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Skinner, Richard. "Structural biology of antithrombin." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627475.
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Bruce, David. "Antithrombin : structural variants and thrombosis." Thesis, Open University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386084.
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Fitton, Hazel Louise. "Modulation of antithrombin by heparin." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624993.
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Jin, L. "Antithrombin structures and the heparin pentasaccharide." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605606.
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Antithrombin, the major inhibitor of blood coagulation, is relatively inactive until it binds to, and is achieved by the heparan sidechains that line the microvasculature. The binding specifically occurs to a core pentasaccharide, present both in the heparans and in their therapeutic derivative heparin. This specific binding can cause antithrombin's conformational change which is required for activation. The crystal structure of a dimer of inhibitory(I) and latent(I) antithrombin, each in complex with the high-affinity pentasaccharide, was solved at 2.9A resolution. To achieve this, a new approach to the effective crystallisation of antithrombin was developed involving equal-molar mixing of inhibitory and latent antithrombin, in this case, in the additional presence of the heparin pentasaccharide. The structure elucidated, for the first time, the binding details and accompanying conformational change of antithrombin which is fundamental for activation. The pentasaccharide binds to antithrombin by hydrogen-bonding or salt-bridging of its sulphates and carboxylates to Arg129 and Lys125 on the D-helix, to Asn45, Arg46 and Arg47 on the A-helix, to Lys114 and Glu113 on the new induced P-helix and to LKys11 and Arg13 in a cleft formed by the amino-terminus. Inhibitory activation results from a shift in the main β-sheet of the molecule(the A-sheet) from a partially six-stranded to a five-stranded form with extrusion of the reactive loop to give a more exposed orientation. There is a tilting and elongation of the D-helix with the formation of a new 2-turn P-helix between the C and D helices. Comparing the concomitant conformational changes at the heparin binding site of the I and L molecules also explains structurally both the initial tight binding of antithrombin to the heparans and the subsequent release of the antithrombin/protease complex into the circulation. The clear definition of the binding site and interaction details has given a new insight into the molecular pathology of antithrombin deficiency and provides a structural basis for developing heparin analogues which are more specific towards their intended target, antithrombin, and therefore less likely to exhibit side-effects.
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Christey, Peter B. "Heparin binding and activation of antithrombin." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315820.
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CORNO, ANNA ROSA. "CARENZA CONGENITA DI ANTITROMBINA E DIAGNOSI DI LABORTORIO: QUALE TEST FUNZIONALE?" Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/233996.
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Introduzione - La carenza congenita di Antitrombina (AT), che espone a rischio trombotico di tipo prevalentemente venoso, viene classificata in tipo I (difetto quantitativo) o tipo II (difetto qualitativo). I difetti qualitativi possono interessare il sito reattivo (Reactive Site, RS) o il sito di legame dell’AT con l’eparina (Heparin Binding Site, HBS), oppure possono avere effetto pleiotropico (PE). I test di screening, che misurano la capacità dell’AT, presente nel plasma, di neutralizzare la trombina (attività anti-IIa) o il Fattore Xa (attività anti-Xa) in presenza di eparina, sono in grado di evidenziare la maggior parte dei difetti dell’AT; tuttavia, sono stati osservati risultati discrepanti (valore normale vs. valore patologico) con i due differenti metodi. Scopo della tesi è quello di valutare la concordanza tra un test AT anti-Xa e un test AT anti-IIa e di valutare la relativa capacità di individuare le carenze di AT.
Materiali e Metodi – La popolazione in studio è costituita dal gruppo “routine e trombofilici” (493 soggetti con prescrizione del test AT) e dal gruppo “carenti noti” (23 soggetti con carenza nota di AT e 18 familiari). I dosaggi dell’attività dell’AT sono stati effettuati con i metodi AT anti-Xa (HemosIL, Instrumentation Laboratory) e AT anti-IIa (home-made). Una popolazione di controllo (n= 100) è stata utilizzata per definire i relativi intervalli di riferimento. In 21 soggetti con carenza di AT è stata effettuata la ricerca di mutazioni nel gene SERPINC1 (Universitair Ziekenhuis di Bruxelles).
Risultati – I risultati di AT% ottenuti con i due metodi sono altamente correlati (rho di Spearman >0.70); tuttavia, sono stati riscontrati 8 dati discordanti (3 nel gruppo “routine e trombofilici”, 5 nel gruppo “carenti noti”). L’analisi genetica ha identificato la presenza di mutazioni nel gene SERPINC1 in 18/21 soggetti studiati, 5 dei quali con valori di attività AT discordanti. Infatti, valori normali di AT anti-Xa si sono ottenuti per il difetto Cambridge II (II RS), mentre il test AT anti-IIa ha fornito valori normali per un difetto HBS. Valori di AT patologici concordi sono stati ottenuti per 5 carenze di tipo I, mentre si sono ottenuti risultati di AT normali con entrambi i metodi per altre 2 carenze HBS. Nella popolazione indagata la sensibilità del test AT anti-Xa è 61.1%, quella del test AT anti-IIa è 55.6%. Se si considerano entrambi i test la sensibilità diventa 72.2%. Se si utilizza in aggiunta anche il rapporto tra l’attività AT anti-IIa e l’attività anti-Xa, la sensibilità aumenta a 88.9%.
Conclusioni – I metodi funzionali attualmente a disposizione per il dosaggio dell’AT non sono in grado di individuare tutti i tipi di difetti molecolari dell’AT. L’utilizzo combinato di un test anti-Xa e di un test anti-IIa e del rapporto AT anti-IIa/AT anti-Xa potrebbe aumentare la capacità diagnostica dei dosaggi. I risultati dei test di laboratorio vanno comunque considerati alla luce della storia clinica personale e familiare del soggetto.Introduction – Antithrombin (AT) deficiency, associated with an increased risk for venous thrombosis, is classified into type I (quantitative defect) and type II (qualitative defect). Qualitative defects may affect the reactive site (RS), the heparin binding site (HBS) of AT, or they may have a pleiotropic effect (PE). Screening tests, which measure the ability of AT, in the presence of heparin, to inhibits either thrombin (anti-IIa activity) or FXa (anti-Xa activity), are able to detect most AT deficiencies; however, few cases of discrepancies have been described (i.e. normal vs. pathological value) with the two different methods. Aim of the study was the evaluation of agreement between an anti-Xa assay and an anti-IIa assay for AT, and the evaluation of their ability in detecting AT defects. Materials and Methods – The study population consisted of the “routine and thrombophilic” group (493 patients for which AT test was required) and the “historical deficiencies” group (23 subjects with known AT deficiency and 18 relatives). Anti-Xa HemosIL Antithrombin kit (from Instrumentation Laboratory) and a home-made anti-IIa method were used to measure AT activities. A control group (n= 100) was used to determine AT reference ranges. SERPINC1 gene analysis was carried out for 21 patients (Universitair Ziekenhuis in Bruxelles). Results – The results provided by the two methods showed a high correlation (Spearman rho>0.70); however, 8 discrepant results were observed (3 in the “routine and thrombophilia” group and 5 in the “historical deficiencies” group). Gene analysis confirmed the presence of a molecular defect in 18/21 subjects, 5 of which had also descrepant AT results. In fact, normal anti-Xa AT values were obtained for Cambridge II defect (RS), whereas anti-IIa test provided normal values for a HBS defect. Both methods provided pathological AT values for 5 type I deficiencies but normal AT values for other 2 HBS defects. In the study population AT anti-Xa and AT anti-IIa sensitivity was 61.1% and 55.6%, respectively; when both tests were used, sensitivity increased to 72.2%. When the ratio between AT anti-IIa and AT anti-Xa was added, sensitivity increased to 88.9%. Conclusions – Currently avaible screening tests are not able to detect all molecular defects. However, when anti-Xa assay is carried out together with anti-IIa method, and the ratio between the results provided by both is considered, the diagnostic power is increased. Anyway, laboratory test results should be considered together with personal and familiar clinical history of the single subject under evaluation.
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Chen, Iris Ye Wu. "The interactions between human antithrombin and heparin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0005/NQ42731.pdf.
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Perry, David James. "The genetic basis of human antithrombin deficiency." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283014.
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Belzar, Klara Jane. "The allosteric activation of antithrombin by heparin." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621213.
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Bourti, Yasmine. "Evaluation d'un variant d'antithrombine dans différentes indications thérapeutiques." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS404/document.
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Notre équipe s’intéresse à la relation structure-fonction d’une protéine, l’antithrombine (AT), un inhibiteur physiologique de la coagulation, en vue d’un développement thérapeutique. Cette protéine anticoagulante, capable de lier un motif pentasaccharidique sur les dérivés hépariniques, possède en outre, à fortes concentrations (500%), des propriétés anti-inflammatoires médiées par sa liaison aux héparan-sulfates cellulaires. Ce profil a mené à l’évaluation de l’AT dans des situations associant un emballement de la coagulation et de l’inflammation, comme c’est le cas au cours du sepsis sévère et d’autres situations d’ischémie-reperfusion (I/R). Cependant, les fortes concentrations utilisées dans les études précliniques nécessiteraient d’administrer des doses d’AT incompatibles avec le profil de sécurité de cette protéine anticoagulante.Dans ce contexte, nous avons, au cours de ce travail, caractérisé un variant d’AT (AT-N135Q-Pro394) dépourvu d’activité anticoagulante et doué d’une affinité augmentée pour l’héparine. Ce variant est capable de piéger des dérivés hépariniques et apparait comme un candidat idéal pour une utilisation comme antidote en cas de surdosage en héparine non fractionnée (HNF), héparines de bas poids moléculaire (HBPM) ou fondaparinux. Par ailleurs, ce variant pourrait être utilisé à des doses cytoprotectrices, sans risque hémorragique.Afin de tester cette dernière hypothèse, nous avons développé un modèle d’I/R rénale chez la souris, qui s’accompagne d’une augmentation significative de marqueurs de dysfonction rénale (Urée, Créatinine, Kim-1) et de l’inflammation (expression tissulaire de cxcl-1, il-6). L’AT avait déjà été montrée protectrice (Mizutani et al, Blood 2003) dans un modèle murin comparable. De façon surprenante, nous n’avons observé aucun des effets protecteurs décrits, ni sur l’inflammation ni sur la fonction rénale, et que ce soit avec de l’AT plasmatique, de l’AT recombinante ou encore avec un mélange équimolaire d’AT latente et native. Ce même modèle nous a pourtant permis de mettre en évidence les effets nephroprotecteurs et anti-inflammatoires d’une autre protéine anticoagulante, la protéine C activée. Ces résultats décevants font écho à la rétractation pour fraude de l’article de Mizutani et al. en 2013. Le travail approfondi que nous avons mené nous permet de clarifier la littérature et d’affirmer que l’AT, d’origine plasmatique ou recombinante, ne possèdent pas d’effet protecteur dans l’I/R rénale chez la souris. Dans ces conditions, le variant AT-N135Q-Pro394 n’a pas été testé.Concernant la seconde indication, l’AT-N135Q-Pro394 avait déjà été évaluée in vivo comme antidote aux dérivés hépariniques, HNF, HBPM et fondaparinux, avec d’excellents résultats. Néanmoins, cet effet antidote a été exploré spécifiquement par mesure de l’activité anti-facteur Xa alors que l’AT inhibe plusieurs enzymes de la cascade de coagulation tel que les facteurs VIIa, IXa et IIa. Nous avons donc exploré cet effet antidote dans un test plus global de la coagulation, le test de génération de thrombine (TGT) pour pouvoir le comparer aux autres stratégies non spécifiques utilisées pour antagoniser les dérivés hépariniques (facteur VII activé recombinant, concentré de complexes prothrombiques activés ou protamine). De façon intéressante, dans un plasma mimant un surdosage, notre variant présente un effet antidote supérieur aux agents hémostatiques et au sulfate de protamine vis-à-vis du fondaparinux et des HBPMs, respectivement, et équivalent au sulfate de protamine vis-à-vis de l’HNF. Enfin, dans du plasma en l’absence d’anticoagulant, l’AT-N135Q-Pro394 ne montre aucun effet sur la génération de thrombine contrairement aux agents hémostatiques et au sulfate de protamine qui, ajoutés seuls dans du plasma, modifient significativement le profil des TGTOur team topic focuses on the structural-function relationship of a natural anticoagulant, antithrombin (AT), in order to develop potential therapeutic agents. AT inhibits several serine proteases of the coagulation cascade and its inhibitory activity is increased when AT binds to a pentasaccharidic motif contained within in the heparin derivatives. At high concentrations (500%), AT also exerts anti-inflammatory and cytoprotective properties through its binding to heparan sulfate proteoglycans, making it a good candidate for supportive therapy in clinical settings associating inflammation and coagulation activation. Indeed, AT has already been evaluated in vivo in various models of ischemia-reperfusion injury (IRI) and AT even reached a large-scale clinical trial in severe sepsis. However, the high concentrations of AT that are needed to exert anti-inflammatory properties are inconsistent with the safety profile of this anticoagulant protein.In this context we have further characterized an AT variant (AT-N135Q-Pro394) with increased affinity to heparin but devoid of anticoagulant activity. Indeed, this variant was described to be able to trap heparin derivatives and our work was to pursue the characterization of this variant as an antidote toward heparin derivatives in clinical situations of overdosing. In addition, this AT variant binds to heparan sulfate proteoglycans with higher affinity, as compared to native AT, and appears as a promising cytoprotective agent whose administration would not be associated with any bleeding risk.To test the latter hypothesis, we developed a murine model of renal IRI in which the renal function was severely impaired, as attested by increased kidney injury markers (urea, creatinine, kim-1) and local kidney inflammation (renal gene expression of il-6 and cxcl-1). Indeed, in 2003, Mizutani et al. reported a protective effect of AT in a similar murine model of renal IRI. Surprisingly, we observed none of the described protective effects, neither on inflammation nor renal function, with plasma AT, recombinant AT and an equimolar mixture of native and latent AT. Nevertheless, the same model enabled us to highlight the nephroprotective and anti-inflammatory properties of another anticoagulant protein, activated protein C (APC), as previously reported. These disappointing results coincided with the withdrawal in 2013 of the study of Mizutani et al., and our work allowed us to clarify the literature and to claim that neither recombinant nor plasma-derived native nor latent forms of AT exhibit a protective effect in renal IRI in mice. Under these conditions, AT-N135Q-Pro394 variant has not been tested in our model.AT-N135Q-Pro394 has also been previously shown to efficiently neutralise the anticoagulant activity of heparin derivatives, including unfractionated heparin (UFH), low molecular weight heparins (LMWH) and fondaparinux in vivo. Nevertheless, this reversal effect was only explored by anti-factor Xa assays whereas AT inhibits a number of coagulation proteases, including factors VIIa, IXa and IIa. Therefore, we explored AT-N135Q-Pro394 variant in a more global coagulation assay, the thrombin-generation assay (TGA), in order to compare its activity with non-specific reversal agents used toward heparin derivative overdose (recombinant-activated factor VII, activated prothrombin-complex concentrate or protamine). Interestingly, in plasma mimicking an overdose, our variant demonstrated greater reversal efficiency as compared to hemostatic agents and protamine sulfate toward fondaparinux and LMWH, respectively, and was as efficient as protamine sulfate toward UFH. Finally, when added to native plasma (in the absence of heparin derivative), AT-N135Q-Pro394 showed no effect on thrombin generation unlike hemostatics and protamine sulfate that all significantly affect the TGA profile
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Mushunje, Alec. "Antithrombin conformational transitions and their implications in thrombosis." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620006.
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Brinkmeyer, Stephan. "Experimente zur Aktivierung von Heparinkofaktor II durch Heparin und Dermatansulfat unter Verwendung eines reversiblen molekularen Schalters." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=963784730.
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Zilker, Susanne. "Aktivitätsgesteuerte Therapie der schweren chirurgischen Sepsis mit Antithrombin III." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-99495.
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Oldeen, Molly Elisabeth. "Optimizing Anticoagulation Therapy in ECMO Patients using Antithrombin III." Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/228500.
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One of the most fundamental aspects of extracorporeal membrane oxygenation (ECMO) is maintaining proper anticoagulation management in order to prevent hemorrhagic or thrombotic events. Anticoagulation on ECMO is most commonly achieved with the use of unfractionated heparin to maintain a minimum anticoagulation level as monitored by activated clotting time (ACT). Heparin's main effect is exerted by binding to and potentiating antithrombin III. Many factors may contribute to a sub-therapeutic ATIII level that may decrease the effectiveness of heparin. A retrospective record review was performed on all adult ECMO patients at the University of Arizona Medical Center between 2008 and 2011, in order to determine optimal ATIII levels for maintaining proper anticoagulation. In addition, we investigated correlations between ATIII levels and hemorrhagic and/or thrombotic events. Variables measured include, ACTs, heparin dose, ATIII dose, ATIII levels, blood product use, and adverse events. Thirty-five patients received ATIII over the course of the ECMO run. Six patients did not receive ATIII and they were found to have used significantly more blood products than those who did receive ATIII. Also, heparin dose dropped significantly 24h after the first dose of ATIII. There is a significant positive correlation between the amount of ATIII given per day and the amount of packed red blood cells transfused per day. The results suggest an ideal therapeutic range of ATIII dosing, where lack of or too much ATIII administration can lead to excessive bleeding.
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Fazavana, Judicaël. "Développement d’une antithrombine modifiée inactive comme antidote des anticoagulants hépariniques." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114855/document.
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Les héparines regroupant les héparines standards (HNF), les héparines de bas poids moléculaire(HBPM), et le fondaparinux, sont des médicaments anticoagulants. Ils potentialisent l’antithrombine (AT) : un inhibiteur physiologique de la coagulation. Leur utilisation en thérapeutique est associée à un risque hémorragique majeur. Actuellement, le sulfate de protamine est le seul antidote disponible vis-à-vis des HNF. Il est partiellement efficace vis-à-vis des HBPM, et n’a aucun effet contre le fondaparinux, qui n’a pas d’antidote jusqu’à présent. C’est dans ce contexte que nous proposons des AT modifiées inactives, mais capables de se lier aux molécules d’héparines. Ces AT déplaceraient les molécules d’héparines de l’AT plasmatique, et neutraliseraient leur effet anticoagulant. Pour produire de telles AT, nous avons choisi une approche recombinante et une approche chimique. Dans la première approche, nous avons exprimé le variant AT-N135Q-Pro394. Ce variant possède une activité anti-Xa ou anti-IIa inférieure à 0,02% en présence de dérivés hépariniques, et une affinité à l’héparine 3 fois meilleure, comparée à l’AT plasmatique. En revanche, dans l’approche chimique, nous avons modifié l’AT plasmatique par la 2,3-butanedione (AT-BD), un réactif chimique de caractérisation des arginines. Contrairement au variant, cette AT-BD a une perte d’activité anticoagulante modérée, puis une affinité à l’héparine 20 fois meilleure, comparée à l’AT plasmatique. Malgré ces différences de propriétés biochimiques, ces 2 AT modifiées neutralisent d’une façon similaire les héparines in vitro et sur un modèle murin. Par ailleurs, à l’inverse du sulfate de protamine, nos antidotes n’ont pas d’activité anticoagulante propre sur un test de céphaline activée. Ainsi, ce travail de thèse a permis non seulement de proposer les premiers et les seuls antidotes spécifiques au fondaparinux décrits, mais aussi des antidotes alternatifs pour tous les anticoagulants hépariniquesUnfractionnated heparin (UFH), low molecular weight heparins (LMWH), and fondaparinux are used therapeutically as anticoagulants. They potentiate antithrombin (AT): a physiological inhibitor of coagulation. Their therapeutic use is associated with a major risk of bleeding. Currently, protamine sulfate is the only antidote available for UFH. It is partially effective for LMWH, and has no effect against fondaparinux, which has no antidote. So, we propose modified inactive AT, but able to bind heparin molecules as antidote of these heparins. These molecules would compete with plasmatic AT for binding to heparins, and neutralize their anticoagulant effect. To produce that AT, we realized a genetic approach and a chemical approach. In the first approach, we expressed the variant AT-N135Q-Pro394 that had an anti-Xa or anti-IIa activity below 0.02% in the presence of heparins, and heparin affinity three times higher, compared to the plasmatic AT. In the chemical approach, we modified the plasmatic AT by 2,3-butanedione (AT-BD), a chemical reagent for arginin’s characterization. The AT-BD had a moderate loss of anticoagulant activity, and a heparin affinity 20 times higher, compared to the plasmatic AT. Despite these differences in biochemical properties, these two modified AT neutralize similarly heparins in vitro and in a mouse model. Moreover, unlike protamine sulfate, our antidotes had not an intrinsic anticoagulant effect in activated partial thromboplastin test. Thus, this PhD-work offers the first and the only specific antidote described to fondaparinux, and it can be used too alternatively for all anticoagulant heparins
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Elnerud, Maja. "Method development for studying the interactions between antithrombin and heparin." Thesis, Linköping University, The Department of Physics, Chemistry and Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-11208.
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Antithrombin (AT) is one of the most important anticoagulant factors in the blood, and its effects are increased by the interaction with glycosaminoglycans, especially heparin. AT appears in two additional variants, other than the native form, and those variants have antiangiogenic properties and also bind to heparin. AT is found in two distinct isoforms (alfa, beta) where the difference lie in the degree of glycosylation. This project has shown interesting results regarding the dependence of calcium ions on the binding between heparin and antithrombin. The results show that the beta-isoform increases its affinity for heparin in the presence of calcium in contrast to the alfa-isoform, which shows a decrease in the heparin affinity under the same conditions. This project has also given results that after further investigation and development could be used for an improved set-up of the immobilisation of AT variants in a surface plasmon resonance system. The results show that immobilisation of a protein in the reference channel gives a better shielding effect between the negatively charged heparin molecules and the negatively charged dextran matrix. Furthermore a more significant difference was seen between the two heparin moieties used during binding affinity studies, especially for native AT.
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Wells, Michael John. "Identification and characterization of rabbit hepatic receptors for thrombin-antithrombin complexes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0003/NQ42771.pdf.
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Kittel, Florina Luisa [Verfasser], and Hinnak [Akademischer Betreuer] Northoff. "Schwingquarzbasierte Bestimmung von Antithrombin III / Florina Luisa Kittel ; Betreuer: Hinnak Northoff." Tübingen : Universitätsbibliothek Tübingen, 2015. http://d-nb.info/1197057986/34.
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Evington, J. R. N. "Protein-polysaccaride interactions and the catalysis of the thrombin/antithrombin reaction." Thesis, University of Bristol, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370826.
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Kittel, Florina [Verfasser], and Hinnak [Akademischer Betreuer] Northoff. "Schwingquarzbasierte Bestimmung von Antithrombin III / Florina Luisa Kittel ; Betreuer: Hinnak Northoff." Tübingen : Universitätsbibliothek Tübingen, 2015. http://d-nb.info/1197057986/34.
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Van, der Merwe Liesel Laura. "The effect of haemolysis on antithrombin concentration as determined by a chromogenic method." Diss., University of Pretoria, 2005. http://hdl.handle.net/2263/22875.
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The presence of free haemoglobin in serum or plasma can markedly affect the outcome of laboratory tests. Normal concentrations of plasma haemoglobin in carefully obtained specimens are less than 0.025g/l. The presence of free haemoglobin in a sample increases the spectrophotometric absorbance of tests run at wavelengths within the absorbance range of haemoglobin (400 – 440nm). Little is known about the effects of haemolysis on the determination of antithrombin levels in canine plasma samples. Two plasma pools, designated AT 100 and AT 70 were prepared. The AT 70 pool was prepared by diluting pooled plasma with 0.9% saline in a ratio of 7:3. A unit of whole blood was collected from a healthy donor animal. The erythrocytes were lysed by freezing and thawing. The solution was centrifuged, the supernatant collected and filtered using 1.2 um and 0.22 um filters sequentially to remove residual red cell stroma. The haemoglobin concentration of the solution was determined using a modification of the automated Drabkin method. Intermediate haemoglobin solutions of decreasing known concentrations were prepared by the addition of saline. The intermediate solutions were added to the plasma pools in a 1+9 manner and a series of samples were prepared with final calculated and measured haemoglobin concentrations of 0.0; 0.5; 1.5; 2.5; 3.5; 4.5 and 5.5 g/l. The AT determinations were performed using a functional chromogenic assay and the spectrophotometric absorbances were read using a 405 nm filter, as specified. Increasing concentrations of haemoglobin resulted in a decrease in the AT value measured. A simple linear regression analysis was performed on both AT70 and AT100 using a two-step regression analysis. The slopes up to [Hb] 1.5g/l were not significant whereas the slopes at between [Hb] 1.5 – 5.5 g/l were significant ( p< 0.001). The slope equation for AT 100 was y= -5.742X+ 115.24 with R 2 = 0.794 and for AT 70 was y = - 4.2037X + 66.821, with R 2 = 0.936. A conversion table was created by interpolation of data between these two lines. These results show that it is possible, using a conversion equation, to perform the AT assay in haemoglobinaenic serum, thus opening the way to further evaluation of the coagulation status in patients with haemolytic disease processes.Dissertation (MMedVet (Med))--University of Pretoria, 2005.
Companion Animal Clinical Studies
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Hagel, Stefan. "Protein C- und Antithrombin III-Aktivität : Stellenwert bei der Diagnose und Verlaufsbeurteilung unterschiedlicher systemischer Entzündungssyndrome bei kritisch kranken Patienten /." Saarbrücken VDM Verlag Dr. Müller, 2006. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=015040669&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Zamorskii, I. I. "Antithrombin DNA aptamers as a renoprotective agents against the rhabdomyolysis-induced acute kidney injury." Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18254.
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Pfannenschmidt, Gerd. "Der Effekt von Antithrombin III auf die pulmonalvaskuläre Freisetzung von Big Endothelin-1, Endothelin-1 und Prostanoiden unter septischen und nichtseptischen Bedingungen sowie seine Mechanismen." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2000. http://dx.doi.org/10.18452/14540.
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Die Arbeit sollte klären, ob die pulmonalprotektiven Effekte von AT III bei LPS-induziertem ARDS auch auf einer Stimulation der pulmonalvaskulären PGI2-Freisetzung beruhen. Die Freisetzung von Big ET-1 und ET-1 unter septischen Bedingungen sollte quantifiziert sowie mögliche Effekte von AT III auf diese Freisetzung untersucht werden. Dabei wurde das Modell der isolierten Rattenlunge verwendet. Die Perfusion der Lunge mit LPS führte zu einer Steigerung der Kon-zentration von 6-Keto-PGF1(, dem stabilen Metaboliten von PGI2, auf das 1,6fache und der Konzentration von TxB2, dem stabilen Metaboliten von TxA2, auf das 2,9fache gegenüber der Kontrollgruppe. Die Konzentration von ET-1 erhöhte sich unter LPS auf das 1,6fache, während der Big ET-1 Spiegel konstant blieb. Die Gabe von AT III hatte keinen Effekt auf die Freisetzung von PGI2 und TxA2. Die kombinierte Gabe von LPS und AT III wirkte ebenso wie die Gabe von LPS allein. Die Konzentrationen von Big ET-1 und ET-1 erhöhten sich unter 2 U/ml AT III auf das 1,7- bzw. 1,2fache und unter 5 U/ml AT III auf das 1,6- bzw. 1,3fache gegen-über den Kontrollen. Die kombinierte Gabe von LPS und AT III führte zu einem signifikant höheren Big ET-1-Spiegel vom 2,6fachen des Basalwertes, während sich die Konzentration von ET-1 nicht von der unter LPS bzw. AT III allein unterschied. Die Gabe von Cicaprost, einem stabilen synthetischen PGI2-Analogon, beeinflußte weder die basale noch die durch 2 U/ml AT III und 50 µg/ml LPS stimulierte Big-ET-1- und ET-1-Freisetzung. Nicardipin, ein Blocker der L-Typ-Kalzium-Kanäle, Heparin und N-Acetyl-Heparin, ein nicht an AT III bindendes Heparin, antagonisierten jeweils den stimulierenden Effekt von AT III auf die Big-ET-1- und ET-1-Freisetzung komplett. Staurosporin, ein Proteinkinase C-Inhibitor und Genistein, ein Tyrosinkinase-Inhibitor hatten keinen Effekt auf die durch AT III stimulierte Big-ET-1- und ET-1-Freisetzung. SCHLUßFOLGERUNGEN: Das für den protektiven Effekt des AT III bei ARDS verantwortlich gemachte PGI2 scheint nichtpulmonalen Ursprungs zu sein. Eine PGI2-mediierte Hemmung der pulmonalen ET-1-Sekretion war nicht zu beobachten und scheint somit nicht am protektiven Effekt des AT III beim septischen ARDS beteiligt zu sein. Der beobachtete stimulierende Effekt des AT III auf die Freisetzung der pulmonalen Endotheline ist von möglicher pathophysiologischer Relevanz, da er die erwähnte protektive Wirkung des AT III mit hoher Wahrscheinlichkeit abschwächt. Dieser stimulierende Effekt des AT III scheint dabei an der intakten Rattenlunge weder von der Proteinkinase C noch von Tyrosinkinasen vermittelt zu sein. Weiterhin ist festzustellen, daß die stimulierende Wirkung des AT III auf die pulmonalvaskuläre Freisetzung von Big ET-1 und ET-1 von einem Kalziumeinstrom durch L-Typ-Kalzium-Kanäle und damit von der intrazellulären Kalziumkonzentration abhängig ist. Wie die gleiche Wirksamkeit von Heparin und N-Azetyl-Heparin zeigt, erfordert die Blockade des AT-III-Effektes durch die Heparine keine direkte Bindung an AT III, was auf die zusätzliche Rolle der intrazellulären Kalziumfreisetzung über IP3 hinweist.The aim of the present study was to clarify if the pulmonary protective effects of AT III in LPS-induced ARDS can be attributed to a stimulation of the pulmonary vascular release of PGI2. The pulmonary vascular release of big ET-1 and ET-1 under septic conditions and the possible influence of AT III was to be investigated. To this end, we used the model of the isolated perfused rat lung. Exposure of the lung to LPS increased the release of 6-Keto-PGF1(, the stable metabolite of PGI2, 1.6fold and the production of TxB2, the stable metabolite of TxA2, 2.9fold compared with control lungs. The release of ET-1 increased 1.6fold under LPS, whereas the concentration of big ET-1 was unchanged. The application of AT III had no effect on the release of PGI2 and TxA2. The effects following combined application of LPS and AT III were similar to the effects of LPS alone. Compared with controls, AT III, at 2 U/ml, increased the perfusate levels of big ET-1 and ET-1 1.7fold and 1.2fold, respectively; the administration of 5 U/ml AT III raised big ET-1 and ET-1 1.6fold and 1.3fold, respectively. Combined application of LPS and AT III resulted in a 2.6fold rise of big ET-1 levels compared with controls, whereas concentrations of ET-1 did not differ from those in the presence of LPS or AT III alone. Cicaprost, a stable PGI2 analogue, affected neither the basal nor the AT III plus LPS-stimulated release of big ET-1 and ET-1. Nicardipin, an L-type calcium channel blocker, heparin and N-acetyl heparin, a heparin derivative devoid of AT III affinity, each antagonized completely the AT III-stimulated increase in big ET-1 and ET-1 levels. Staurosporin, an inhibitor of protein kinase C, and genistein, an inhibitor of tyrosine kinases, did not influence the AT III effects on endothelins. CONCLUSIONS: In ARDS, the well-known rise in plasma PGI2 in response to AT III obviously originates from non-pulmonary sources. PGI2 does not suppress the pulmonary ET-1 secretion; therefore, this mechanism seems not involved in the AT III-induced lung protection during septic ARDS. The AT III-mediated stimulation of the release of pulmonary endothelins is of potential pathophysiological relevance, because it may blunt the protective effects of AT III in ARDS. In the intact rat lung, this stimulatory effect of AT III is mediated neither by protein kinase C nor by tyrosine kinases. Moreover, the observed effect of AT III on pulmonary endothelins is based on calcium influx through L-type calcium channels and depends on the intracellular calcium activity. The equipotency of heparin and N-acetyl heparin in inhibiting the AT III action demonstrates that direct binding of AT III is not essential for the blocking effect of heparins. This fact points to additional involvement of an IP3-dependent intracellular calcium release.
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Borg, Jeanne-Yvonne. "Antithrombines trois rouen : anomalies constitutionnelles avec defaut isole de liaison a l'heparine : etude structurale et fonctionnelle, analyse physiopathologique." Paris 7, 1987. http://www.theses.fr/1987PA077193.
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Yamashiro, Kenji. "Inhibitory Effects of Antithrombin III against Leukocyte Rolling and Infiltration during Endotoxin-induced Uveitis in Rats." Kyoto University, 2003. http://hdl.handle.net/2433/148459.
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Raghuraman, Arjun. "Designing Non-saccharide Heparin/Heparan Sulfate Mimics." Online version available 8/19/2013, 2008. http://hdl.handle.net/10156/2269.
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de, la Morena Barrio Mª Eugenia. "Identificación de nuevos elementos implicados en la regulación de antitrombina= Identification of new elements involved in antithrombin regulation." Doctoral thesis, Universidad de Murcia, 2013. http://hdl.handle.net/10803/116861.
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Deficiency of antithrombin caused by mutations affecting the gene encoding this key anticoagulant (SERPINC1) significantly increases the risk of thrombosis. We aim to identify new mechanisms involved in antithrombin deficiency. Using molecular, cellular and biochemical methods, we studied 29 patients with antithrombin deficiency without SERPINC1 mutation, a family study, three case-control studies including 2,980 patients and 3,996 controls, and two patients with congenital disorder of glycosylation (CDG). We identified the first mutation affecting the SERPINC1 promoter causing antithrombin deficiency. We confirmed the low genetic variability of SERPINC1 and its minor role on the heritability of antithrombin. Genome wide association studies and silencing experiments identified the first modulating gene of antithrombin, LARGE. We diagnosed a patient with CDG based on his antithrombin deficiency. Finally, we described a new disorder with identical biochemical features than CDGs, but only thrombosis, which is caused by a single mutation in PMM2 and concomitant alcohol consumption.La deficiencia de antitrombina causada por mutaciones en el gen SERPINC1 incrementa el riesgo trombótico. Nuestro objetivo fue identificar nuevos mecanismos implicados en la deficiencia de este anticoagulante. Empleando metodología molecular, celular y bioquímica estudiamos 29 pacientes con deficiencia de antitrombina sin mutaciones en SERPINC1, un estudio familiar, tres estudios caso-control (2,980 pacientes/3,996 controles) y dos pacientes con trastornos congénitos de glicosilación (CDG). Identificamos la primera mutación en el promotor de SERPINC1 que causa deficiencia de antitrombina. Confirmamos la baja variabilidad genética en SERPINC1 y su escasa influencia en la heredabilidad de antitrombina. Un GWAS y experimentos de silenciamiento mostraron que LARGE es el primer gen modulador de antitrombina. Diagnosticamos un CDG por la deficiencia de antitrombina de un paciente con trombosis recurrente y descubrimos nuevo desorden con patrón bioquímico similar al CDG pero solo con trombosis que es causado por una sola mutación en PMM2 y consumo de alcohol.
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Zani, Karen de Morais. "Estudo da atividade anti-inflamatória da antitrombina nativa da serpente Bothrops jararaca. Clonagem da antitrombina." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-06062013-154512/.
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A antitrombina de B. jararaca foi isolada por meio de cromatografia de afinidade em coluna HiTrap Heparin HP (GE Healthcare). A análise da interação da antitrombina humana ou de B. jararaca com a heparina em sistema BIAcoreT200 demonstrou que a antitrombina de B. jararaca apresenta maior afinidade pela heparina que a antitrombina humana. Com relação à sua atividade anti-inflamatória, os resultados obtidos evidenciaram o efeito anti-inflamatório do pré e do pós-tratamento com a antitrombina de B. jararaca na resposta inflamatória aguda. A análise proteômica do exsudato inflamatório de camundongos identificou algumas proteínas possivelmente relacionadas ao mecanismo de inibição da antitrombina, como a enzima C3 do sistema complemento, a sorotransferrina, a a1-antitripsina, a apolipoproteína AI, o fibrinogênio, o cininogênio e a albumina. O processo de clonagem permitiu a obtenção da sequência completa da antitrombina de B. jararaca e apesar da longa distância evolutiva entre serpentes e humanos, diversas características da antitrombina encontram-se conservadas.B. jararaca antithrombin was isolated by affinity chromatography using HiTrap Heparin HP column (GE Healthcare). The interaction analysis of human or B. jararaca antithrombin with heparin using a BIAcoreT200 system (GE Healthcare) demonstrated that the affinity of B. jararaca antithrombin for heparin is higher than human antithrombin. Regarding the anti-inflammatory activity of B. jararaca antithrombin, the results showed the anti-inflammatory effect of pre- and post-treatment with this molecule in acute inflammation. The proteomic analysis of inflammatory exudate of mice identified some proteins possibly related to the mechanism of inhibition of antithrombin, such as C3 complement, serum transferrin, a1-antitrypsin, apolipoprotein AI, fibrinogen, albumin and kininogen. The molecular cloning process allowed the determination of the complete sequence of B. jararaca antithrombin and despite the evolutionary distance between snakes and human, a number of characteristics are preserved in antithrombin molecule.
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Morais, Karen Batista de. "Purificação e caracterização da antitrombina do plasma da serpente Bothrops jararaca (Wied, 1824) (Ophidia: Viperidae, Crotalinae)." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/41/41135/tde-13072009-160524/.
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O presente trabalho teve como objetivo caracterizar o desenvolvimento da semente de Araucaria angustifolia através da proteômica comparativa, buscando compreender as alterações fisiológicas e metabólicas que ocorrem durante esse processo. Inicialmente, foram avaliados três diferentes metodologias de extração de proteínas. A metodologia composta por solução de extração contendo 7 M de uréia, 2 M de tiouréia, 1% de ditiotreitol, 2% de Triton-100, 1 mM de fluoreto de fenilmetilsulfonil e 5 µM de pepstatina, seguido de precipitação em 20% de ácido tricloroacético apresentou géis de maior resolução e reprodutibilidade, tendo sido escolhida como metodologia de extração protéica para o estudo das alterações no proteoma da semente de A. angustifolia. Uma dificuldade associada ao estudo do proteoma de espécies não sequenciadas é a baixa representatividade nos bancos de dados protéicos, resultando em identificações baseadas em homologia. Estratégias proteômicas baseadas em fracionamento em gel resultam em grandes contaminações por fragmentos de queratina. Sendo assim, foi desenvolvido um programa de remoção de espectros de baixa qualidade para utilização em proteômica baseada em homologia. As análises mostraram que o programa reduz o tempo de busca, melhora a qualidade dos alinhamentos e não resulta em perda de identificações positivas. Finalmente, utilizando as metodologias descritas, foram estudadas as alterações no proteoma durante o desenvolvimento da semente de A. angustifolia. Noventa e seis proteínas foram identificadas e agrupadas de acordo com sua função biológica e padrão de detecção. Os resultados obtidos permitiram o estabelecimento de marcadores protéicos no início e final do desenvolvimento embrionário. A análise das proteínas abundantes no início da embriogênese indica um maior controle no metabolismo oxidativo em relação aos estádios finais. Contrariamente, o final da embriogênese é caracterizado por um alto metabolismo de assimilação de carbono e acúmulo de proteínas de reserva. As implicações dos resultados obtidos no controle e melhoramento de sistemas de embriogênese somática na espécie também foram discutidasThe aim of the present work was to characterize the seed development of Araucaria angustifolia through proteomics in order to understand the physiological and biochemical changes during this process. For that, initially, three different protein extraction methods were evaluated. The extraction based on protein solubilization in 7 M urea, 2 M thiourea, 1% dithiothreitol, 2% Triton-100, 1 mM phenylmethylsulphonyl fluoride, 5 µM pepstatin, followed by 20% trichloroacetic acid precipitation showed the highest gel resolution and reprodutivity and, thus, was chosen to be used in the analysis of the proteome of A. angustifolia seeds. One aspect that hampers the proteome study of unsequenced species is the low protein representativity in databases. So, protein identification is usually carried out through homology. Strategies based on 2-DE result in high keratin contamination. In the present work a spectra filtering software was developed and evaluated for use in homology driven proteomics. The software reduced the time of search, improved alignment quality and did not result in lost of positive identifications. Finally, using the described strategies, the changes in the proteome of A. angustifolia seeds were studied. Ninety six proteins were identified and classified according to their biological functions and expression profiles during seed development. The identified proteins may be used as protein markers of early and late embryogenesis. Proteins involved in the control of oxidative metabolism were highly expressed during the early stages of seed development; while, carbon metabolism and storage proteins were highly expressed in late stages. Considerations on the improvement and control of somatic embryogenesis through medium manipulation and protein markers screening using data generated are also discussed.
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Vecchietti, D. G. "Low Molecular Weight Heparins : in depth structural characterization to understand their different biological properties." Doctoral thesis, Università degli Studi di Milano, 2008. http://hdl.handle.net/2434/59669.
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Heparin is a linear, heterogeneous, highly sulfated polysaccharide belonging to the family of glycosaminoglycans, endowed with anticoagulant and antithrombotic properties. Its linear chains are made up of 15-200 disaccharide units of N-sulfated or N-acetylated D-glucosamine linked to hexuronic (glucuronic or iduronic) acid.
Low molecular weight heparins (LMWHs), developed to circumvent some unwanted side effect of unfractionated heparins (UFH), are obtained from UFH by diverse chemical and enzymatic depolymerisation processes. Fragments generated by cleavage of heparin may therefore structurally differ from each other more than the original chains because of the modification induced by the depolymerisation methods and the heterogeneity of the UFH. Only about one-third of heparin chains contains a unique pentasaccharide sequence (AGA*IA), which specifically binds antithrombin (AT) thus promoting the inhibition of certain proteases of the coagulation cascade. Such a sequence, characterized by a central trisulfated glucosamine (A*), is believed to survive the depolymerising procedures used for the preparation of LMWHs.
Functional assays performed in vitro, evaluating plasma protein binding and antiprotease activity AT mediated, showed wide variations among the commercially available LMWHs, indicating that their compositional differences have an important impact on function.
With the aim of contributing to the elucidation of structure-activity relationship of LMWHs, the present work is focusing on the in depth study of the oligosaccharide composition of different LMWH preparations. Three of the most popular commercial preparations Enoxaparin, Dalteparin and Tinzaparin were analysed.
Their compositional differences were determined by analyzing their oligosaccharidic populations by gel permeation chromatography, a very characteristic fingerprint for each sample was revealed.
Affinity chromatography on AT-Sepharose was performed to separate and quantify the high affinity fraction,. Structural characterization of all samples was obtained by 1D and 2D NMR spectroscopy and all molecular weight parameters were evaluated through HP-SEC/TDA. All the HA fractions exhibited a considerably higher molecular weight and a reduced polydispersity with respect to NA fractions.
To deepen the characterization of HA components, HA heparin chains of each LMWH were further fractionated into three subfractions with graded affinity toward AT HA1>HA2>HA3.
All the above fractions were analysed via NMR evaluating the average content of all the monosaccharide components and, in particular, the percentage of A* (N-glucosamine tri-sulfated) and G-A* (disaccharide composed by glucuronic acid and A*) both regarded as markers of heparin active site for AT (AGA*IA).
Selected oligomeric fractions and the HA1, HA2, HA3 fractions were analysed via ESI-TOF (as detector after a SEC chromatography). The molecular weight of all HA subfractions were estimated by two different methods: HP-SEC/ESI-MS and NMR.
The results suggest that neither the molecular weight nor the sulfation degree calculated via NMR exhibited any correlation with the degree of affinity for AT.
By combining information obtained by NMR (G-A* content) and the chain length (calculated by Mw evaluation)the AGA*IA content per chain was approximately calculated pointing out the presence of some chains containing more than an active pentasaccharide (HA1 of enoxaparin and dalteparin).
Preliminary data on biological activity in vitro indicated that the different anti-Xa activities were directly related to the degree of AT affinity and the overall structural considerations.
The present work represents the first insight into the detailed and comparative structural characterization of three commercial LMWHs differing in manufacturing process. Important and characteristic structural parameters were defined, including the precise oligomeric composition, the relative content of AT interacting species, and their molecular weight, together with the relative content of variously substituted monosaccharide components. Further studies are required to unravel the correlation of structural features with LMWH functional properties.
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Hashim, R. Bt. "The use of fluorescent probes in the study of the interaction of the interaction of heparin with antithrombin III and polycations." Thesis, University of Salford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356175.
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Bäck, Jennie. "The Plasma Contact System : New Functional Insights from a Hemostatic and Thrombotic Perspective." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-160343.
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The physiological role of the plasma contact system still remains a partial enigma. The aim of the presented work was to expand our understanding of the plasma contact system, focusing on its physiological activation and function, principally from a hemostatic perspective. It also explored contact system activation under pathological conditions. We found that when human platelets become activated in blood, plasma proteins of the contact system bind to platelets and initiate contact activation. The platelet-triggered contact activation contributed to clot formation by shortening the clotting time and enhancing clot stability. We demonstrated that the regulation of contact activation elicited by activated platelets differed from the previously described contact activation elicited by negatively charged material surfaces. Platelet-triggered contact activation and activation propelled by clotting blood were found to be regulated by antithrombin, whereas material-induced activation was regulated by C1 inhibitor. We also showed that the fibrin fibers that are formed during the clot process further enhance and propagate the contact activation initially induced by activated platelets. Fibrin not only activated factor XII but also seemed to increase the affinity of antithrombin for the proteases of the contact system, leading to the generation of contact enzyme-antithrombin complexes during clot formation. To determine whether the contact system might be involved in the inflammation and vascular disease associated with systemic lupus erythematosus (SLE), we analyzed plasma samples from SLE patients. These patients were found to have altered levels of contact enzyme-serpin complexes, supporting the concept that the contact system may be involved in the pathophysiology of SLE. The contact enzyme-antithrombin complexes were clearly linked to platelet activation in vivo. Altered levels of both FXIIa-antithrombin and FXIIa-C1 inhibitor were found to be correlated with previous vascular disease and may therefore be potential biomarkers for assessing the risk of thrombotic events in SLE patients. These findings add to our knowledge of how the plasma contact system is activated and functions in vivo and will help us to understand the role of the contact system, not only in hemostasis but also in vascular disease and thrombotic conditions.
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Wahlgren, Carl Magnus. "Mechanisms of thrombosis and restenosis after vascular injury /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-260-8/.
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Pfannenschmidt, Gerd. "Der Effekt von Antithrombin-III auf die pulmonalvaskuläre Freisetzung von Big-Endothelin-1, Endothelin-1 und Prostanoiden unter septischen und nichtseptischen Bedingungen sowie seine Mechanismen." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=960868755.
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Sanchez, Caroline. "Influences génétique et environnementale de la génération de thrombine." Thesis, Aix-Marseille 2, 2011. http://www.theses.fr/2011AIX20658.
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Dans ce travail nous nous sommes intéressés à caractériser les modulateurs génétiques et environnementaux de la génération de thrombine (ETP).Nous avons montré que le taux d’antithrombine (AT) peut être considéré comme un facteur continu de risque de thrombose. L’ETP, le plus élevé, est observé chez les porteurs d’un déficit quantitatif en AT. Les porteurs de la mutation AT Cambridge II présentent également une augmentation de l’ETP. Parallèlement à l’AT, nous avons confirmé l’effet positif de l’allèle PT 20210A sur la génération de thrombine d’autant plus qu’il existe des antécédents personnels de thrombose veineuse (TV). A côté de ces contributions, nous avons confirmé le rôle des taux plasmatiques de fibrinogène et de facteur II, du groupe sanguin et de la prise de contraceptifs oraux sur l’ETP.Nos résultats montrent également que chez le rat, un régime riche en graisses a un effet sur la génération de thrombine. Le régime gras maintient des taux élevés d’ETP après le sevrage, alors qu’une alimentation standard le diminue. Cet effet est partiellement expliqué par l’élévation des taux de facteur VII coagulant et ne suit pas l’évolution des modifications classiques du métabolisme glucidolipidique. Les niveaux élevés d’ETP observés pendant une alimentation riche en graisses se normalisent quatre semaines après le retour à une alimentation standard.En conclusion nos données suggèrent que l’ETP peut être considéré comme un indicateur de l’état prothrombotique des patients, mais son utilisation à l’échelle individuelle dans la prédiction du risque de thrombose veineuse reste à approfondir. La mesure de la génération de thrombine peut être un outil utile pour évaluer les conséquences des modifications du régime alimentaire ou des médicaments pour traiter l’obésité sur le potentiel procoagulant circulantIn this work, we studied genetic and environmental modulators of thrombin generation by endogenous thrombin potential (ETP).We showed that plasma levels of antithrombin (AT) can be considered as risk factors for thrombosis. ETP levels are higher in patients presenting a quantitative defect of AT. In addition, mutation AT Cambridge II is also associated with an increase of ETP. Besides the AT, we confirmed a positive effect of the prothrombin 20210A allele on thrombin generation, especially in presence of venous thrombosis antecedents. These contributions, we have confirmed the role of plasma fibrinogen and factor II, blood group and oral contraceptives on thrombin generation.In addition, our results also showed an effect of high fat diet on thrombin generation in rats. Conversely to the standard fat diet, high fat diet maintened high levels of ETP after weaning. High fat diet-induced effects persisted four weeks after switching to standard fat diet. This effect could be partially explained by higher rates of coagulation factors VII and did not follow classical changes in glucidolipidic metabolism.In conclusion our data suggest that ETP can be considered as an indicator of the prothrombotic state in patients, but require more explanation to predict a risk of venous thrombosis. The measurement of thrombin generation may be a useful tool for assessing the impact of changes in diet or medication to treat obesity on circulating procoagulant potential
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Arnljots, Björn. "On prevention of microarterial thrombosis role of protein C and protein S and thrombin inhibition /." Lund : Dept. of Plastic and Reconstructive Surgery, Malmö University Hospital, University of Lund, 1995. http://catalog.hathitrust.org/api/volumes/oclc/39055869.html.
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Migoney, Touze Véronique. "Fonctionnalisation de la surface interne de matériaux tubulaires : étude de l'inhibition de la thrombine par l'antithrombine III à la surface de ces matériaux." Paris 13, 1986. http://www.theses.fr/1986PA132006.
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Modification chimique de polystyrène greffé sur la surface interne de tubes en polyethylène pour rendre anticoagulante la surface interne de ces tubes employés comme catheter. Fixation de groupes fonctionnels sulfonate et sulfamide d'acide aspartique par liaison covalente en para des cycles benzeniques du polystyrène
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Nienaber, Cornelie. "Haemostatic variables in African adolescents : the PLAY study / Cornelie Nienaber." Thesis, North-West University, 2006. http://hdl.handle.net/10394/1322.
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Sié, Pierre. "Biologie et pharmacologie du second cofacteur de l'heparine." Paris 7, 1987. http://www.theses.fr/1987PA077082.
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Linden, Matthew D. "The haemostatic defect of cardiopulmonary bypass." University of Western Australia. School of Surgery and Pathology, 2003. http://theses.library.uwa.edu.au/adt-WU2006.0009.
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[Truncated abstract] Cardiac surgery involving cardiopulmonary bypass is a complex procedure that results in significant changes to blood coagulation, fibrinolytic biochemistry, platelet number and function, and the vasculature. These are due to pharmacological agents which are administered, haemodilution and contact of the blood with artificial surfaces. Consequently there are significant risks of thrombosis and haemorrhage associated with this procedure. The research presented in this thesis utilises in vitro, in vivo, and a novel ex vivo model to investigate the nature of the haemostatic defect induced by cardiopulmonary bypass. The components studied include the drugs heparin, protamine sulphate, and aprotinin, different types of bypass circuitry (including heparin bonded circuits) and procedures such as acute normovolaemic haemodilution. Patient variables, such as Factor V Leiden, are also studied. Each of these components is assessed for the effects on a number of laboratory measures of haemostasis including activated partial thromboplastin time, prothrombin time, activated protein C ratio, antithrombin concentration, heparin concentration, thrombin-antithrombin complex formation, prothrombin fragment 1+2 formation, markers of platelet surface activation and secretion, activated clotting time, haemoglobin concentration and coagulation factor assays.
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Desroys, du Roure François. "Influence de la concentration en chlorure de sodium sur l'inhibition de la thrombine par l'antithrombine III en présence d'héparine standard et de trois héparines de bas poids moléculaire." Paris 5, 1993. http://www.theses.fr/1993PA05P010.
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Camprubí, Rimblas Marta. "Nebulized anti-coagulants as a therapy for acute lung injury and acute respiratory distress syndrome." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/663961.
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La síndrome de distrés respiratori agut (ARDS) és una insuficiència respiratòria aguda amb una incidència global a Europa de 17,9 per cada 100.000 persones-any. Tot i els avenços en el tractament de suport dels pacients amb ARDS, la mortalitat continua sent alta (40%) i els pacients que sobreviuen presenten seqüeles persistents. Actualment no existeix un tractament efectiu.
La fisiopatologia de l’ARDS es caracteritza per l’activació de la coagulació i la inflamació a nivell pulmonar, juntament amb el trencament de la barrera alveolar-capil·lar. Això comporta la formació d’edema proteic, la infiltració dels neutròfils cap al compartiment alveolar i l'activació dels macròfags cap a un fenotip pro-inflamatori.
Estudis previs en models pre-clínics de lesió pulmonar aguda (ALI) i en pacients amb ARDS han demostrat els efectes beneficiosos del anti-coagulants, tot i que aquests efectes positius es veuen contrarestats pel risc d’hemorràgia sistèmica. Els anti-coagulants podrien ser efectius gràcies a la seva activitat anti-inflamatòria a més de les seves propietats anti-coagulants. Atesa l’estreta interacció entre aquestes vies i la seva influència en la permeabilitat, els anti-coagulants també podrien restaurar la barrera alveolar-capil·lar. La nebulització dels anti-coagulants directament al compartiment alveolar podria augmentar l'eficàcia local i disminuir el risc d'hemorràgia sistèmica.
La hipòtesi d'aquesta tesi és que l'heparina nebulitzada i/o antitrombina (ATIII) limitaran la resposta pro-inflamatòria i pro-coagulant pulmonar després de la LPA, promovent, també, la restauració de la barrera alveolar-capil·lar. La co-administració dels anti-coagulants directament als pulmons mitjançant nebulització produirà un efecte sinèrgic que potenciarà les propietats de l'heparina i l’ATIII, reduint la lesió pulmonar i evitant el risc d'hemorràgia sistèmica.
Com a part d’aquesta tesi es mostren els resultats de l'acció de l'heparina o l’ATIII específicament en poblacions pulmonars primàries de cèl·lules humanes lesionades i l'administració directa d'heparina i/o ATIII als pulmons per nebulització en un model de rata d’ALI.
La nebulització d'heparina i/o d’ATIII atenuen la inflamació i coagulació pulmonar sense produir hemorràgia sistèmica en el model d’ALI. El tractament amb heparina nebulitzada modula els macròfags alveolars mitjançant la reducció dels efectors de TGF-β i NF-κB i la via de coagulació i disminueix el reclutament de neutròfils a l'espai alveolar. L'administració local d'ATIII augmenta els efectes beneficiosos en la coagulació, mentre que la combinació d'ATIII i heparina tenen un major impacte en la reducció de la permeabilitat i la disminució de la infiltració de macròfags en el compartiment alveolar. En estudiar l'acció translacional en humans d'ambdós anti-coagulants en poblacions cel·lulars humanes lesionades aïllades de biòpsies pulmonars, l'heparina disminueix l'expressió de marcadors proinflamatoris en els macròfags alveolars i desactiva la via NF-κB en cèl·lules alveolars tipus II; disminuint l'expressió dels seus mediadors i efectors. D’altra banda, l'ATIII redueix els nivells de mediadors proinflamatoris i augmenta les unions estretes en les cèl·lules alveolars tipus II lesionades.
Els estudis actuals demostren que l'heparina nebulitzada i l'ATIII poden ser un tractament potencial per a la ARDS, ja que actuen en diferents vies i processos de la fisiopatologia d’aquesta síndrome. L'administració local d'anti-coagulants atenua la lesió pulmonar disminuint la inflamació, la coagulació i proveeix millores en la permeabilitat sense causar hemorràgia sistèmica.Acute respiratory distress syndrome (ARDS) is an acute respiratory failure with a global incidence in Europe of 17.9 per 100,000 person-year. Although significant advances have been performed in supportive care of patients with ARDS, mortality remains high (40%) and survivors present persistent sequelae. An effective pharmacological therapy for this syndrome is not available yet. ARDS pathophysiology involves pulmonary activated coagulation and inflammation together with the breakdown of the alveolar-capillary barrier. This leads to proteinaceous edema, neutrophils infiltration into the alveolar compartment and the activation of macrophages towards a pro-inflammatory phenotype. Beneficial effects of anti-coagulants have been proved in pre-clinical models of acute lung injury (ALI) and in ARDS patients, although systemic bleeding offset its positive effects. Anti-coagulants could be effective for their anti-inflammatory activity in addition to their anti-coagulant properties. Moreover, given the cross talk of these pathways and their influence on permeability, anti-coagulants could also restore the alveolar-capillary barrier. Nebulization of anti-coagulants directly into the alveolar compartment might increase local efficacy and decrease the risk of systemic bleeding. The hypothesis of this thesis is that nebulized heparin and/or antithrombin (ATIII) limit the pro-inflammatory and pro-coagulant response in the lungs after ALI, also promoting the restoration of the alveolar-capillary barrier. The co-administration of both anti-coagulants directly into the lungs via nebulization produces a synergistic effect enhancing the properties of heparin and ATIII, reducing lung injury and avoiding the risk of systemic bleeding. As part of this thesis we are showing the results of the action of heparin or ATIII in specific primary human injured cell lung populations and the direct administration of heparin and/or ATIII into the lungs by nebulization in a rat model of ALI. Nebulized heparin and/or ATIII attenuated pulmonary inflammation and coagulation and did not produce systemic bleeding in the model of ALI. Treatment with nebulized heparin modulated alveolar macrophages through reducing TGF-β and NF-κB effectors and the coagulation pathway and decreased the recruitment of neutrophils into the alveolar space. Local administration of ATIII alone increased beneficial effects in coagulation, while combined ATIII and heparin had a higher impact reducing permeability and decreasing the infiltration of macrophages into the alveolar compartment. The translational action into humans of both anti-coagulants was also studied. In injured human cell lung populations isolated from lung biopsies, heparin diminished the expression of pro-inflammatory markers in alveolar macrophages and deactivated the NF-κB pathway in alveolar type II cells; decreasing the expression of its mediators and effectors. Also, ATIII decreased levels of pro-inflammatory mediators and increased levels of tight junctions in injured alveolar type II cells. The current studies prove that nebulized heparin and ATIII might be a potential treatment for ARDS, as they act in different pathways and processes of the pathophysiology of this syndrome. Local administration of anti-coagulants attenuates lung injury decreasing inflammation, coagulation and proving ameliorations on permeability without causing systemic bleeding.
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Kuusisto, M. (Milla). "Translational research on challenges in the treatment of diffuse large B-cell lymphoma." Doctoral thesis, Oulun yliopisto, 2015. http://urn.fi/urn:isbn:9789526210643.
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Abstract In the present study, some of the difficulties in the treatment of the most common malignant lymphoma, diffuse large B-cell lymphoma (DLBCL), were evaluated. Some patients develop local or central nervous system (CNS) relapse after first-line treatment. The treatment of relapsed disease is challenging and despite all efforts, some patients die of the disease. Chemoresistant disease also remains challenging because some patients suffer from refractory disease of a progressive nature. The antioxidant enzymes peroxiredoxins (Prxs) and thioredoxin-1 (Trx) were evaluated as prognostic and predictive markers of DLBCL. High cytoplasmic expression of Prx VI was found to correlate with poor prognosis in patients with DLBCL. Trx knockdown in lymphoma cell culture revealed a possible predictive role of Trx. Trx knockdown sensitized cells to doxorubicin, a widely used chemotherapeutic agent in treatment schemas of DLBCL. Etoposide, another widely used chemotherapeutic agent, on the other hand, killed more native DLBCL cells than did doxorubicin. Patients with high Trx expression at the diagnostic stage of the disease benefitted from etoposide-containing high-dose chemotherapy and autologous stem cell transplantation and did not develop post-transplantation relapses which Trx-negative patients did. Antithrombin III (AT III) in cerebrospinal fluid has been suggested to be a biomarker in previous studies of CNS lymphoma. In the present study, AT III was evaluated in patients with CNS lymphoma and with neurological diseases. High concentrations of AT III in cerebrospinal fluid reflected the magnitude of blood-brain barrier leakage and because of this, AT III should not be used as a biomarker in clinical practiceTiivistelmä Tutkimuksessa arvioitiin osaa yleisimmän pahanlaatuisen imukudossyövän eli lymfooman, diffuusin suurisoluisen B-solulymfooman, hoidon haasteista. Osa potilaista saa ensilinjan hoidon jälkeen joko paikallisen tai aivoston alueen taudin uusiutuman. Uusiutuneen taudin hoito on haasteellista, ja hoitoyrityksistä huolimatta osa potilaista kuolee tautiinsa. Solunsalpaajille resistentti tauti on myös yksi haastavista hoitotilanteista, ja osa potilaista kärsiikin hoitojen läpi etenevästä taudista. Antioksidatiivisia entsyymejä, kuten peroksiredoksiineja ja tioredoksiinia, arvioitiin ennusteellisina ja ennakoivina merkkiaineina diffuusissa suurisoluisessa B-solulymfoomassa. Peroksiredoksiini VI:n korkea sytosolinen ilmaantuvuus korreloi tavallista huonompaan diffuusin suurisoluisen B-solulymfooman ennusteeseen. Tioredoksiinin hiljentäminen lymfoomasoluviljelyssä paljasti sen mahdollisen ennakoivan merkityksen hoitoon liittyvässä päätöksenteossa. Solut herkistyivät tiodredoksiinin hiljentämisen vuoksi doksorubisiinille, jota käytetään laajalti diffuusin suurisoluisen B-solulymfooman solunsalpaajahoidoissa. Etoposidi, joka on huomattavasti myrkyllisempi solunsalpaaja, päinvastoin tappoi enemmän tavallisia diffuusia suurisoluisia B-solulymfoomaa edustavia soluja kuin doksorubisiini. Potilaat, joilla oli korkea tioredoksiinin määrä taudin diagnostisessa vaiheessa, hyötyivät etoposidia sisältävästä korkea-annoshoidosta sekä autologisesta kantasolusiirrosta. Näille potilaille ei kehittynyt kantasolusiirron jälkeisiä taudin uusiutumia kuin taas niitä kehittyi potilaille, joilla oli tioredoksiini negatiivinen. Antitrombiini III:a on ehdotettu soveltuvaksi aikaisempien tutkimusten perusteella aivoston lymfooman merkkiaineeksi aivo-selkäydinnesteestä. Tässä tutkimuksessa antitrombiini III:n määrää mitattiin potilailta, joilla oli aivoston lymfooma tai neurologinen sairaus. Korkeat konsentraatiot antitrombiini III:a aivo-selkäydinnesteessä kuitenkin vain heijastivat veri-aivoesteen vuotamisen määrää, ja näin ollen antitrombiini III:a ei tulisi käyttää kliinisessä käytössä
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Al-Horani, Rami. "Designing Direct and Indirect Factor Xa Inhibitors." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/329.
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Anticoagulants are the basis for treatment and prevention of thrombotic diseases. The currently available medicines are associated with a wide range of adverse reactions that mandates developing new anticoagulants. Several lines of evidence support the superiority of factor Xa (FXa) as a promising target to develop novel anticoagulants. This work focuses on the design of direct and indirect FXa inhibitors using an interdisciplinary approach. As indirect FXa inhibitors, a focused library of tetrasulfated N–arylacyl tetrahydroisoquinoline (THIQ) nonsaccharide allosteric antithrombin activators was designed, synthesized, and biochemically evaluated to establish their structure–activity relationship (SAR). An N–arylacyl THIQ analog having carboxylate at position–3, two sulfate groups at positions–5 and –8 of THIQ moiety, butanoyl linker, and two sulfate groups at positions–2 and –5 of the phenolic monocyclic moiety was identified as the most promising nonsaccharide antithrombin activator with KD of 1322 ± 237 μM and acceleration potential of 80–fold. Its biochemical profile indicates a strong possibility that it activates antithrombin by the pre–equilibrium pathway rather than the induced–fit mechanism utilized by heparin analogs. A similar interdisciplinary approach was exploited to design direct FXa inhibitors that possess high selectivity and are potentially orally bioavailable. Structurally, the designed direct FXa inhibitors are neutral THIQ dicarboxamides. THIQ dicarboxamide is a privileged structure with a semi–rigid character, a structural feature that potentially offers high selectivity for targeting FXa over other coagulation and digestive proteases. It can also be thought of as an amino acid–like structure, which affords accessibility to a large number of compounds using well established peptide chemistry. Mechanistically, the designed inhibitors were expected to bind to FXa in the active site and function as orthosteric inhibitors. These direct FXa active site inhibitors are also likely to inhibit clot–bound enzyme. Nearly 60 THIQ dicarboxamides were synthesized and biochemically evaluated. Through detailed SAR analysis, the most potent analog was designed and found to exhibit an IC50 of 270 nM (Ki = 135 nM), an improvement of more than 207–fold over the first inhibitor synthesized in the study. The most potent inhibitor displayed at least 1887–fold selectivity for FXa over other coagulation enzymes and a selectivity index of at least 279–fold over the digestive serine proteases. This analog doubled plasma clotting times at 17–20 μM, which are comparable to those of agents being currently studied in clinical trials. Overall, allosteric and orthosteric approaches led to the design of indirect and direct small molecule inhibitors of FXa based on the THIQ scaffold. This work introduces two promising molecules, a tetrasulfated N–arylacyl THIQ analog as a heparin mimetic and a neutral THIQ dicarboxamide as a potent, selective, and potentially bioavailable peptidomimetic, for further advanced medicinal chemistry studies.
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Fatah, Kamaran Tahir. "Studies on fibrin gel structure /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980608fata.
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Vidaud, Dominique. "Pathologie des inhibiteurs des sérines protéases (serpines) : Etude moléculaire d'un cas d'alpha1-antitrypsine Pittsburgh et de plusieurs déficits en antithrombine III." Paris 13, 1991. http://www.theses.fr/1991PA132003.
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L'utilisation des techniques récentes de biologie moléculaire et plus particulièrement l'amplification génique par pcr (polymerase chain reaction) nous a conduits à identifier les anomalies moléculaires en cause dans un cas d'alpha1-antitrypsine Pittsburgh chez un patient sans antécédent hémorragique et dans plusieurs déficits en antithrombine III. Pour ces derniers, la connaissance des mutations couplée à l'analyse protéique nous a permis d'apporter de nouvelles données concernant le site de fixation de l'héparine (antithrombine III Genève) et de mettre en évidence un premier cas de double hétérozygotie (antithrombine III Marseille). Par ailleurs, la caractérisation de 7 nouvelles mutations dans des déficits de type i nous a permis de confirmer, d'une part le rôle important joué par la partie c-terminale dans l'expression, la sécrétion et/ou la stabilité de la protéine, et d'une part, la grande hétérogénéité des défauts moleculaires en cause
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Forest, Alain. "Deficit congenital en antithrombine iii : a propos d'une observation familiale." Saint-Etienne, 1989. http://www.theses.fr/1989STET6221.
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Fazavana, Judicaël. "Développement d'une antithrombine modifiée inactive comme antidote des anticoagulants hépariniques." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00976551.
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Les héparines regroupant les héparines standards (HNF), les héparines de bas poids moléculaire(HBPM), et le fondaparinux, sont des médicaments anticoagulants. Ils potentialisent l'antithrombine (AT) : un inhibiteur physiologique de la coagulation. Leur utilisation en thérapeutique est associée à un risque hémorragique majeur. Actuellement, le sulfate de protamine est le seul antidote disponible vis-à-vis des HNF. Il est partiellement efficace vis-à-vis des HBPM, et n'a aucun effet contre le fondaparinux, qui n'a pas d'antidote jusqu'à présent. C'est dans ce contexte que nous proposons des AT modifiées inactives, mais capables de se lier aux molécules d'héparines. Ces AT déplaceraient les molécules d'héparines de l'AT plasmatique, et neutraliseraient leur effet anticoagulant. Pour produire de telles AT, nous avons choisi une approche recombinante et une approche chimique. Dans la première approche, nous avons exprimé le variant AT-N135Q-Pro394. Ce variant possède une activité anti-Xa ou anti-IIa inférieure à 0,02% en présence de dérivés hépariniques, et une affinité à l'héparine 3 fois meilleure, comparée à l'AT plasmatique. En revanche, dans l'approche chimique, nous avons modifié l'AT plasmatique par la 2,3-butanedione (AT-BD), un réactif chimique de caractérisation des arginines. Contrairement au variant, cette AT-BD a une perte d'activité anticoagulante modérée, puis une affinité à l'héparine 20 fois meilleure, comparée à l'AT plasmatique. Malgré ces différences de propriétés biochimiques, ces 2 AT modifiées neutralisent d'une façon similaire les héparines in vitro et sur un modèle murin. Par ailleurs, à l'inverse du sulfate de protamine, nos antidotes n'ont pas d'activité anticoagulante propre sur un test de céphaline activée. Ainsi, ce travail de thèse a permis non seulement de proposer les premiers et les seuls antidotes spécifiques au fondaparinux décrits, mais aussi des antidotes alternatifs pour tous les anticoagulants hépariniques.
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Mauray, Sandrine. "Activités anticoagulante et antithrombotique de polysaccharides sulfatés." Paris 13, 1995. http://www.theses.fr/1995PA132026.
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Les fucanes sont des polysaccharides sulfatés extraits d'algues brunes et doués d'activité anticoagulante. Les carboxymethyl dextrane benzylamide sulfonates (cmdbs), polysaccharides synthétiques également pourvus d'une activité anticoagulante sont préparés à partir de dextrane par substitution statistique de fonctions hydroxyles par des fonctions chimiques carboxymethyles, benzylamides, sulfonates et sulfates. L'activité anticoagulante des fucanes et des cmdbs dépend de leur composition chimique, notamment du taux de groupements sulfates, et de leur masse molaire. Ces composes catalysent préférentiellement la réaction d'inhibition de la thrombine par le second cofacteur de l'héparine, mais aussi par l'antithrombine. Le but de ce travail a été d'étudier les mécanismes d'action impliques dans l'activité anticoagulante de ces deux polysaccharides, comparés aux héparines. Des tests de génération de thrombine ont été réalisés en plasma humain en présence de fucane et de cmdbs. Une inhibition de la génération de thrombine est obtenue après activation de la phase contact en présence des deux polysaccharides, avec une phase de latence prolongée précédant la génération de thrombine, par rapport au témoin. La génération de thrombine obtenue après activation par le facteur tissulaire, est inhibée par le fucane et les cmdbs, avec un allongement de la phase de latence uniquement en présence de cmdbs. L'étude cinétique des réactions d'inhibition des facteurs ixa et xa par l'antithrombine a permis de mettre en évidence un effet catalytique faible de ces composes par rapport aux héparines. La détermination des constantes de dissociation des complexes du fucane ou du cmdbs avec chaque protéine (enzyme ou inhibiteur), associée à l'utilisation d'un modèle cinétique permet d'émettre l'hypothèse de la formation d'un complexe préalable du fucane avec l'inhibiteur, avant la formation du complexe stable enzyme-inhibiteur. Le cmdbs formerait un complexe préalable avec l'enzyme. L'activité antithrombotique du fucane a été mise en évidence dans un modèle de thrombose veineuse de type Wessler chez le lapin. Une dose vingt fois plus importante de fucane que d'héparine est nécessaire pour obtenir le même effet antithrombotique, mais l'effet du fucane est plus prolongé