signalling using the pan- VEGFR inhibitor axitinib significantly impaired thrombus resolution. Axitinib treated thrombi remained larger and more occlusive for an extended period of time and this was associated with significant reductions in thrombus neovascularisation, macrophage recruitment and collagen deposition. Inhibition of PHD activity promotes thrombus neovascularisation, but other mechanisms are likely to regulate the removal of thrombus. Studies of thrombus resolution in Phd2 gene specific knockouts indicate that PHD2 activity does not play a major role in thrombus resolution. However, endogenous VEGFR signalling activity, downstream of HIF, is necessary for thrombus resolution.
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Rouchaud, Aymeric. "Optimisation biologique du traitement endovasculaire des anévrysmes intracrâniens." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCD046/document.
Повний текст джерелаАнотація:
La genèse d’un anévrysme intracrânien n’est pas uniquement due à un effet mécanique mais à un ensemble d’éléments biologiques. Parmi eux, le thrombus intra-anévrysmal a un rôle majeur car il est le site d’activation de nombreuses métalloprotéinases et d’une protéolyse importante. Cependant, le thrombus du sac anévrysmal est également un substrat indispensable à la cicatrisation des anévrysmes après traitement endovasculaire car il sert de support à la recolonisation de l’anévrysme par des cellules mésenchymateuses. Dans les différents travaux présentés dans cette thèse, nous avons pu analyser une partie des phénomènes biologiques impliqués dans le succès ou l’échec des traitements endovasculaires. Les travaux présentés sont basés sur des expérimentations dans le modèle d’anévrysme à l’élastase chez le lapin et traités par coils, flow-diverters ou dispositifs intra-sacculaires (WEB). Ces travaux permettent de mieux comprendre les mécanismes biologiques mis en jeu par les différents traitements endovasculaires. L’analyse de ces phénomènes est indispensable pour comprendre les causes d’échec, mais aussi afin de développer de nouveaux outils biologiquement actifs pour le traitement des anévrysmes intracrâniens. Nous proposons ainsi le développement de stents flow-diverters biologiquement actifs. Nous proposons également trois approches différentes de thérapie cellulaire par voie endovasculaire, utilisant des cellules souches mésenchymateuses autologues, permettant une recolonisation du thrombus intraanévrysmal et une cicatrisation accélérée de l’anévrysme. Au total, le traitement des anévrysmes intracrâniens ne peut plus être basé uniquement sur des considérations mécaniques. Le développement des futurs dispositifs endovasculaires devra inclure une dimension biologique pour optimiser la cicatrisation complète des anévrysmes intracrâniensThe genesis of an intracranial aneurysm is not only due to a mechanical effect but to a set of biological elements. Among them, intra-aneurysmal thrombus plays a major role, as it is the site of activation of many metalloproteinases and an important site of proteolysis. However, the thrombus of the aneurysmal sac is also crucial for the healing of the aneurysm after endovascular treatment, because it serves as a support for the recolonization of the aneurysm by mesenchymal cells. In the various works presented in this thesis, we analyzed some of the biological phenomena involved in the success or failure of endovascular treatments. The presented works are based on experiments in the elastase aneurysm model in the rabbit and treated with coils, flow-diverters or intra-saccular devices. This work enables to better understand the biological mechanisms involved in the various endovascular treatments. The analysis of these phenomena is essential to understand the causes of failure, but also to develop new biologically active devices for the treatment of intracranial aneurysms. We propose the development of biologically active flow-diverter stents. We also propose three different approaches of endovascular cell therapy, using autologous mesenchymal stem cells, allowing recolonization of the intra-aneurysmal thrombus and accelerated healing of the aneurysm. The treatment of intracranial aneurysms can no longer be based solely on mechanical considerations. The development of future endovascular devices should include a biological dimension to improve the complete healing of intracranial aneurysms
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BRIOIS, JEAN-MICHEL. "Thrombus mobile de l'oreillette droite : a propos de 12 cas." Reims, 1991. http://www.theses.fr/1991REIMM021.
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Sutherland, Michael R. "Thrombin production on herpesviruses." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq28465.pdf.
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Myles, Timothy. "Interactions of recombinant thrombin." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627578.
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Flannery, Conor James. "Thrombus Formation under High Shear in Arterial Stenotic Flow." Thesis, Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/6943.
Повний текст джерелаАнотація:
Acute thrombotic and thromboembolic occlusion of atherosclerotic vessels are events that precipitate most heart attacks and strokes. In arterial stenotic flow, thrombus formation is shear dependent and may or may not lead to complete occlusion of the vessel. Platelets in whole blood adhere to collagen-coated surfaces and as they accumulate the resistance of the stenosis increases because of the decreasing passageway of the occluded stenosis. As a model of blood clotting in stenoses, porcine blood is heparinized and perfused over tubular glass test sections that are coated with collagen type I. Each test section has a preexisting stenosis and its severity varies so that higher percent stenoses produce higher shear rates on the blood. The hypothesis of this thesis is that high shear rates due to stenosis in arteries are a necessary feature for occlusive thrombosis.
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Mooe, Thomas. "Left ventricular thrombus and stroke after acute myocardial infarction." Doctoral thesis, Umeå universitet, Medicin, 1997. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-100547.
Повний текст джерелаАнотація:
A left ventricular thrombus develops in approximately 40% of patients following an anterior myocardial infarction. Embolization from these thrombi has been regarded as the most important cause of stroke following a myocardial infarction. The occurrence and characteristics of left ventricular thrombi and stroke after anterior myocardial infarction may, however, have changed after the introduction of aspirin and thrombolytics as standard therapy. The occurrence of left ventricular thrombi was examined in 99 patients with an acute anterior myocardial infarction, 74 of whom were treated with streptokinase. Thrombi were equally common in the thrombolysis group (46%, 95% confidence interval [Cl], 35-57%) as in the non-thrombolysis group (40%, 95% Cl, 21-59%). The risk of thrombus formation was related to the degree of left ventricular segmental dysfunction. Using serial echocardiographic examinations, the formation and resolution of thrombi was found to be highly dynamic. The majority of thrombi diagnosed during the hospital stay had resolved at follow-up one month later, irrespective of treatment with streptokinase or anticoagulants. The development of new thrombi was, however, observed at every follow-up examination interval. One-hundred-and-twenty-four patients suffering a stroke within 28 days of an acute myocardial infarction were identified in the northern Sweden MONICA stroke registry between 1985 and 1994. The overall event rate of ischemic myocardial infarction-related stroke was 1.07%. The risk of a stroke was highest duringt he first 5 days after the infarction. Only approximately half the strokes were preceded by an anterior myocardial infarction. In a case-control analysis, atrial fibrillation (chronic or new onset), ST elevation and a history of a previous stroke were found to be independent predictors of stroke. There was a long-term trend towards a lower incidence and event rate for myocardial infarction-related stroke. Clinical stroke characteristics were examined in 103 patients with a first-ever stroke within 28 days of a myocardial infarction and compared with stroke characteristics in 206 control subjects without a recent myocardial infarction. The sudden onset of neurological symptoms, an impairment of consciousness, a progression in neurological deficits and a stroke of the total anterior circulation infarction subclass were more common in cases than in controls. The risk of a recurrent stroke during one year of follow-up was not influenced by a recent myocardial infarction, but patients who had suffered a myocardial infarction had markedly higher mortality. To conclude, thrombolytic treatment does not reduce the occurrence of left ventricular thrombi after a myocardial infarction. The risk of thrombus formation is related to the extent of the myocardial injury. The development and resolution of thrombi is a highly dynamic process. There is a long-term trend towards a lower incidence and event rate of ischemic stroke after a myocardial infarction. Although the clinical stroke characteristics differ, they are not specific enough to differentiate between patients with and without a recent myocardial infarction.S. 1-84: sammanfattning, s. 85-136: 5 uppsatser
digitalisering@umu
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Humphries, Julia. "Monocyte recruitment and fibrinolytic activity in venous thrombus resolution." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407326.
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Couturaud, Francis. "Risque de maladie thrombo-embolique veineuse chez les membres de familles au premier degré de patients ayant une maladie thrombo-embolique veineuse idiopathique." Lyon 1, 2006. http://www.theses.fr/2006LYO10184.
Повний текст джерелаАнотація:
Rationnel: Les patients ayant une maladie veineuse thrombo-embolique (MVTE) idiopathique ont un risque élevé de récidive thrombo-embolique et sont fréquemment porteurs d’une thrombophilie héréditaire. Notre hypothèse scientifique est, qu’en l’absence de thrombophilie héréditaire détectable, ces patients ont en fait une thrombophilie encore non connue à ce jour. Objectif : Evaluer, chez les membres de la famille au premier degré de patients ayant une MVTE idiopathique, le risque de survenue d’une première MVTE selon que les propositi sont porteurs ou non d’une thrombophilie héréditaire. Si notre hypothèse est vraie, alors le risque familial de MVTE est identique, que les propositus présentent ou non une thrombophilie détectable. Méthodes: Etude transversale multicentrique internationale réalisée sur 1778 membres de la famille au premier degré de 348 patients (propositus) recrutés consécutivement pour une MVTE idiopathique objectivement diagnostiquée. Au moyen d’un questionnaire prédéfini et standardisé , les membres de familles ont été classés comme « ayant eu une MVTE certaine », « MVTE incertaine » et « n’ayant pas eu de MVTE ». Tous les propositus ont été testés pour la mutation Leiden et la mutation G20210A sur le gène de la prothrombine. Résultats: En analyse multivariée, lorsque les MVTE « incertaines » sont classées comme « pas de MVTE », nous observons une tendance à un risque accru de MVTE chez les membres de familles lorsque le propositus est porteur d’une thrombophilie héréditaire (risque relatif de 1,52 [0,98 – 2,37], p = 0,06) ; lorsque les MVTE « incertaines » sont classées comme « certaines », ce risque est proche de 1 (1,18 [0,87-1,60], p = 0,3). En revanche, quel que soit le niveau de précision du critère diagnostic de MVTE, le risque de MVTE est significativement accru chez les femmes au premier degré et d’autant plus que le propositus est jeune. Conclusion: Chez les membres de famille au premier degré de patients ayant une MVTE idiopathique, le risque de MVTE est faiblement influencé par la présence d’une thrombophilie héréditaire chez les propositus. Ce résultat plaide en faveur de notre hypothèse scientifique. Une des implications majeures est qu’une prévention du risque de MVTE ne devrait pas être proposée qu’aux seuls membres de famille de patients ayant une MVTE associée à une thrombophilie héréditaire détectableRational : In patients with idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high and a large proportion of these patients carry inherited thrombophilia. Our hypothesis is that patients with idiopathic VTE without detectable inherited thrombophilia have a genetic prothrombotic state not yet discovered. Objective : To evaluate the risk of VTE in first degree relatives of patients with idiopathic VTE and with or without inherited thrombophilia. If our hypothesis is true, this risk should be similar, with or without thrombophilia. Methods : In this international multicentre study, 1778 first degree relatives of 348 propositus with objectively diagnosed idiopathic VTE were included. Relatives were classified as having “certain VTE”, “uncertain VTE” or “no VTE” according to a predefined and standardised questionnaire. All the propositus were tested for the Leiden mutation and the G20210A prothrombin gene mutation. Results : In multivariate analysis, when “uncertain VTE” were classified as “No VTE”, we observed a trend of an increased risk of VTE in first degree relatives of probants with an inherited thrombophilia (relative risk of 1,52 [0,98 – 2,37], p = 0,06); when “uncertain VTE” were classified as “certain VTE”, the relative risk of VTE was closed to 1. 0 (1,18 [0,87-1,60], p = 0,3). For each level of VTE diagnosis criteria precision, there was an increased risk of VTE in first degree relatives women and in relatives from younger probants. Conclusion : The presence of an inherited thrombophilia in patients with idiopathic VTE is weakly associated with an increased risk in their first degree relatives. This observation supports our scientific hypothesis. One the main implications of this study is that the prevention of VTE should not be proposed in only first degree relatives of patients with VTE and inherited thrombophilia
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Day, Jonathan Robert Stewart. "Therapeutic inhibition of thrombin signalling." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434321.
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Sidhu, Preetpal. "Designing Allosteric Inhibitors of Thrombin." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/295.
Повний текст джерелаАнотація:
Thrombin is a key enzyme of the coagulation cascade exhibiting important roles in both pro-coagulation and anti-coagulation processes. Most clinically used anticoagulant drugs, including polymeric heparin, warfarin, hirudin, argatroban and the recently approved dabigatran, aim to reduce thrombin activity. There are several binding domains on thrombin including the active site, anion-binding exosites I and II, and the sodium binding site. We hypothesized that thrombin may be better regulated through an allosteric process mediated by small molecules binding to either exosite I or II. An appropriately designed allosteric regulator that reduces the procoagulant signal in a finely tuned manner may maintain a delicate balance between procoagulant and anticoagulant signals in blood resulting reduced bleeding complications. In this work, we synthesized and studied a library of potent, small, aromatic molecules as allosteric inhibitors of thrombin. Of the 28 potential inhibitors, 11 molecules inhibited thrombin with reasonable potency. Structure activity relationship studies showed that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. Michaelis-Menten kinetic studies indicated a non-competitive, allosteric mechanism of inhibition. Site-directed mutagenesis, competitive binding and molecular modeling studies led to the identification of the most plausible binding pose for a potent sulfated dimer. To further improve the potency, a small library of sulfated benzofuran trimers was synthesized and studied for thrombin inhibition. Further, to find new scaffold to inhibit thrombin allosterically, docking-based virtual screening approach was used. All these molecules were found to be moderately potent thrombin inhibitors and can serve as lead to develop allosteric inhibitor. Overall, this work presents the first small, synthetic, sulfated aromatic molecules as potent allosteric modulators of thrombin. Finally, this work also highlights the opportunity of exploring allosteric modulators of other coagulation enzymes, e.g., factors Xa, IXa and XIa, based on the sulfated benzofuran scaffold.
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Desai, Bijoy. "Novel Allosteric Inhibitors of Thrombin." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1914.
Повний текст джерелаАнотація:
Thrombin is a critical enzyme involved in blood coagulation and haemostasis. For this reason the study of its interactions with substrates, inhibitors and modulator is essential. It is also a unique enzyme in the serine protease family because unlike enzymes like trypsin and chymotrypsin its activity is modulated by various endogenous and exogenous ligands. This is due to the presence of “exosites” on the thrombin surface. Exosite II, unlike exosite-I, has not been characterized for its allosteric effect. In order to understand the structural basis of interaction and inhibition of inhibitor 4AS, which possibly interacts with exosite-II, native bovine thrombin crystals and human thrombin crystals grown in presence of 4-AS were prepared. X-ray diffraction data was collected on 4AS soaks of native bovine thrombin as well as human thrombin crystals. The data were phased by molecular replacement using appropriate search models. The structures were refined to R factors of 0.24 and 0.27 for native bovine thrombin-4AS soaks and human thrombin-4AS co-crystals respectively. Examination of a 2Fo-Fc electron density map revealed no density for 4-AS. Low affinity of the inhibitor may be the reason for its absence in the solved structures. In the process of solving these structures, unliganded native bovine thrombin in a new crystal form, previously unreported in literature, was solved. The structure shows an overall topology similar to that found in previously published thrombin molecules. Examination of the crystal packing shows that the exosite-II is solvent exposed. This crystal form can be used in the future to study interaction of exosite-II ligands. To characterize the interaction of sucrose octasulfate with thrombin, which may interact with thrombin exosite-II, fluorimetric equilibrium binding titrations were performed using the active site fluorescent probe para-amino benzamidine. At physiological salt concentrations, the KD was found to be ~22 μM, which is lower than heparin fragment of corresponding length. The higher affinity was attributed to the high charge density of the ligand. Measurement of KD at different salt concentrations showed a significant amount of contribution to the binding energy from ionic interactions. Based on the salt dependence experiments, the number of charged interactions per sucrose octasulfate molecule interacting with thrombin was found to be 3.5. Competitive experiments of sucrose octasulfate with FDs (a sulfated dehydro-polymer being investigated in the lab for its anticoagulant properties) for inhibition of thrombin activity showed competitive effects that did not appear to follow Dixon-Webb competitive phenomenon. It was found that sucrose octasulfate itself is a weak inhibitor of thrombin. To investigate the mode of interaction, co-crystals of sucrose-ocasulfate complexed with thrombin were prepared. High resolution data (2.2 Å) was collected. The structure solved using this data showed weak density for two sucrose octasulfate molecules. Sucrose octasulfate was modeled into this density and refined. The refined structure shows that two sucrose octasulfate molecules bind to two thrombin monomers of the asymmetric unit at exosite-II. One of the sucrose octasulfate molecules interacts with both monomers, and could be present as an artifact of crystal packing. The second molecule interacts with exosite-II of only one of the thrombin monomers. The key residues involved in the interaction are Lys236, His91, Arg93 and Arg101. The thrombin-sucrose octasulfate structure does not show any major deviation from unliganded structure. It is possible that the conformational change may have been masked due to crystal packing. Characterization of this novel interaction mode of sucrose octasulfate interaction with thrombin adds one more candidate to the list of compounds that interact with exosite-II in a manner very similar to heparin, but unlike heparin can inhibit thrombin activity.
30
Jones, Chris I. "Haematological and clinical factors influencing thrombus formation, structure and fibrinolysis." Thesis, University of Leicester, 2007. http://hdl.handle.net/2381/29893.
Повний текст джерелаАнотація:
This work investigates how changes in the thrombus over time, and in the action of platelets, brought about by physiological or therapeutic factors, influence the susceptibility of thrombi to fibrinolysis. Resistance to fibrinolysis increased with thrombus age, and was associated with expression and/or release of FXIII, TAFI, PAI-1, and FXI, by cells within the thrombus, the recruitment of which was largely platelet dependant. Platelets increase resistance to fibrinolysis through release of FXIII and TAFI, and act pro-fibrinolytically through the recruitment of monocytes, and, by a yet undetermined mechanism, when hyper-activated. Overall, the action of platelets is anti-fibrinolytic, as evidenced by the increase in fibrinolysis associated with reduced platelet number or activity. The plasma expander dextran had no discemable direct effect on platelets, although it did significantly increase the generation of plasmin and the rate of fibrinolysis. This, indirectly, led to a reduction in vWF activity and platelet response to thrombin, but not to TRAP, collagen, or ADP, indicating the these effects result non-specific proteolytic cleavage by plasmin. The contrast media lodixanol or lohexol increased both thrombus formation and resistance to fibrinolysis, whilst Ioxaglate inhibited thrombus formation. These change may in part be due to increased degranulation but is more likely to result from their effect on fibrin fibre formation. These data have implications for clinical resolution of occlusive arterial thrombotic events. Thrombolytic therapy may be more successful if targeted to individuals with lower platelet counts or on long term anti-platelet therapy, and if administered rapidly after thrombus formation. Furthermore low dose Dextran therapy maybe a useful adjuvant to pre-hospital thrombolytic therapy.
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Acosta, Stefan. "On Acute Thrombo-Embolic Occlusion of the Superior Mesenteric Artery." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl.[distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4147.
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GARREAU, OLIVIER. "Thrombus recidivant de l'aorte ascendante diagnostique par echocardiographie trans-oesophagienne." Reims, 1994. http://www.theses.fr/1994REIMM072.
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André, Jean-Claude. "Le thrombus neoplasique cave superieur : a propos de deux observations." Lyon 1, 1993. http://www.theses.fr/1993LYO1M096.
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Kobold, Jonathan. "Deep Learning for lesion and thrombus segmentation from cerebral MRI." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLE044.
Повний текст джерелаАнотація:
L'apprentissage profond est le meilleur ensemble de méthodes aumonde pour identifier des objets sur des images. L'accident vascu-laire cérébral est une maladie mortelle dont le traitement nécessitel'identification d'objets par imagerie médicale. Cela semble être unecombinaison évidente, mais il n'est pas anodin de joindre les deux.La segmentation de la lésion de l'IRM cérébrale a retenu l'attentiondes chercheurs, mais la segmentation du thrombus est encore inex-plorée. Ce travail montre que les architectures de réseau de neur-ones convolutionnels contemporaines ne peuvent pas identifier demanière fiable le thrombus sur l'IRM. En outre, il est démontrépourquoi ces modèles ne fonctionnent pas sur ce problème. Fort decette connaissance, une architecture de réseau neuronal récurrente aété développée, appelée logic-LSTM, capable de prendre en comptela manière dont les médecins identifient le thrombus. Cette ar-chitecture fournit non seulement la première identification fiablede thrombus, mais elle fournit également de nouvelles informationssur la conception des réseaux neuronaux. En particulier, les méthodesd'augmentation du champ récepteur sont enrichies d'une nouvelleoption sans paramètre. Enfin, le logic-LSTM améliore également lesrésultats de la segmentation des lésions en fournissant une segment-ation des lésions avec un niveau de performance humaineDeep learning, the world's best set of methods for identifying ob-jects on images. Stroke, a deadly disease whose treatment requiresidentifying objects on medical imaging. Sounds like an obvious com-bination yet it is not trivial to marry the two. Segmenting the lesionfrom stroke MRI has had some attention in literature but thrombussegmentation is still uncharted area. This work shows that contem-porary convolutional neural network architectures cannot reliablyidentify the thrombus on stroke MRI. Also it is demonstrated whythese models don't work on this problem. With this knowledge arecurrent neural network architecture, the logic LSTM, is developedthat takes into account the way medical doctors identify the throm-bus. Not only this architecture provides the first reliable thrombusidentification, it also provides new insights to neural network design.Especially the methods for increasing the receptive field are enrichedwith a new parameter free option. And last but not least the logicLSTM also improves the results of lesion segmentation by providinga lesion segmentation with human level performance
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CARISSIMI, GUY. "Thrombus graisseux de la veine cave inferieure : apports de l'imagerie." Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX20066.
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Andersen, Henrik. "Human protease activated receptor 4 and its role in platelet activation /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/9235.
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Laurent, Pierre-Alexandre. "Rôles des phosphoinositides 3-kinases (PI3Ks) α et β de classe IA dans les processus de l'activation plaquettaire et de la thrombose". Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30296.
Повний текст джерелаАнотація:
Les plaquettes jouent un rôle majeur dans l'hémostase mais également dans les maladies cardiovasculaires qui représentent une des principales causes de mortalité dans les pays industrialisés. Au cours de l'activation plaquettaire, les phosphoinositides 3-kinases (PI3Ks) de classe I génèrent des seconds messagers lipidiques (D3-phosphoinositides) participant activement à la transmission des signaux en aval des principaux récepteurs plaquettaires. Comme l'inhibition de la PI3Kbeta protège des thromboses occlusives sans augmenter le risque de saignement, cette kinase a été proposée comme nouvelle cible antithrombotique. Toutefois, le rôle de la PI3Kbeta dans des modèles de thrombose in vivo et ex vivo, dans des conditions de forces de cisaillement élevées, restait mal documenté au début de ma thèse. Le rôle de la PI3Kalpha?était également mal connu bien que l'utilisation d'inhibiteurs peu spécifiques suggérait son implication en aval du récepteur GPVI. L'objectif de ma thèse a été d'étudier le rôle de la PI3Kbeta dans la formation du thrombus in vivo et ex vivo, et de caractériser la fonction de la PI3Kalpha plaquettaire. Grâce à des souris présentant une invalidation de la PI3Kbeta ou alpha spécifiquement dans la lignée mégacaryocytaire, j'ai montré que la PI3Kbeta plaquettaire jouait un rôle essentiel dans la stabilité du thrombus dans des conditions de forces de cisaillement élevées. Son inhibition affecte l'activation d'Akt et empêche l'inhibition de son effecteur GSK3 au sein même du thrombus. De façon intéressante, l'inhibition de GSK3 restaure la stabilité du thrombus. Ainsi, la PI3Kbeta joue un rôle critique dans le maintien de l'intégrité du thrombus exposé à des forces de cisaillement élevées et cet effet ne peut être compensé par la PI3Kalpha. D'autre part, l'absence de la PI3Kalpha plaquettaire se traduit par un défaut d'agrégation et d'activation d'Akt lors d'une stimulation de faible intensité de GPVI. In vivo, le thrombus formé par les plaquettes invalidées pour la PI3Kalpha consécutivement à une lésion superficielle des artères, est de plus petite taille que chez les souris sauvages. En condition de flux ex vivo, il est noté un retard de formation du thrombus sur les fibres de collagène suggérant l'implication de la PI3Kalpha dans la phase d'adhésion des plaquettes à la matrice. En effet, des études d'adhésion en flux sur une matrice de facteur de von Willebrand (vWF) montrent que la PI3Kalpha est essentielle pour l'adhésion stable des plaquettes à cette matrice via la signalisation outside-in de l'intégrine alphaIIbbeta3. En conclusion, mes travaux de thèse mettent à jour un rôle spécifique des PI3Ks alpha et beta de classe I dans les plaquettes. La PI3Kbeta? est cruciale dans la régulation de la croissance et de la stabilité du thrombus dans des conditions de forces de cisaillement élevées, tandis que la PI3Kalpha?est requise dans la phase initiale d'adhésion des plaquettes sur une matrice de vWF. Ce travail apporte des nouvelles données qui seront utiles notamment dans le contexte du développement d'inhibiteurs sélectifs de PI3Ks en thérapie anticancéreuse et antithrombotiquePlatelets play a major role in cardiovascular diseases which is one principal cause of worldwide death. Class I phosphoinositide 3-kinases (PI3Ks) are important signaling enzymes in the process of blood platelet activation, producing lipid second messengers (D3-phosphoinositides) that are actively involved downstream of major platelet receptors. PI3Kbeta has been proposed as a potential drug target to treat arterial thrombosis. Indeed, inhibition of this lipid kinase leads to protection against occlusive thrombosis without bleeding risk. Nevertheless, nothing is known regarding the role of this kinase in vivo and ex vivo during growth, stabilization, and resistance upon elevation of shear rate. One study, using pharmacological inhibitors, has suggested that both PI3Kalpha and beta are required, in a non redundant way, for full platelet activation through collagen receptor GPVI, but the role of PI3Kalpha still remains elusive in platelets. The aim of my thesis was to study the role of PI3Kbeta during thrombus formation in vivo and ex vivo, and to characterize the role of PI3Kalpha in platelets. For that, I used pharmacological approach and mice with selective deletion of PI3Kbeta?or?PI3Kalpha in the megakaryocyte lineage (PF4-Cre/p110betaflox/flox and PF4-Cre/p110alphaflox/flox). I showed that PI3Kbeta is essential for thrombus growth and stability at high shear rates. Within the growing platelet thrombus, PI3Kbeta inactivation impairs the activating phosphorylations of Akt and the inhibitory phosphorylation of GSK3. In line with these data, pharmacological inhibition of GSK3 restores thrombus stability. Thus, platelet PI3Kbeta has a critical role in maintaining the integrity of the formed thrombus upon elevation of shear rate. In this condition, I showed that PI3Kbeta absence cannot be compensated by PI3Kalpha. In vitro, PI3Kalpha depletion in platelets leads to a light defect of aggregation and Akt activation in response to CRP showing implication of PI3Kalpha downstream GPVI. I observed that, in vivo, thrombi formed by PI3Kalpha depleted platelets after superficial lesion of mesenteric arterial are smaller, and ex vivo, thrombus formation under flow conditions on collagen matrix is delayed. Furthermore, perfusion of these platelets on von Willebrand factor matrix (vWF) shows that PI3Kalpha is required for stable adhesion of platelets through "outside in" signaling. Altogether, these results show an involvement of PI3Kalpha in the course of early step of platelet adhesion. In conclusion, my thesis work highlights an isoform specific role of PI3Ks in platelets. PI3Kbeta is crucial in the regulation of thrombus growth and stability at a high shear rate and PI3Kalpha is required in initial stages of platelet adhesion. Since class I PI3Ks selective inhibitors are under development as cancer treatment, these results may help to anticipate the potential side effects of such treatment on haemostasis
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Rowand, Judith K. "Comparative structural studies of proteolyzed human thrombin forms and bovine thrombin through use of hirudin analogs /." The Ohio State University, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487688973685458.
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Pianfetti, Christophe. "Thrombus intracardiaque simulant un myxome dans le cadre du syndrome des antiphospholides." Montpellier 1, 1998. http://www.theses.fr/1998MON11135.
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Mehrabadi, Marmar. "Effects of red blood cells and shear rate on thrombus growth." Diss., Georgia Institute of Technology, 2014. http://hdl.handle.net/1853/53082.
Повний текст джерелаАнотація:
Thrombosis formation upon rupture or erosion of an atherosclerotic plaque can lead to occlusion of arteries. An occlusive thrombus is the most common cause of clinical events such as angina, myocardial infarction, ischemic attacks and strokes. Occlusive thrombi can cause ischemic cardiac arrest in less than an hour. Thrombosis formation requires rapid platelet accumulation rates exceeding thrombosis lysis and embolization rates. Hemodynamics greatly affects platelet accumulation rate through affecting platelet transport to the surface of a growing thrombus. The presence of red blood cells (RBCs) in blood increases platelet transport rate by several orders of magnitude compared to transport due to Brownian motion. Margination of platelets towards the vessel walls also results in higher platelet concentration at the RBC-depleted layer relative to the bulk. In this thesis, we studied the effects of hemodynamics on thrombus growth. We investigated the effects of important flow and particle properties on margination of particles in RBC suspensions by direct numerical simulation (DNS) of cellar blood flow. We derived a scaling law for margination length. Based on this scaling law, margination length increases cubically with channel height and is independent of shear rate. Using DNS, we verified the proposed scaling law for margination length in straight channels. We also showed that rigidity and size both lead to particle margination. We show that platelet margination can be explained by RBC-enhanced shear-induced diffusion of platelets in the RBC-filled region combined with platelet trapping in the RBC-free region. A simple continuum model is introduced based on the proposed mechanism. Using an experimental correlation for effective diffusivity in blood, the continuum model can recover experimental results from the literature over a wide range of tube diameters. We created an in vitro experimental model of thrombosis with and without RBCs. Surprisingly, we found that rapid thrombus growth does not require enhanced platelet transport in the presence of RBCs at high shear. Instead, our results suggest that thrombus growth rate at high shear is dependent on the availability of vWF-A1 domains as opposed to convective transport of platelets. Finally, we obtained empirical correlations for thrombus growth and lag time based on flow parameters by using an in vitro model of thrombosis. We developed a simple model for predicting thrombus formation using the obtained empirical correlations. We demonstrated the capability of the model in predicting thrombus formation over a wide range of experimental geometries. This model may be useful for designing blood-contacting devices to avoid unwanted thrombosis.
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Auger, Jocelyn M. "Investigation of the signalling events that underline thrombus formation under flow." Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433505.
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Shand, Ray Ann. "Investigations of thrombus formation in an animal model of arterial thrombosis." Thesis, University of Leeds, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236715.
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CHRETIEN, CLAUDINE. "Maladies thrombo-emboliques et affections malignes : a propos de 11 observations." Reims, 1989. http://www.theses.fr/1989REIMM086.
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BONNAUD, MARC. "Anomalies du plasminogene et phenomenes thrombo-emboliques : a propos d'un cas." Aix-Marseille 2, 1989. http://www.theses.fr/1989AIX20185.
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Yvorra, Serge. "La maladie veineuse thrombo-embolique ambulatoire : donnees epidemiologiques, etiologiques, et suivi." Aix-Marseille 2, 1992. http://www.theses.fr/1992AIX20856.
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Bobbert, Thomas. "Thrombin-induzierte Differenzierung neonataler glatter Gefämuskelzellen." [S.l.] : [s.n.], 2003. http://www.diss.fu-berlin.de/2003/58/index.html.
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Giesen, Peter Leonardus Arnoldus. "Production of thrombin at macroscopic surfaces." Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1992. http://arno.unimaas.nl/show.cgi?fid=5672.
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Kakkar, Ajay Kumar. "Tissue factor, thrombin generation and cancer." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286352.
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Bevan, Shaun Patrick. "The clinical utility of thrombin generation." Thesis, Queen Mary, University of London, 2011. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1398.
Повний текст джерелаАнотація:
The Calibrated Automated Thrombogram (CAT) thrombin generation assay is a technique that allows the characterisation of an individual’s capacity to produce thrombin in response to a procoagulant stimulus. As such it is a global screening test for both hyper and hypocoagulable bleeding disorders. This project focused on the introduction of the CAT assay into routine use in the haemostasis laboratory at the Royal London hospital and to assess its clinical utility. Initial experimentation focused on determining the suitability of the assay for routine use, including ascertaining the levels of inter and intra assay variation, the effects of sample handling and storage, the limits of detection, variation in an individual with time and establishing a normal range. All of these experiments returned favourable results. The assay was then used to characterise the thrombin generation profile of a cohort of women with pre-eclampsia. Women with pre-eclampsia were found to have higher thrombin generation parameters (Endogenous thrombin potential and peak height) when compared to normotensive pregnant women (p= <0.001). Re-analysis of the data showed the use of thrombin generation could detect pre-eclampsia with a specificity and sensitivity of 83% and 43% respectively when combined with the Pre-eclampsia community guideline screen. There were also statistically significant correlations between the measurement of thrombin generation and both birth weight and the length of stay in hospital at delivery. Further analysis by flow cytometry and studies involving filtration of plasma revealed that the sensitivity of the assay to the detection of pre-eclampsia may be associated with the increased levels of microparticles present in the blood of pre-eclamptic women. There were statistically significant correlations (p= <0.05) between changes in thrombin generation parameters and the number of microparticles post filtration. This suggests that the CAT assay is sensitive to the number of microparticles in a patient’s plasma.
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Lisiak, Karolina. "The role of platelets in the activation of TAFI in model thrombi." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=24805.
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