Orientador: Cláudio Chrysostomo Werneck / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T04:57:03Z (GMT). No. of bitstreams: 1 Nery-Diez_AnaClaudiaCoelho_D.pdf: 21192177 bytes, checksum: 572bd54be1e7496c1fd325e94812ecc1 (MD5) Previous issue date: 2013 / Resumo: As mutações no gene da fibrilina-1, presente na fibra elástica, estão relacionadas à síndrome de Marfan, doença genética autossômica dominante. Acredita-se que a maioria dos seus sintomas esteja relacionada a uma hiper-ativação do fator TGF-?. Quando camundongos modelo para síndrome são tratados com losartan apresentam uma melhora significativa nos sinais clínicos. Assim, neste estudo, investigamos o papel de fibrilina-1 na análise de trombose arterial em modelos de camundongos para a síndrome de Marfan (Fbn1mg?/+). Foram analisados a formação de trombos, os níveis de plaquetas, APTT, PT e TT, agregação e adesão plaquetária, parâmetros hemodinâmicos, níveis de TGF-?, atividade das MMPs, bem como a morfologia das plaquetas, das fibras elásticas e dos trombos. Foi observado que os animais Fbn1mg?/+ necessitam de cerca de 120±21,07 minutos para formarem o trombo, enquanto os animais selvagens precisam de 58±7,16 minutos. Mas, quando os animais Fbn1mg?/+ foram tratados com anti-hipertensivos losartan e captopril, ocorreu uma recuperação no tempo de formação do trombo, com redução de 57,5% e 67,5% no tempo, respectivamente. Além disso, constatou-se que os animais Fbn1mg?/+ apresentam um aumento na atividade das MMPs e TGF-? ativos, quando tratados com os anti-hipertensivos, houve uma diminuição apenas na atividade das MMPs. Ademais, não foi verificada diferença significativa entre todos os outros parâmetros analisados. Este estudo sugere que, de alguma forma, as drogas interferem na remodelação da matriz elástica, devido a uma diminuição da atividade das metaloproteinases de matriz e, consequentemente, leva á recuperação na formação do trombo / Abstract: Recent works show that an increased activation of the TGF-? is associated with most of the symptoms of the Marfan syndrome. Studies using mouse models of Marfan treated with losartan have been shown to prevent the degradation of the elastic matrix. Other investigators suggest that the metalloproteinases and the noncanonical ERK signaling are involved in the breakdown of the elastic fiber, which results in the aneurysm. In this study we investigated the role of fibrillin-1 in the arterial thrombosis model using mouse models of Marfan. We analyzed thrombus formation, platelet levels, APTT, PT and TT time, hemodynamic parameter, TGF-? levels, MMP activity as well as platelets, elastic fibers morphology and thrombus. This study demonstrated that Fbn1mg?/+ mice take about 120±21,07 minutes for the thrombus to be formed when compared with wild type, 58±7,16. When these Fbn1mg?/+ mice were treated with antihypertensive losartan and captopril the time taken for the thrombus formation was reduced in 57,5% and 67,5%, respectively. The activity of metalloproteinases and activity TGF-? was increased in the Fbn1mg?/+, however no significant difference between the hemodynamic parameters, levels of totals TGF-?, morphological platelets, elastic fiber and thrombus were observed. Finally, the results suggested that fibrillin-1 interferes with this process and antihypertensive affect the physiology of Fbn1mg?/+ mice. This study suggested that somehow drugs interfere with elastic matrix remodeling due to a decrease in the activity of matrix metalloproteinases which results in the recovery time of thrombus formation / Doutorado / Bioquimica / Doutora em Biologia Funcional e Molecular

Objectifs: Malgré beaucoup de progrès dans la gestion médico-électrique, certains problèmes demeurent et plusieurs patients souffrant d'insuffisance cardiaque sont encore dans l'impasse. Ainsi, les dispositifs d'assistance ventriculaire gauche (LVAD) ont été développés pour réduire les conséquences de l'insuffisance cardiaque et améliorer la qualité de vie. Malgré les avantages évidents, plusieurs complications : thrombo-embolie, infection dû au câble d'alimentation externe, dépendance aux batteries demeurent. L'ICOMS est un nouveau concept de LVAD mélangeant une pompe entièrement intraventriculaire, synchronisé avec le cœur et relié à une batterie interne. Méthodes et résultats : L'intervalle de fonctionnement prévu est un débit de 0.8 to 6.7 10-5 m3/s à une vitesse de rotation de 733 to 942 rad/s, avec des pressions physiologiques. Le point de fonctionnement choisi pour la conception est un débit de 3.3 10-5 m3/s et 10.6 103 Pa . Dans cette étude, Une simulation numérique est réalisée avec des profils de lames différents pour chaque région de fluide étudié. Les performances telles que l'efficacité, la contrainte de cisaillement sont analysée pour vérifier l'efficacité pour les patients atteints d'insuffisance cardiaque. Afin d'obtenir le meilleur résultat avec le logiciel ANSYS, le modèle k-ε turbulent a été appliquée pour obtenir des caractéristiques d'écoulement entre l'entrée et à la sortie de l'évacuateur du redresseur de la pompe. Les résultats numériques montrent une performance acceptable pour les adultes pour délivrer des pressions physiologiques avec une efficacité hydraulique de 10 à 37% ainsi qu'un niveau acceptable de stress de cisaillement maximale le long de la surface de la partie mobile de la pompe. La deuxième partie de l'étude est une étude expérimentale où un prototype a été testé sur banc d'essai. Les résultats ont montré que la pompe pourrait fonctionner et améliorer le débit cardiaque de 1.7 à 6.7 10-5 m3/s. Les résultats in vitro convergent vers les résultats numériques. Pour les tests in vivo, 6 moutons ont été opérés pour l'implantation du LVAD. L'ICOMS a été implanté dans l'apex du ventricule gauche. Plusieurs paramètres hémodynamiques et échocardiographiques ont été stockés dans des conditions normales ou pathologiques. Conclusion: Nous avons montré que l'ICOMS pourrait présenter un effet potentiel pour réduire les conséquences de l'insuffisance cardiaque. De nouvelles expérimentations sont nécessaires pour confirmer notre résultat et optimiser ce nouveau LVAD / Objectives: Despite much progress in medical-electrical management, some problems remain and several heart failure patients are still in a no option solution. In this way, artificial hearts as Left Ventricular Assist Device (LVAD) have been developed. Despite evident benefits, several complications as thromboembolism, driveline infection, batteries dependency remain. ICOMS is a new LVAD concept mixing a fully intraventricular pump, heat rate-synchronized and connected with intracorporeal batteries. Methods and Results : It is expected to deliver 0.8 to 6.7 10-5 m3/s at rotational speeds of 733 to 942 rad/s over physiologic pressures and has a selected design point of 3.3 10-5 m3/s and 10.6 103 Pa . In this study, the axial blood pump with motor connected to impeller has been selected to numerical simulation. This selection is based on axial flow pump with different blade profile for each fluid region and studied on its performance such as efficiency, wall shear stress and considering effective operation for cardiac failure patients. In order to achieve the best result with the ANSYS software, k-ε turbulent model has been applied to obtain the flow characteristics from inducer inlet to straightener outlet of the pump. Numerical results show acceptable performance to deliver physiologic pressures with hydraulic efficiency of 10 to 37 % as well as acceptable maximum shear stress level along the blade tip surface of the impeller. The second part of the study is an experimental investigation where a prototype device was tested in a test bench circulation loop have shown that the pump could operate and improve the cardiac output of 1.7 to 6.7 10-5 m3/s. In vitro results converge to numerical results. For test vivo 6 sheep were operated for the LVAD implantation with the support of cardiopulmonary by-pass. The ICOMS was implanted into the LV apex. Several hemodynamic and echocardiographic parameters were stored as well as in normal or pathological conditions and analyzed. Conclusion: We showed that the ICOMS could present a potential effect in the LV support reducing the heart failure criteria. As evidence, further experimentations are necessary to confirm our result and to optimize this new LVAD

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 circulant / In 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.

Orientador: Joyce Maria Annichinno-Bizzacchi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T02:29:39Z (GMT). No. of bitstreams: 1 Mello_TayanaBezerraTeixeira_D.pdf: 2343820 bytes, checksum: be3d8e4b057cd84ec6771c67b8b1407d (MD5) Previous issue date: 2006 / Resumo: Nos últimos anos tem sido demonstrada uma associação entre níveis elevados de certos fatores da coagulação e risco de tromboembolismo venoso (TEV). Entretanto, o número de estudos é pequeno e a maioria estão restritos a populações caucasóides. Neste estudo caso-controle emparelhado por idade, sexo e etnia investigamos os níveis plasmáticos do fibrinogênio, FVII, FVIII, FIX, FX, FXI, FvW e grupo sanguíneo (GS) ABO no risco trombótico. Foram analisados 175 pacientes com TEV (122 mulheres e 53 homens), com idade mediana de 36 anos (13-63), acompanhados no Ambulatório de Hemostasia da Unicamp no período de julho de 2002 a julho de 2005. Na análise univariada, níveis elevados de FVIII (OR: 5,3 IC95% 2,9-9,6), FvW (OR: 4,9 IC95% 2,7-8,9), FIX (OR: 2,4 IC95% 1,3-4,4), FXI (OR: 2,1 IC95% 1,1-4,0) e GS não O (OR: 3,0 IC95% 1,9-4,6) foram fatores de risco para TEV. O FVIII, FvW e GS não O foram associados ao risco tanto em membro inferior como em sítio incomum da doença. A análise de todas estas variáveis, segundo critério de seleção ¿stepwise¿, mostrou o FVIII (OR: 3,1 IC95% 1,6-6,0), FvW (OR:2,8 IC95% 1,4-5,4) e o GS não-O (OR:2,2 IC95% 1,3-3,5) como fatores de risco independentes para TEV e que o FIX e FXI agiram sinergicamente a estas variáveis no acréscimo do risco trombótico. Risco de recorrência foi conferido por elevações do FIX (OR: 4,7 IC95% 1,8-11,9) e FXI (OR: 3,4 IC95% 1,8-8,7). Os determinantes dos níveis plasmáticos do FVIII não estão totalmente esclarecidos. Como a LRP (Low density lipoprotein receptor related protein) tem um papel no catabolismo do FVIII, foram pesquisados os polimorfimos C200T, o A775P e o D2080N no gene codificador dessa proteína, como fator de risco para TEV e a influência dos mesmos sobre os níveis do FVIII e FvW. Não houve diferença nas prevalências destes polimorfismos entre pacientes e controles. No entanto, no grupo-controle, o genótipo DN, do polimorfismo D2080N, foi associado a menores concentrações do FVIII (77,4 UI/dl) e FvW (70,2 UI/dl), quando comparado ao genótipo DD (127 UI/dl e 108,4 UI/dl, respectivamente p<0,05). Em conclusão, nesta população brasileira miscigenada, o FVIII, FvW , FIX, FXI e GS não O foram associados ao risco de TEV e o polimorfismo D2080N, no gene da LRP, interferiu com os níveis plasmáticos de FVIII e FvW / Abstract: During the last years an association between high levels of certain coagulation factors and the risk for venous thromboembolism (VTE) has been demonstrated. The number of studies, however, is small, and most of them are restricted to Caucasian populations. In this case control study, matched for age, sex and ethnicity, we investigated the plasma levels of fibrinogen, FVII, FVIII, FIX, FX, FXI, vWF and the ABO blood group (BG) in the thrombotic risk. It was analyzed 175 patients with VTE (122 women and 53 men), median age 36 years (13-63), followed at the hemostasis outpatient clinic at the State University of Campinas ¿ UNICAMP, between July 2002 and July 2005. In univariate analysis, elevated levels of FVIII (OR: 5.3 95%CI 2.9-9.6), FvW (OR: 4.9 95%CI 2.7-8.9), FIX (OR: 2.4 95%CI 1.3-4.4), FXI (OR: 2.1 95%CI 1.1-4.0) and non O BG (OR: 3.0 95%CI 1.9-4.6) were risk factors for VTE. FVIII, FvW and non O BG were associated with the risk both in lower limbs and unusual sites of disease. Analysis of all these variables by stepwise selection criteria showed FVIII (OR:3.1 95%CI 1.6-6.0), FvW (OR:2.8 95%CI 1.4-5.4) and non O BG (OR:2.2 95%CI 1.3-3.5) as independent risk factors for VTE, and FIX and FXI increased synergistically the risk of thrombosis of these variables. Risk of recurrence was conferred by FIX (OR:4.7 IC95% 1.8-11.9) and FXI (OR:3.4 IC95% 1.8-8.7). The FVIII plasma levels determinants are not well established. Since LRP (Low density lipoprotein receptor related protein) has a role in the catabolism of FVIII, we evaluated the C200T, A775P and, D2080N polymorphisms in the gene coding of this protein, as risk factor for VTE and their influence upon the levels of FVIII and vWF. There was no difference regarding the prevalence of these polymorphisms between patients and controls. However, in the control group, the DN genotype, of the D2080N polymorphism, was associated with lower concentrations of FVIII (77.4 UI/dl) and vWF (70.2 UI/dl), when compared to DD genotype (127 UI/dl e 108.4 UI/dl, respectively p<0.05). In conclusion, in these Brazilian miscigenous population, increased levels of FVIII, FvW, FIX, FXI and non O BG were associated with VTE risk and the D2080N polymorphism, in the LRP gene, influenced plasma levels of FVIII and vWF / Doutorado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Doutor em Fisiopatologia Medica

Orientador: Claudio Chrysostomo Werneck / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-24T08:25:27Z (GMT). No. of bitstreams: 1 Pereira_DanielleSousa_M.pdf: 8911447 bytes, checksum: c9bf5559a19db5c16b953e4b7a760966 (MD5) Previous issue date: 2014 / Resumo: MAGP1 (Microfibril-Associated GlycoProtein1) é um os constituintes das microfibrilas. Numerosos estudos têm demonstrado que MAGP1 interage com outras moléculas in vitro e sua expressão é de grande importância para o desenvolvimento vascular em zebrafish. Dados obtidos em nosso laboratório a partir do modelo fotoquímico de indução de trombo em animais deficientes em MAGP1 sugerem a importância deste componente da microfibrila no processo trombótico. Entre as técnicas para indução da formação de trombo, têm-se o cloreto férrico. Tal mecanismo, quando aplicado em pequenos animais, gera uma lesão endotelial de alta intensidade em apenas dois minutos. Além disso, com o auxílio da microscopia intravital, o cloreto férrico permite a captura de imagens do vaso sanguíneo em tempo real. A microscopia intravital possibilita a análise do processo de formação do trombo e as possíveis diferenças deste processo nos camundongos deficientes em MAGP1. Sendo assim, o presente trabalho objetivou estabelecer a técnica de trombose arterial induzida por cloreto férrico e assistida por microscopia intravital, a fim de verificar a função de MAGP1 no processo de formação do trombo. Para isto, as células brancas e as plaquetas de animais selvagens e deficientes em MAGP1 foram coradas com Rhodamina 6G e analisadas por microscopia intravital / Abstract: MAGP1 (Microfibril - Associated GlycoProtein1) is a constituent of the microfibrils. Numerous studies have shown that MAGP1 interact with other molecules in vitro and its expression is of importance for vascular development in zebrafish. Data obtained in our laboratory from the photochemical model of thrombus induction in animals deficient in MAGP1 suggest the importance of this component of the microfibril in the thrombotic process. Among the techniques for inducing thrombus formation, it has been ferric chloride. This mechanism when applied in small animals generates a high intensity endothelial injury in just two minutes. Furthermore, with the aid of intravital microscopy, ferric chloride enables the capture of blood vessel images in real time. The intravital microscopy allows the analysis of the process of thrombus formation and possible differences of this process in mice deficient in MAGP1. Therefore, this study aimed to establish the technique of arterial thrombosis induced by ferric chloride and assisted intravital microscopy, in order to verify the function of MAGP1 in the process of thrombus formation. For this, white cells and platelets MAGP1 deficient and wild animals were stained with Rhodamine 6G e analyzed by intravital microscopy / Mestrado / Bioquimica / Mestra em Biologia Funcional e Molecular

A trombocitopenia induzida por heparina (TIH) é uma síndrome imunohematológica mediada por um anticorpo que causa ativação plaquetária na presença de heparina, induz à agregação plaquetária e pode estar associada a graves e paradoxais complicações trombóticas e morte. A freqüência de TIH nos pacientes que recebem heparina por mais de cinco dias é de 1% a 5%, e está relacionada a vários fatores. Este é um estudo pioneiro no Brasil, que objetivou avaliar aqui a freqüência de TIH nos pacientes em uso de heparina, a relação ao gênero, ao tipo de heparina e a associação do genótipo da FcRIIa de receptores plaquetários. Foram selecionados 278 pacientes das Unidades de Terapia Intensiva e Unidades Coronariana do InCor-HCFMUSP, que receberam anticoagulação por heparina não fracionada (HNF) e/ou heparina de baixo peso molecular (HBPM), por pelo menos 5 dias, e excluídas as possíveis causas conhecidas de trombocitopenia. Foi realizada a contagem plaquetária pré e pós terapia com heparina, e o teste de detecção do anticorpo anti-fator 4 plaquetário/heparina (ID-PaGIA, DiaMed; e Asserachrom®-HPIA, Stago). O estudo da genotipagem da FcRIIa de receptores plaquetários foi realizado pelo método de digestão com enzima de restrição alelo específica. A freqüência de TIH encontrada foi de 6 (2,2%), e a freqüência de trombocitopenia com a presença do anticorpo anti-fator 4 plaquetário foi de 24,3%. A análise do gênero do paciente não demonstrou correlação com a TIH, nem com a trombocitopenia e nem com o anticorpo anti-fator 4 plaquetário. As mulheres apresentaram mais trombose do que os homens. A trombocitopenia ocorreu com maior freqüência nos pacientes que utilizaram os dois tipos de heparina (HNF-HBPM) e, com menor freqüência, nos que utilizaram apenas HBPM. O genótipo da FcRIIa de receptores plaquetários não apresentou relação com o gênero, nem com a TIH. Este estudo determinou a freqüência de TIH em uma população brasileira com uso de heparina e auxiliou no diagnostico. O melhor teste para detectar o anticorpo anti-fator 4 plaquetário/heparina, na presença de trombocitopenia e trombose, foi o teste de imunoaglutinação ID-PaGIA (DiaMed). A utilização dos dois tipos de heparina promoveu uma maior freqüência de trombocitopenia. Porém, novos estudos precisam confirmar as relações entre o tipo de heparina, com a trombocitopenia e com a TIH / Heparin induced thrombocytopenia (HIT) is an immune-hematologic syndrome mediated by a heparin dependent antibody that causes platelet activation, platelet aggregation, and can be associated with thrombosis and death. HIT occurs in about 1-5% of patients receiving heparin therapy up to 5 days or more. Many factors influence on the frequency of HIT. This is a pioneer Brazilian study to determine the frequency of HIT on patients under heparin therapy, and the relationship of HIT with gender, heparin type and the FcRIIa platelet receptor genotype. 278 patients from the Intensive Care Unit and Cardiac Care Unit at InCor-HCFMUSP treated with Unfractionated Heparin (UFH) and/or Low Molecular Weight Heparin (LMWH) for 5 or more days were studied. Known causes of thrombocytopenia were excluded. Platelet count was monitored pre and post heparin therapy. All selected patients were tested for detection of anti-heparin/PF4 antibody (ID-PaGIA, DiaMed; and Asserachrom®-HPIA, Stago). HIT frequency found was 6 (2,2%) and the frequency of thrombocytopenia (determined by a decrease in the platelet count below 50%, after the introduction of heparin therapy) and positive anti-heparin/PF4 antibody test was 24,3%. Patients gender was not related to TIH, neither to thrombocytopenia nor to the presence of antiheparin/ PF4 antibody. Thrombosis events were more frequent in women than in men. Thrombocytopenia, related to the type of heparin, was more frequent in patients that had used both types of heparin and less frequent in those that used only LMWH. FcRIIa platelet receptor genotype was associated with neither HIT nor with gender. This study has provided the frequency of HIT in a Brazilian patient population under heparin therapy and auxiliary in the HIT diagnosis. The ID-PaGIA (DiaMed) was shown to be the best test to correlate the presence of anti-heparin/PF4 antibody to thrombocytopenia and thrombosis event. The use of both heparin types promotes more thrombocytopenia. New studies are needed to confirm the relationship between heparin type and thrombocytopenia with HIT

<p>Tromboza danas, u većini razvijenih zemalja, predstavlja vodeći uzrok obolevanja i umiranja. Poslednjih godina veoma aktuelna su istraživanja venskog tromboembolizma, obzirom da je incidenca ovog oboljenja 2/1000 osoba godi&scaron;nje, a njegov razvoj posledica udruženog delovanja vi&scaron;e genetskih i stečenih faktora rizika. &Scaron;to preciznije prepoznavanje i sagledavanje &scaron;to većeg broja ovih faktora osnovni je cilj u borbi, kako protiv prve epizode venske tromboze, tako i protiv recidiva ove bolesti. Brojni faktori rizika već su prepoznati kao sastavne karike patofiziolo&scaron;kog lanca venskog trombotskog procesa, ali je evidentno da otkrića mnogih od njih tek predstoje. Među najaktulenijim istraživanjima na ovom polju nalazi se i ispitivanje uloge poremećaja fibrinoliznog mehanizma u venskoj tromboembolijskoj bolesti. Iako su već pruženi dokazi da suprimirana fibrinolizna aktivnost povećava rizik od nastanka ovog oboljenja, jo&scaron; uvek postoje brojna otvorena pitanja, koja se pre svega odnose na ulogu pojedinačnih činilaca fibrinoliznog mehanizma u venskoj trombozi, kao i na globalnu ulogu fibrinoliznog mehanizma u različitim tipovima i lokalizacijama venske trombotske bolesti. Pored toga, ispitivanje uticaja pojedinih genskih mutacija na pojadinačne činioce fibrinoliznog mehanizma, njegovu globalnu funkcionalnost i posredno na rizik za nastanak venske tromboze, takođe zaokuplja pažnju stručne javnosti, obzirom na nekonzistentnost rezultata dobijenih studijama koje se bave ovom problematikom. Cilj ovoga istraživanja je ispitivanje kako globalne funkcionalnosti fibrinoliznog mehanizma, tako i njegovih pojedinačnih činilaca, kod bolesnika sa različitim tipovima i lokalizacijama venske tromboze i poređenje ovih parametara sa njihovim vrednostima u zdravoj populaciji. Pored toga, cilj istraživanja je i ispitivanje zastupljenosti 4G/5G PAI-1 polimorfizma kod bolesnika sa venskom trombozom u poređenju sa zdravim osobama. Ispitivanu grupu je sačinjavalo 100 bolesnika koji su doživeli trombozu dubokih vena a kontrolnu grupu je činilo 100 zdravih ispitanika, koji nikada nisu imali trombozni incident. Iz ispitivanja su isključene: osobe sa prethodno dokazanim poremećajem hemostaznog mehanizma, osobe koje uzimaju lekove za koje se zna da mogu imati uticaja na hemostazni mehanizam, osobe koje su imale akutnu bolest u momentu uzorkovanja krvi ili 6 nedelja pre toga, osobe sa malignitetom, trudnice, osobe sa težim du&scaron;evnim bolestima, bolestima jetre i bubrega, autoimunim bolestima, ispitanici koji su odbili da potpi&scaron;u pristanak informisanog ispitanika. Kao test za procenu globalne funkcionalnosti fibrinoliznog mehanizma kori&scaron;teno je euglobulinsko vreme lize koaguluma, dok su od pojedinačnih činilaca određivani: tkivni aktivator plazminogena (t-PA) i trombinom aktivi&scaron;ući fibrinolizni inhibitor (TAFI) - ELISA metodom, kao i inhibitor aktivatora plazminogena-1 (PAI-1) - metodom hromogenog substrata. Genetskim ispitivanjem je utvrđivano prisustvo PAI-1 4G/5G genskog polimorfizma. Prema rezultatima istraživanja kod 56% bolesnika bila je prisutna spontana venska tromboza, dok je 44% njih imalo trombozu provociranu jednim od priznatih faktora rizika. U odnosu na lokalizaciju venskog tromboznog procesa proksimalna venska tromboza bila je prisutna kod 63% bolesnika, izolovana distalna venska tromboza kod 29% bolesnika, a atipično lokalizovana venska tromboza kod 8% bolesnika. Posmatrajući zastupljenost pojedinih faktora rizika uočili smo da je značajno vi&scaron;i procenat osoba sa hipertenzijom bio prisutan u grupi bolesnika sa primarnom trombozom dubokih vena u odnosu na grupu bolesnika sa provociranom trombozom dubokih vena (61% vs.16%; p=0.000). &Scaron;to se funkcionalnosti fibrinoliznog mehanizma tiče, prema na&scaron;im rezultatima bolesnici koji su doživeli trombozu dubokih vena imaju značajno duže vreme lize koaguluma, odnosno suprimiranu funkcionalnost fibrinolize u poređenju sa zdravim kontrolama (204.34&plusmn;51.24 vs. 185.62&plusmn;42.30; p=0.011), a kada posmatramo podgrupe bolesnika u odnosu na lokalizaciju i vrstu venske tromboze uočavamo da podgrupa bolesnika sa izolovanom distalnom venskom trombozom ima značajno duže euglobulinsko vreme lize koaguluma u odnosu na kontrolnu grupu (218.32&plusmn;41.12 vs.185.62&plusmn;42.30: p=0.001), kao i bolesnici koji su imali provociranu vensku trombozu u poređenju sa kontrolama (208.18&plusmn;48.53 vs. 185.62&plusmn;42.30; p=0.018). Ispitivanjem pojedinačnih komponenti fibrinoliznog mehanizma do&scaron;li smo do rezultata da bolesnici koji su doživeli venski trombozni incident imaju značajno vi&scaron;e koncentracije TAFI u poređenju sa osobama koje nikada nisu imale vensku trombozu (19.70 ng/ml &plusmn; 5.17 vs.17.13 ng/ml &plusmn; 4.25; p=0.001). Poređenjem bolesnika sa provociranom trombozom dubokih vena i kontrolnih ispitanika uočili smo da bolesnici iz ove podgrupe imaju značajno vi&scaron;e vrednosti plazminogena u poređenju sa zdravim osobama (127.14 % &plusmn; 27.73 vs.117.09 % &plusmn; 24.49; p= 0.044), kao i značajno vi&scaron;e koncentracije t-PA (20.02 ng/ml &plusmn; 11.07 vs. 16.78 ng/ml &plusmn; 8.08; p=0.042). &Scaron;to se tiče TAFI, bolesnici sa distalnom trombozom dubokih vena u poređenju sa kontrolama (20.72 ng/ml &plusmn; 4.96 vs.17.13 ng/ml &plusmn; 4.25; p=0.001), kao i bolesnici sa proksimalnom trombozom dubokih vena u poređenju sa kontrolama (19.37 ng/ml &plusmn; 5.33 vs.17.13 ng/ml &plusmn; 4.25; p=0.013) imaju značajno vi&scaron;e koncentracije TAFI. Koncentracija ovog inhibitora fibrinoliznog procesa značajno je veća i kod bolesnika sa provociranom trombozom dubokih vena u poređenju s zdravim osobama (19.93 ng/ml &plusmn; 3.97 vs.17.13 ng/ml &plusmn; 4.25; p=0.000), kao i kod bolesnika sa primarnom trombozom dubokih vena u poređenju sa zdravim ispitanicima (19.53 ng/ml &plusmn; 5.97 vs.17.13 ng/ml &plusmn; 4.25; p=0.023). &Scaron;to se genetskih analiza tiče, u okviru grupe bolesnika imali smo 25% homozigotnih i 58% heterozigotnih nosilaca mutacije gena za PAI-1, dok 17% bolesnika nije imalo pomenutu gensku mutaciju. U okviru kontrolne grupe pak, bilo je 30% homozigotnih i 56% heterozigotnih nosilaca mutacije a 14% ispitanika nije imalo mutaciju. Nije uočena značajna razlika u zastupljenosti 4G/4G genotipa između bolesnika sa različitim lokalizacijama venskog trombotskog procesa (distalna DVT 29% vs. proksimalna DVT 21% vs. DVT retke lokalizacije 12%; p=0.501), kao ni u zastupljenosti ovoga genotipa kod provocirane i spontane tromboze dubokih vena (27% vs. 23%; p=0.642), niti kod izolovane tromboze dubokih vena u poređenju sa plućnom tromboembolijom (25% vs. 33%; p=0.735). Procena rizika za nastanak venske tromboze u odnosu na postojanje poremećaja globalne funkcionalnosti fibrinoliznog mehanizma, u odnosu na patolo&scaron;ke koncentracije pojedinih komponenti fibrinoliznog mehanizma, kao i u odnosu na postojanje 4G/4G mutacije u genu za PAI-1, pokazala je da suprimirana funkcionalnost fibrinoliznog mehanizma trostruko povećava rizik za nastanak tromboze dubokih vena (OR 3.02; CI 1.26-7.22), povi&scaron;en nivo PAI-1 nema uticaja na rizik od nastanka tromboze dubokih vena, na &scaron;ta ukazuje OR od 0.86 sa CI 0.59-1.25, povi&scaron;en nivo t-PA antigena ne utiče na rizik od nastanka tromboze dubokih vena (OR 1.53; CI 0.79-2.94), ali povi&scaron;ena koncentracija TAFI vi&scaron;e od dvostruko povećava ovaj rizik (OR 2.25; CI 1.16-4.35). Prema na&scaron;im rezultatima PAI-1 4G/4G genotip nema uticaja na rizik od nastanaka venske tromboze, &scaron;to potvrđuje OR koji iznosi 0.57 (0.27-1.20). Na osnovu dobijenih rezultata zaključujemo da bolesnici sa trombozom dubokih vena imaju suprimiranu funkcionalnost fibrinoliznog mehanizma u poređenju sa zdravim osobama, da je nivo t-PA antigena, kao i plazminogena značajno vi&scaron;i kod bolesnika sa provociranom venskom trombozom nego kod zdravih osoba, da nema razlike u koncentraciji PAI-1 između bolesnika sa venskom trombozom i zdravih osoba, ali da bolesnici sa trombozom dubokih vena, bez obzira na njenu lokalizaciju ili vrstu imaju značajno vi&scaron;e nivoe TAFI u poređenju sa zdravim ispitanicima. Pored toga možemo zaključiti da ne postoji razlika u zastupljenosti 4G/5G polimorfizma između bolesnika sa venskom trombozom i zdravih ispitanika. Konačno, možemo reći da na osnovu na&scaron;ih rezultata možemo zaključiti da suprimirana funkcionalnost fibrinoliznog mehanizma trostruko povećava rizik od nastanka tromboze dubokih vena, a povi&scaron;en nivo TAFI-a dvostruko povećava ovaj rizik, dok 4G/5G PAI-1 polimorfizam nema uticaja na rizik za nastanak venskog tromboembolizma.</p> / <p>Thrombosis is nowadays leading cause of morbidity and mortality worldwide. Lately, studies dealing with venous thromboembolism are very actual, since incidence of this disease is 2/1000 persons per year and its development is consequence of joint action of many different inherited and acquired risk factors. Precise recognition and understanding as many of those factors as possible represents imperative in fight against the first episode of venous thrombosis, and also against the recurrence of the disease. Numerous risk factors have been already recognized as constituent links of pathophysiological chain of venous thrombotic process, but it is also clear that the discovery of many of them are yet to come. Investigations of the role of fibrinolytic mechanism disorders in venous thrombosis are topical in the field. Although, we have some evidences that suppressed fibrinolytic activity increases the risk of this disease, still there are many open issues, especially those dealing with the role of individual factors of fibrinolytic mechanism in venous thrombosis, and with the role of global fibrinolytic function in different types and localizations of venous thrombotic disease. Further, investigation of the effects of gene mutations on individual fibrinolytic mechanism components, its global functionality and indirectly to the risk of venous thrombosis, also attracts the attention of experts, given the inconsistency of results obtained from studies dealing with this issue. The aim of this study was to evaluate fibrinolytic mechanism global functionality, as well as functionality of its integral individual components in patients with different venous thrombosis types and localizations, and to compare them with those of the healthy persons. In addition, the aim was to evaluate presence of 4G/5G PAI-1 polymorphism in patients with venous thrombosis compared with healthy subjects. The case group consisted of 100 patients with deep vein thrombosis and the control group consisted of 100 healthy subjects who had never had thrombotic incident. Exclusion criteria were: documented haemostatic disease, taking drugs proven to affect fibrinolytic function, acute illness within 6 weeks before blood sampling, malignancy, pregnancy, severe mental illness, kidney or liver diseases, autoimmune diseases, examinee refusal to sign the informed consent. We used euglobulin cloth lysis time test as test for global fibrinolytic mechanism function estimation, and also determined: t-PA and TAFI concentrations using ELISA method and PAI-1 concentrations using chromogenic substrate method. The presence of PAI-1 4G/5G gene polymorphism was determined by genetic testing. According to results 56% of patients had unprovoked and 44% had provoked venous thrombosis. Proximal venous thrombosis was present in 63% of cases, distal venous thrombosis in 29% of cases and atypical venous thrombosis in 8% of them. Significantly higher frequency of hypertension was present in patients with primary deep vein thrombosis than in the group of patients with provoked deep vein thrombosis (61% vs. 16%, p = 0.000). Patients who have experienced deep vein thrombosis had a significantly longer clot lysis time, and suppressed fibrinolysis function compared with healthy controls (204.34 &plusmn; 51.24 vs. 185.62 &plusmn; 42.30, p = 0.011). Also, this parameter was significantly longer in patients with isolated distal deep vein thrombosis compared with healthy controls (218.32&plusmn;41.12 vs. 185.62&plusmn;42.30: p=0.001), such as in patients with provoked venous thrombosis compared with controls (208.18&plusmn;48.53 vs. 185.62&plusmn;42.30; p=0.018). Patients with venous thrombosis had significantly higher TAFI concentrations in comparison with healthy volunteers (19.70 ng/ml &plusmn; 5.17 vs. 17.13 ng/ml &plusmn; 4.25; p=0.001). Patients with provoked venous thrombosis had significantly higher concentrations of plasminogen (127.14 % &plusmn; 27.73 vs. 117.09 % &plusmn; 24.49; p= 0.044) and t-PA (20.02 ng/ml &plusmn; 11.07 vs. 16.78 ng/ml &plusmn; 8.08; p=0.042), in comparison with controls. Regarding TAFI, we noticed that patients with isolated distal deep vein thrombosis have higher values of this parameter compered with healthy people (20.72 ng/ml &plusmn; 4.96 vs. 17.13 ng/ml &plusmn; 4.25; p=0.001), such as patients with proximal deep vein thrombosis (19.37 ng/ml &plusmn; 5.33 vs. 17.13 ng/ml &plusmn; 4.25; p=0.013). The same was obtained when compared patients with provoked venous thrombosis and controls (19.93 ng/ml &plusmn; 3.97 vs. 17.13 ng/ml &plusmn; 4.25; p=0.000), and patients with unprovoked venous thrombosis and controls (19.53 ng/ml &plusmn; 5.97 vs. 17.13 ng/ml &plusmn; 4.25; p=0.023). As far as genetic analysis, in the group of patients we had 25% homozygous and 58% heterozygous carriers of PAI-1 gene mutation, whereas 17% of patients did&#39;t have this mutation. In controls, we had 30% homozygous and 56% heterozygous carriers of mutation and 14% of those without mutation. There was no significant difference in the frequency of 4G/4G genotype between patients with different localization of venous thrombotic process (distal DVT 29% vs. proximal DVT 21% vs. rare localization DVT 12%, p = 0.501), as well as the representation of this genotype in provoked and unprovoked deep vein thrombosis (27% vs. 23%, p = 0.642), or in isolated deep vein thrombosis compared to pulmonary thromboembolism (25% vs. 33%, p = 0.735). Finaly, our results show that suppressed fibrinolytic functionality threefold increases risk of venous thrombosis (OR 3.02, CI 1.26-7.22), elevated levels of PAI-1 have no effect on the risk of deep vein thrombosis, as evidenced by OR of 0.86 with CI 0.59-1.25, elevated levels of t-PA antigen do not affect the risk of deep venous thrombosis (OR 1.53; CI 0.79-2.94), but increased concentration of TAFI increases more than twice this risk (OR 2.25; CI 1.16-4.35). PAI-1 4G/4G genotype does not affect venous thrombotic risk (OR 0.57; CI 0.27-1.20). Based on these results, we conclude that patients with deep vein thrombosis have suppressed fibrinolytic mechanism functionality compared to healthy subjects, the levels of t-PA antigen and plasminogen are significantly higher in patients with provoked venous thrombosis than in healthy subjects, there is no difference in PAI-1 concentration in patients with venous thrombosis and healthy persons, but the patients with deep vein thrombosis, regardless of its localisation or the type have a significantly higher level of TAFI as compared with healthy subjects. In addition, we can conclude that there is no difference in the prevalence of 4G/5G polymorphism in patients with venous thrombosis and healthy persons. Finally, we can say that suppressed fibrinolytic mechanism functionality threefold increases risk of deep vein thrombosis, elevated level of TAFI-a double increases this risk, while PAI-1 4G/5G polymorphism has no influence on the risk of venous thromboembolism.</p>

Orientador: Carmen Maria Casquel Monti Juliani / Resumo: Objetivos: caracterizar o risco de tromboembolismo venoso e o uso de profilaxia em pacientes clínicos e cirúrgicos, avaliando a conformidade ou não-conformidade da prescrição de profilaxia medicamentosa e desvelar a percepção dos enfermeiros frente ao uso do protocolo de profilaxia de tromboembolismo venoso. Métodos: Estudo descritivo, com abordagem multimétodos ou método misto, utilizando técnicas quantitativas (estudo transversal) e qualitativas (fenomenologia), com a finalidade de realizar a interação entre os métodos, fornecendo melhores possibilidades analíticas. Resultados: A taxa global de profilaxia de tromboembolismo venoso foi 70% e os pacientes clínicos apresentaram maior conformidade de prescrição de profilaxia em relação ao protocolo e a quantidade de fatores de risco/pacientes foi maior em pacientes clínicos em relação aos cirúrgicos. Os enfermeiros costumam preencher o protocolo no momento da admissão do paciente e, quando não conseguem, informam a necessidade durante passagem do plantão. Há um consenso entre os enfermeiros que médicos fixos nos setores prescrevem mais adequadamente a medicação profilática em relação aos rotativos. Conclusão: Para que todos os usuários se beneficiem da profilaxia, é necessária educação permanente/continuada associada a estratégias para envolvimento da equipe multiprofissional, além de divulgação maciça do protocolo de profilaxia de tromboembolismo venoso, a fim de diminuir as lacunas do conhecimento e instrumentalizar as equipe... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Objectives: To characterize the risk of venous thromboembolism and the use of prophylaxis in clinical and surgical patients, to evaluate a measure or non-compliance of prescribing medication prophylaxis and to develop nurses' perceptions regarding the use of venous prophylaxis protocol. Methods: Descriptive study with a multimedia approach or method, using quantitative (cross-sectional) and qualitative (phenomenology) techniques, using an interaction between methods, providing better analytical alternatives. Results: An overall rate of venous thromboembolism prophylaxis was 70% and clinical patients with a higher prevalence of prophylaxis prescription compared to the protocol and a number of risk factors / patients were the highest in clinical patients compared to physicians. Nurses usually complete the protocol at the time of patient admission and, when unable to do so, provide the necessary information during the passage of planting. There is a consensus among nurses that doctors fix in the prescribed sectors more that use prophylactic medication in relation to rotary ones. Conclusion: For all users who benefit from prophylaxis, it is mandatory / continued associated with multiprofessional team participation strategies, in addition to the massive dissemination of venous thromboembolism prophylaxis protocol, an end of loss as knowledge gaps and to instrumentalize as teams with the specific practice in using. / Doutor

Introduction et buts de la thèse<p>La survie du patient et du greffon se sont nettement améliorées depuis les débuts de la transplantation rénale. Les recommandations de pratiques cliniques basées sur l’évidence aident les cliniciens à améliorer la prise en charge standardisée des patients. Cependant, de nombreux programmes de recherche sont actuellement axés sur la découverte de biomarqueurs qui peuvent prédire les différents résultats chez les patients transplantés rénaux. Ces biomarqueurs sont nécessaires pour personnaliser la gestion et le traitement des patients.<p>Le but des travaux résumés dans cette thèse est d'évaluer l'impact potentiel de plusieurs facteurs biologiques acquis et génétiques spécifiques sur les résultats après la transplantation rénale, en particulier les facteurs de thrombophilie et les polymorphismes génétiques associés au diabète post-transplantation.<p>1. Facteurs de thrombophilie<p>Les patients en insuffisance rénale terminale présentent des anomalies complexes de la coagulation, dont les mécanismes sous-jacents ne sont pas connus à ce jour. La thrombose des vaisseaux du greffon et les événements thromboemboliques comme la thrombose veineuse profonde et / ou l’embolie pulmonaire sont des complications graves, mais relativement rares après transplantation rénale. Au cours de la dernière décennie, plusieurs études ont évalué l'impact des facteurs de thrombophilie sur les résultats après la transplantation rénale, tels que les événements thrombo-emboliques, y compris la thrombose de l’artère ou la veine du greffon, le rejet aigu, les événements cardiovasculaires ou la survie du greffon. Cependant, les limitations méthodologiques et l'hétérogénéité de ces études rendent les conclusions ou les recommandations difficiles. D’autre part, la prévalence exacte des facteurs de thrombophilie dans la population de patients en insuffisance rénale terminale et la correction éventuelle de ces facteurs après transplantation ne sont pas connues. Dans ce contexte, nous avons réalisé une étude prospective afin d’évaluer l’impact d’un panel de 11 facteurs de thrombophilie testés le jour de la transplantation et 1 mois plus tard, sur les événements thrombo-emboliques et le rejet aigu durant la première année de greffe [58]. Nous avons également évalué la prévalence de 7 facteurs de thrombophilie non-génétiques chez les patients en insuffisance rénale terminale et le taux de correction après la transplantation rénale dans une cohorte de 215 patients [59]. <p>2. Diabète post-transplantation<p>Le diabète post-transplantation est une complication métabolique grave et fréquente après la transplantation. Les patients transplantés rénaux souffrant d’un diabète post-transplantation ont un risque plus élevé d'événements cardiovasculaires majeurs, de décès et d’échec de greffe. Une étude prospective rapporte une incidence de 20,5% durant les six premiers mois de greffe rénale, en utilisant les critères stricts de l'ADA (American Diabetes Association). La plupart des facteurs de risque identifiés sont communs avec le diabète de type 2 dans la population générale: l'âge, les antécédents familiaux, l’ethnie (africaine et hispanique), l'indice de masse corporelle élevé, une sérologie hépatite C positive et la présence d’un syndrome métabolique. Certains traitements immunosuppresseurs sont des facteurs de risque de diabète post-transplantation spécifiques et modifiables. Les inhibiteurs de la calcineurine sont diabétogènes et il a été clairement montré que le tacrolimus est plus diabétogène que la cyclosporine. En se basant sur ces données, nous avons remplacé le tacrolimus par la cyclosporine chez une série de patients ayant développé un diabète post-transplantation sous tacrolimus. Nous avons évalué rétrospectivement l’efficacité et la sécurité de cette approche [60]. Nous avons également élaboré des recommandations pour la prise en charge du diabète post-transplantation sur base de notre expérience et des études publiées [62]. <p>La susceptibilité génétique du diabète post-transplantation a été étudiée par des approches «gènes candidats », mais les faibles effectifs et l'absence de réplication dans des cohortes indépendantes rendent les conclusions difficiles. Les études pan-génomiques de type « genome wide association study (GWAS) apportent un éclairage neuf sur les origines génétiques du diabète de type 2. Plus de 10 loci de susceptibilité ont été associés au diabète de type 2 dans la population générale, avec des odds ratio (OR) allant de 1.10 à 1.20, excepté un variant commun du gène TCF7L2 pour lequel le risque de la maladie augmente de 37% par allèle à risque. Nous avons utilisé une approche gène candidat en sélectionnant 11 variants génétiques associés au diabète de type 2 à travers ces GWAS et nous avons évalué leur association avec le risque de diabète post-transplantation durant les 6 premiers mois post-transplantation, dans une large cohorte de Caucasiens (N = 1076) [61].<p>Méthodologie générale<p>L’unité de transplantation rénale de l'Hôpital Erasme (Université Libre de Bruxelles) a créé une base de données clinique incluant les patients transplantés depuis 1964 dans l'institution et une biocollection (ADN et sérum) depuis 2001. En outre, depuis 2007, l'unité de transplantation rénale de l'Hôpital Erasme a développé une collaboration avec d'autres centres européens de transplantation rénale (CHU de Tours, CHU de Limoges, CHU de Brest, CHU de Saint-Étienne, CHRU de Lille, CHU de Poitiers et CHU de Bordeaux actuellement). Nous avons actuellement collecté les données cliniques et l’ADN de plus de 4000 receveurs d'allogreffe rénale.<p>Résultats<p>1. Facteurs de thrombophilie<p>Nous avons enrôlé prospectivement 320 greffes rénales consécutives correspondant à 317 patients greffés dans notre institution entre 2001 et 2006. Onze facteurs de thrombophilie ont étés dosés le jour de la transplantation. Dix patients ont étés exclus en raison de valeurs manquantes pour plus de 3 facteurs. Tous nos patients ont reçu de l’acide acétylsalicylique en prophylaxie, débuté juste avant la greffe. Le taux d'événements thromboemboliques et/ou de rejet aigu durant la première année post-transplantation (critère d’évaluation primaire composite) était de 16,7% chez les patients sans facteur de thrombophilie (N = 60) et de 17,2% chez ceux ayant au moins un facteur de thrombophilie (N = 250) (P=NS) le jour de la greffe. L'incidence du critère d’évaluation primaire était similaire chez les patients sans facteur de thrombophilie et ceux avec au moins deux (N = 135), ou au moins trois (n = 53) facteurs (16,3% et 15,1% respectivement, P=NS) et chez les patients avec au moins un facteur persistant 1 mois après la greffe (15,7%, P=NS). Aucun des facteurs de thrombophilie individuels présents le jour de la transplantation n’était associé au critère d’évaluation primaire. L'incidence des événements cardio-vasculaires à 1 an, la créatinine sérique à 1 an, la survie de greffe actuarielle à 4 ans n’étaient pas influencés par la présence d’au moins un facteur de thrombophilie le jour de la greffe (P= NS).<p>La prévalence des facteurs de thrombophilie était significativement plus élevée chez les patients dialysés que chez les patients non encore dialysés le jour de la greffe (74% vs 52,4%, P =0,03). La prévalence était similaire chez les patients hémodialysés et en dialyse péritonéale (P=NS). Un mois après la transplantation, la prévalence globale des facteurs de thrombophilie a chuté de 74,4% à 44,7% (P <0,001). La plupart des facteurs de thrombophilie avaient disparus après la transplantation. <p>2. Le diabète post-transplantation<p>Nous avons analysé rétrospectivement les paramètres du métabolisme glucidique chez 54 patients greffés rénaux traités par tacrolimus et développant un diabète post-transplantation. Trente-quatre patients ont été convertis à la cyclosporine alors que 20 patients ont poursuivi le tacrolimus (groupe contrôle). Après la conversion, le taux de rémission du diabète post-transplantation était de 42% (IC 95% :24-59%) 1 an après la conversion versus 0% dans le groupe contrôle (P=0,001). La conversion<p>était sûre en termes de fonction du greffon, de rejet aigu, de survie des patients et du greffon.<p>Dans notre étude multicentrique (Hôpital Erasme-Bruxelles, CHU de Tours, CHU de Limoges et CHRU de Lille), nous avons enrôlé 1477 patients greffés successivement. Parmi les 1229 patients éligibles pour l’étude, 1076 étaient Caucasiens (analyses primaires). Un total de 118 patients, soit 11% des Caucasiens ont développé un diabète post-transplantation durant les 6 premiers mois de greffe. En analyse multi-variée, le variant rs7903146 de TCF7L2 était indépendamment associé au diabète post-transplantation (OR = 1,60 pour chaque allèle T, P = 0,002). Les autres facteurs de risque indépendants étaient: l'âge du receveur, l’indice de masse corporelle au moment de la greffe, l'utilisation du tacrolimus et la survenue d'un épisode de rejet aigu traité par corticoïdes.<p>Conclusions<p>Les facteurs de thrombophilie sont très fréquents au stade terminal de l'insuffisance rénale et sont corrigés dans la grande majorité après la transplantation rénale. Cela suggère que la plupart des facteurs sont acquis et associés à l'urémie et / ou la dialyse. En outre, notre étude prospective n’a pas démontré d’impact des facteurs de thrombophilie détectés de manière systématique avant la transplantation sur les résultats après transplantation rénale, dans une population recevant un régime immunosuppresseur moderne et de l’acide acétylsalicylique en prophylaxie.<p>L’effet diabétogène du tacrolimus est réversible. Nos résultats suggèrent une amélioration significative du métabolisme glucidique après la conversion à la cyclosporine chez les patients transplantés rénaux atteints de diabète post-transplantation sous tacrolimus.<p>Le diabète post-transplantation et le diabète de type 2 partagent des facteurs de risque communs, dont un variant du gène TCF7L2. La place de ce type de biomarqueur dans la prédiction de la survenue du diabète post-transplantation et dans les stratégies de modification d’immunosuppression doit faire l’objet d’évaluations prospectives.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Bakgrund: Djup ventrombos (DVT) är en allvarlig komplikation postoperativt och kan leda till ett livshotande tillstånd för patienten. Graderade kompressionsstrumpor (GCS) används på många postoperativa avdelningar tillsammans med andra profylaktiska åtgärder för att förebygga utvecklingen av DVT. Kompressionsstrumpor används även till att förebygga posttrombotiskt syndrom (PTS) efter en DVT. PTS kan utvecklas på grund av att de venösa klaffarna skadas vid en DVT, till följd stockar sig blodet och ödem bildas vilket leder till försämrad näring- och syretillförsel till vävnaderna. Syfte: Syftet var att genom en litteraturstudie undersöka om kompressionsstrumpor hade någon effekt för att förebygga DVT postoperativt samt om kompressionsstrumpor hade någon effekt att förebygga PTS efter en DVT. Metod: Litteraturstudie som baserads på 11 RCT studier. Resultat: GCS utan andra profylaktiska åtgärder visade sig ha en god effekt för att undvika utvecklingen av DVT på patienter som genomgått en operation. Däremot visade sig användandet av GCS i kombination med andra beprövade profylax inte ha någon större effekt för att reducera uppkomsten av DVT ytterligare. Resultatet angående GCS effekt för att undvika utvecklingen av PTS visade ingen entydighet. Slutsats: GCS har en förebyggande effekt för att undvika uppkomsten av DVT. Användningen av GCS i kombination med andra profylax potentierar däremot inte effekten av preventionen för DVT. GCS verkan för att förebygga uppkomsten av PTS är inte entydigt och flera studier behövs för att se evidens kring detta. / ABSTRACT  Background: Deep vein thrombosis (DVT) is a serious complication postoperatively and can lead to a life threatening condition for the patient. Graded compression stockings (GCS) are used in many post-operative departments along with other prophylactic measures to prevent the development of DVT. Compression stockings are also used to prevent postthrombotic syndrome (PTS) after a DVT. PTS can develop because the venous valves are damaged by a DVT, as a result, the blood is stored and edema is formed, which leads to poor nutritional and oxygen supply to the tissues. Aim: The aim of the literature study was to investigate whether compression stockings had any effect in preventing DVT postoperatively, and also whether the compression stockings had any effect in preventing PTS after a DVT. Method: Literature study based on 11 RCT studies. Results: GCS without other prophylactic measures was found to have a good effect in avoiding the development of DVT in patients who underwent surgery. However, the use of GCS in combination with other proven prophylaxis was found to have no significant effect in further reducing the onset of DVT. The results regarding the GCS effect to avoid the development of PTS showed no unambiguity. Conclusion: GCS has a preventive effect to avoid the onset of DVT. However, the use of GCS in combination with other prophylaxis does not potentiate the effect of prevention for DVT. The effect of GCS in preventing the onset of PTS is not unambiguous and several studies are needed to see evidence of this.