Background: The direct factor Xa inhibitor rivaroxaban is approved for the treatment of venous thromboembolism (VTE), based on the results of large phase III trials. Objectives: To confirm rivaroxaban's effectiveness and safety in routine clinical care of patients with VTE. Methods: Data were obtained from prospective, noninterventional registries: the FIRST registry (United Kingdom), DRESDEN NOAC registry (Germany), and SWIVTER (Switzerland). Baseline characteristics of these registries and effectiveness and safety outcome rates for the FIRST and DRESDEN NOAC registries were compared. Results: A total of 1841 rivaroxaban-treated patients with acute VTE (57.9% male, 76.6% deep vein thrombosis [DVT]; 23.4% pulmonary embolism ± DVT; median age, 61 years) were included: 1217 from the FIRST registry, 418 from the DRESDEN NOAC registry, and 206 from SWIVTER. Median time between VTE diagnosis and initiation of rivaroxaban was 1.4 ± 1.81 days (25th–75th percentile 1–1; range, 0–15 days). On-treatment outcome rates for the FIRST and DRESDEN NOAC registries were 0.74 per 100 patient-years (95% confidence interval [CI], 0.35–1.54) versus 0.96 per 100 patient-years (95% CI, 0.46–2.01) for VTE recurrence; 1.16 per 100 patient years (95% CI, 0.64–2.09) versus 2.51 per 100 patient-years (95% CI, 1.58–3.98) for ISTH major bleeding and 1.69 per 100 patient-years (95% CI, 1.21–2.35) versus 1.73 per 100 patient-years (95% CI, 1.27–2.36) for all-cause mortality (intention-to-treat analysis), respectively. Conclusion: Overall treatment outcomes were consistent with the results of the phase III rivaroxaban trials in VTE treatment, indicating that the use of rivaroxaban offers acceptable treatment results also in routine care. However, we observed significant differences in patient characteristics and management patterns across Switzerland, the United Kingdom, and Germany, limiting direct comparisons of unadjusted outcome event rates between registries.

La maladie veineuse thrombombolique (MVTE), associant thrombose veineuse profonde et embolie pulmonaire, peut être le premier signe d’un cancer jusque-là méconnu. Des études anciennes ont rapporté que 6 à 15% des patients étaient diagnostiqués d’un cancer occulte dans l’année suivant l’épisode de MVTE. L'identification précoce d’un cancer occulte au moment du diagnostic de la MVTE non provoquée est fondamentale car la présence d’un cancer va conditionner la prise en charge du patient, que ce soit au niveau de la thrombose ou du cancer. Actuellement, les recommandations préconisent un dépistage limité du cancer en cas de MVTE non-provoquée, basé sur un examen clinique complet (interrogatoire, examen physique), un bilan biologique de base, une radiographie thoracique ainsi que tous les examens communément admis pour le dépistage du cancer en fonction de l’âge et du sexe du patient (PSA chez les hommes, mammographie et examen gynécologique chez les femmes). La tomographie par émission de positon (TEP) au 18F-fluorodéoxyglucose (FDG) est une technique d’imagerie en pleine expansion depuis les années 2000. Elle est largement utilisée en routine clinique pour la détection des foyers tumoraux, leur bilan d’extension, l’évaluation des traitements ainsi que le bilan de possibles récidives. En revanche, aucune étude n’a aujourd’hui évalué l’intérêt de cette technique dans le dépistage du cancer chez les patients présentant une MVTE non provoquée. Afin de répondre à cette problématique, l’objectif de cette thèse a été spécifiquement d’étudier l’intérêt de la TEP au FDG pour la détection des néoplasies dans le bilan étiologique d’une MVTE non provoquée au travers des résultats de l'étude MVTEP, étude multicentrique randomisée comprenant une stratégie de dépistage limitée associée à une TEP au FDG à une stratégie limitée seule. / Venous thromboembolism (VTE), which encompasses deep vein thrombosis and pulmonary embolism, can occur as the first manifestation of an underlying occult malignancy. Previous studies reported that the incidence of undiagnosed cancer is 6% to 15% in the year following an unprovoked VTE épisode, i.e. VTE not provoked by a major risk factor.In patients with unprovoked VTE, extensive screening for cancer has been proposed in order to diagnose occult malignancy as early as possible in the hope of improving the prognosis. Current guidelines for occult cancer screening in patients with unprovoked VTE recommend limited cancer screening, including of a thorough medical history and physical examination, basic laboratory investigations, chest X-ray, as well as age-specific and gender-specific cancer screening (colon, breast, and prostate) according to national guidelines.18F-Fluorodesoxyglucose Positron Emission Tomography combined with Computed Tomography (FDG PET/CT) is routinely used for the diagnosis and staging of various malignancies. The use of FDG PET/CT might overcome the limitations of previous extensive screening strategies as it involves whole-body imaging using a single, non-invasive test. To date, there has been no formal assessment of the additional value of FDG PET/CT for occult malignancy screening in patients with unprovoked venous thromboembolism.To address this issue, we conducted a multicenter randomised controlled trial comparing a limited screening strategy to a strategy combining limited screening and FDG PET/CT in patients with unprovoked venous thromboembolism, and then assessed the additional value of FDG PET/CT in addition to a limited strategy.

Objetivo: Avaliar o impacto de fatores de risco no desenvolvimento de eventos tromboembólicos em pacientes com lesão medular. Métodos: Estudo observacional, prospectivo e cruzado. Pacientes elegíveis (n=100) tinham lesão medular por trauma raquimedular e mais de 18 anos. O grau de lesão sensorial e motora foi avaliado com base na escala ASIA (ASIA Impairment Scale - AIS). Amostras de sangue foram coletadas para exames de coagulação, hemogramas, análises bioquímicas e laboratoriais. Exames de ultrassonografia foram realizados nos sistemas venosos superficial e profundo dos membros inferiores. Experimentos de PCR em tempo real foram realizados com o intuito de investigar mutações nos genes da protrombina (G20210A) e do fator V de Leiden (G1691A). Resultados: O principal achado deste estudo foi a maior ocorrência de Trombose Venosa Profunda (TVP) em pacientes com fator V de Leiden e hiperhomocisteinemia. Não houve associação entre Lesão Medular por TVP, Tromboembolismo Venoso (TEV) e trombofilia. Não houve também relação com lúpus anticoagulante e anti-cardiolipina. Conclusões: Houve importante diferença na incidência de TVP em pacientes com Lesão Medular, tanto aguda quanto crônica (após um ano da lesão). A investigação de trombofilia deve ter como base os fatores clínicos, fatores de risco para TVP e história familiar de trombose / Objective: Evaluate the impact of risk factors in the development of thromboembolic events in patients with spinal cord injury. Design: Observational, prospective and cross study. Eligible patients (n=100) had spinal injury (SI) by spinal cord injury (SCI), older than 18 years of age. The degree of motor and sensory lesion was evaluated based on ASIA Impairment Scale (AIS). Blood samples were collected for coagulation exams, hemogram, laboratory and biochemical analyses. Ultrasonography analyzes were performed from deep and superficial venous systems of lower limbs. Quantitative real-time PCR experiments were performed in order to investigate mutations in the prothrombin (G20210A) and Leiden factor V (G1691A) genes. Results: The main finding of this study was the higher occurrence of Deep Venous Thromboembolism (DVT) in patients with Leiden factor V and hyper homocysteinemia. There was no association between SI for DVT, venous thromboembolism (VT) and thrombophilia. Also, there was no relation between lupus anticoagulant and anti-cardiolipin. Conclusions: There is an important difference in the incidence of DVT in patients with SI by acute SCI and after 1 year. The conduct of the investigation for thrombophilia should be based on clinical factors, risk factors for DVT and family history of thrombosis

Introdução: Pacientes com Doença de Crohn (DC) apresentam alto risco de eventos tromboembólicos (TE), muitas vezes, associados a alta morbimortalidade. É conhecido o papel da inflamação na fisiopatologia da trombose na doença Inflamatória Intestinal (DII), entretanto, o significado da inflamação subclínica ainda se mantém obscuro na literatura. Este estudo avaliou o efeito da atividade endoscópica no perfil de coagulação dos pacientes com DC em remissão clínica. Métodos: entre os dias 22 de maio de 2015 e 26 de abril de 2017, foram triados 261 pacientes com DC em possível remissão clínica, sendo realizadas ao todo 229 colonoscopias. Das 229 colonoscopias realizadas, 164 pacientes estavam realmente em remissão clínica (confirmados com CDAI <= 150) e foram alocados em dois grupos: 75 no grupo de atividade endoscópica (AE) (SES-CD >= 7), 89 no grupo de remissão endoscópica (RE) (SES-CD <= 2). Cinquenta controles saudáveis pareados por sexo e idade foram eleitos. Medimos, nos 3 grupos, além da geração de trombina - pelo método Calibrated Automated Thrombogram (CAT), com e sem trombomodulina, - a atividade do fator tecidual (FT), fibrinogênio, D-dímero, Fator VIII, ADAMTS-13, Fator de von Willebrand - antígeno e cofator de ristocetina (cWF). Coletamos dados sobre a duração da doença, extensão, comportamento, localização, tratamento farmacológico, história prévia de cirurgias, calprotectina fecal, qualidade de vida (por meio do IBDQ), além dos fatores de risco para TE, como hospitalização recente, uso de corticoide atual, status do tabagismo, assim como marcadores de trombofilia hereditária ou adquirida. Seguimos os pacientes por 1 ano de observação, avaliando a variação no CDAI e IBDQ no período. Resultados: A maioria dos pacientes apresentou comprometimento ileocolônico (43%), com comportamento inflamatório (40%), seguido de estenosante (30%) e fistulizante (30%). 67% estavam em uso de imunossupressores e 52% em uso de biológicos. Os fatores de risco para TE e todos os outros marcadores de trombofilia, incluindo deficiência de proteína C e S, anticardiolipina, resistência à proteína C, antitrombina, mutações da protrombina e do Fator V, foram semelhantes em ambos os grupos, exceto pelo anticoagulante lúpico, maior no grupo de AE (8,1% vs. 1,3%, p=0,047). Como esperado, o grupo de AE apresentou níveis significativamente maiores de PCR, calprotectina fecal e plaquetas. Além disso, este grupo apresentou uma maior atividade do fator tecidual vs. o grupo de RE vs. controles (127 vs. 103 vs. 84, p = 0,001). Embora o grupo DC tivesse maiores níveis de FVW:Ag e FVW:RCo, FVW/ADAMTS-13, Fator VIII e trombomodulina vs. controles, não houve diferença estatística entre os grupos de AE e RE. Os níveis de geração de trombina foram semelhantes entre os 3 grupos, com ou sem trombomodulina. Conclusão: Esses dados evidenciam que existe uma disfunção endotelial inerente à DC, e, que, em pacientes com AE, essa disfunção pode ser ainda maior pela maior exposição do FT. Embora, a presença de inflamação e dano endotelial contribuam para esse estado procoagulante, em pacientes com doença subclínica, há um estado de compensação permanente, uma vez que a quantidade de trombina gerada foi a mesma entre os grupos. Este equilíbrio pode estar comprometido diante de outros fatores tromboembólicos, aumentando, assim, o risco de trombose / Background: Crohn\'s disease patients (CD) have a high risk of thromboembolic events (TE), often associated with high morbidity and mortality. Involvement of inflammation in TE is well known, but significance of the sub-clinical inflammation in this process is not the rule. Thus, the aim of this study is to evaluate the effect of the endoscopic activity in the coagulation profile in CD in clinical remission. Methods: Between May/2015 and April/2017, 261 CD patients in supposed clinical remission, were screened, and 229 had a colonoscopy done, resulting in the inclusion of 164 CD patients in clinical remission confirmed by a CDAI <= 150. They were allocated in two groups: 75 in the endoscopic activity (EA) group (SES-CD >= 7), and 89 in the endoscopic remission (ER) group (SES-CD <= 2). 50 healthy controls matched for sex and age were chosen. We measured in the 3 groups, in addition to the generation of thrombin - through the Calibrated Automated Thrombogram (CAT), with and without thrombomodulin, - the activity of tissue factor (TF), fibrinogen, D-dimer, Factor VIII, ADAMTS-13 and von Willebrand Factor - antigen (VWF) and ristocetin cofactor (VWF:RCo). We collected data regarding the duration of the disease, extension, behavior, location, pharmacological treatment, previous history of surgeries, fecal calprotectin, quality of life (through IBDQ), as well as risk factors for TE such as recent hospitalization, current corticoid use, smoking status, as well as markers of hereditary or acquired thrombophilia. We followed the patients for 1 year of observation, evaluating the variation in CDAI and IBDQ. Results: Most of the patients had ileocolonic involvement (43%), with inflammatory behavior (40%), followed by stenosing (30%) and fistulizing (30%). 67% were in use of immunosuppressors and 52% in use of biological drugs. Risk factors for TE besides other markers of thrombophilia, including protein C and S deficiency, anticardiolipin, protein C resistance, antithrombin, prothrombin and Factor V mutations, were similar in both groups except for the lupus anticoagulant, higher in the EA group (8.1% vs. 1.3%, p = 0.047). As expected, the EA group had significantly higher levels of CRP, fecal calprotectin and platelets. In addition, this group had a higher activity of TF vs. ER group vs. controls (127 vs. 103 vs. 84, p = 0.001). Although the DC group had had higher levels of VWF and VWF:RCo, VWF/ADAMTS-13, Factor VIII and thrombomodulin vs. controls, there was no statistical difference between the EA and ER groups. Thrombin generation levels were similar between the 3 groups, with or without thrombomodulin. Conclusion: These data show that there is an inherent endothelial dysfunction in CD, moreover in patients with EA, this dysfunction may be even greater, due to the exposure of TF. Although the presence of inflammation and endothelial damage contribute to this procoagulant condition, in patients with subclinical disease, there is a permanent compensatory state, since the amount of thrombin generated was the same between the groups. This balance may be compromised by other thromboembolic factors, thus increasing the risk of thrombosis

INTRODUÇÃO: Após a embolia pulmonar cerca de 1 a 3% dos pacientes desenvolvem embolismo crônico seguido de elevação da pressão da artéria pulmonar e aumento da resistência vascular pulmonar (RVP) e o aumento contínuo da pressão vascular leva ao remodelamento das pequenas artérias. Considerando estes dados, o objetivo deste estudo foi avaliar o aumento da reatividade da artéria pulmonar após a inalação de óxido nítrico, após à tromboendarterectomia (PTE) em comparação ao pré-operatório. MÉTODOS: Foram inclusos neste estudo vinte pacientes com idade entre 18 e 68 anos, submetidos à tromboendarterectomia no período de janeiro de 2005 a julho de 2008. Todos os pacientes no período pré-operatório foram submetidos a cateterização cardíaca direita, com medida da pressão pulmonar, entre as duas pressões, potência cardíaca e resistência vascular pulmonar. Estes mesmos pacientes foram submetidos à inalação de óxido nítrico (NO) por dez minutos e nova medida de todas as variáveis foi realizada. Três meses após a tromboendarterectomia, treze pacientes passaram por novos exames, antes e após a inalação de NO. Foi avaliada a reatividade pela comparação estatística dos parâmetros hemodinâmicos, antes e após a inalação do NO. Nós também consideramos o teste positivo de acordo com o critério clássico (redução 20% na PAPm e PVR após inalação de NO) e redefinimos o critério (PAPm diminuindo para 40 mmHg ou menos após inalação com NO, com um redução maior que 10 mmHg). RESULTADOS: A análise estatística usada para análise dos dados paramétricos foi o teste student t e para dados não paramétricos utilizou-se o Wilcoxcon Signed Ranks. Significância estatística 5%. Considerando somente os pacientes que completaram os testes hemodinâmicos (n=13), de acordo com o critério clássico seis indivíduos apresentaram resposta positiva ao NO inalado antes PTE, enquanto nove pacientes tiveram resposta positiva após PTE. A diferença entre pré-PTE e pós-PTE não foi estatísticamente significante (p=0,375). Assim, os critérios foram redefinidos. Dois pacientes tiveram resposta positiva na pré-PTE e outros quatro foram positivos na pós-PTE. Nenhuma diferença estatística foi observada entre pré-PTE e pós-PTE respondedores (p=0,688). CONCLUSÕES: Neste estudo, não foi observado aumento da reatividade ao NO inalado em comparação aos testes pré-operatórios / INTRODUCTION: After pulmonary embolism, 1 to 3% of these patients develop a chronic embolism, with elevated pulmonary artery pressure and increased pulmonary vascular resistance (PVR). The continuous elevated pressure leads to the remodeling of the small arteries. The objective of this study is to determinate if there is an increase in the responsiveness to the inhaled nitric oxide, in the post-thromboendaterectomy test, in comparison to the preoperative test. METHODS: The study includes twenty patients, age 18 to 68, submitted to thromboendarterctomy, between January 2005 and December 2007. All patients, in the preoperative period, were submitted to right cardiac catheterization, with the measurement of the pulmonary pressures, wedge pressure, cardiac output and PVR. Afterwards, they inhaled 20 ppm of nitric oxide (NO) for ten minutes, with a new measurement of all variables. Three months after thromboendarterectomy, thirteen patients underwent a new measurement, before and after nitric oxide inhalation. We analyzed the reactivity of the pulmonary artery, considering the statistical changes in the hemodinamical parameters. We also considered a positive test according to classical criterion (reduction 20% in PAPm and PVR after NO inhalation) and redefined criterion (PAPm falling to 40 mmHg or less, after inhaled NO, with a drop higher than 10 mmHg). RESULTS:The statistical analyze used the Student-t test for parametrical data and the Wilcoxon Signed Ranks for non parametrical data. Statistical significance 5%.Regardling only the patients who complete both hemodynamic tests (n = 13), according to the classical criterion, six subjects had positive response to inhaled NO before PTE while nine patients had positive response after PTE. The difference between pre-PTE and post-PTE was not statistical significant: p = 0,375. Concernig the redefined criterion, two subjects had positive response in pre-PTE test and four subjects had positive response in post-PTE test, with no statistically significant difference between pre-PTE and post-PTE responders (p = 0,688). CONCLUSIONS: In this study, we could not find, in the postoperative test, a greater reactivity to inhaled NO, in comparison to the preoperative test

Orientador: Hugo Hyung Bok Yoo / Resumo: A tromboembolia pulmonar (TEP) é uma doença caracterizada pelo bloqueio da circulação pulmonar por êmbolos, que se desloca atravessando as câmaras direitas do coração e obstruindo a artéria pulmonar e/ou um de seus ramos. As alterações vasculares e seu impacto nos sintomas são bem estudadas, porém, a persistência de defeito perfusional residual (DPR), mesmo após a terapia estabelecida, pode gerar disfunções cardiovasculares e pulmonares. Em decorrência dessas complicações, os pacientes podem apresentar sintomas que alterem as atividades da vida diária. Por ser pouco explorada, hipotetizamos que, pacientes que apresentem algum grau de obstrução vascular pulmonar persistente decorrente de TEP manifestem clinicamente com piora da função pulmonar e da qualidade de vida. Objetivos: Avaliar a função pulmonar, a qualidade de vida, a capacidade de exercício e a classificação funcional dos pacientes que já finalizaram o tratamento com anticoagulante. Métodos: Foram avaliados 48 pacientes, com diagnostico confirmado de TEP e que já tinham terminado o tratamento com anticoagulante. Todos os pacientes foram submetidos a uma avaliação clínica, espirometria pré e pós broncodilatador, teste de caminhada de seis minutos (TC6M), questionário de qualidade de vida (SF-36) e classificação funcional (NYHA). Após a verificação dos resultados da cintilografia de perfusão pulmonar, os pacientes foram divididos em dois grupos de acordo com a presença (n=27) ou ausência (n=21) de DPR. Resultados: Os p... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Pulmonary thromboembolism (PTE) is a disease characterized by blockage of the pulmonary circulation by emboli, which travels through the right chambers of the heart and obstructs the pulmonary artery and / or one of its branches. Vascular changes, and their impact on symptoms are well studied, however, the persistence of residual perfusion defect (RPD), even after established therapy can lead to cardiovascular and pulmonary dysfunctions. As result of these complications, patients may experience symptoms that alter the activities of daily life. Since it is not well explained, we hypothesised that, patients presenting with some degree of persistent pulmonary vascular obstruction due to PTE manifest clinically with worsening pulmonary function and quality of life. Objectives: To assess lung function, quality of life, exercise capacity and functional classification of patients who have already completed anticoagulant treatment. Methods: We evaluated 48 patients, with confirmed diagnosis of PTE and who had already finished anticoagulant treatment. All patients underwent clinical evaluation, pre- and post bronchodilator spirometry, six-minute walk test (6MWT), quality of life questionnaire (SF-36) and functional classification (NYHA). After the results of the pulmonary perfusion scintigraphy, the patients were divided into two groups according to the presence (n = 27) or absence (n = 21) of RPD. Results: The patients evaluated had a mean age of 45 ± 12.4 years, of which 34 (70%) we... (Complete abstract click electronic access below) / Mestre

Objetivo: Avaliar o impacto de fatores de risco no desenvolvimento de eventos tromboembólicos em pacientes com lesão medular. Métodos: Estudo observacional, prospectivo e cruzado. Pacientes elegíveis (n=100) tinham lesão medular por trauma raquimedular e mais de 18 anos. O grau de lesão sensorial e motora foi avaliado com base na escala ASIA (ASIA Impairment Scale - AIS). Amostras de sangue foram coletadas para exames de coagulação, hemogramas, análises bioquímicas e laboratoriais. Exames de ultrassonografia foram realizados nos sistemas venosos superficial e profundo dos membros inferiores. Experimentos de PCR em tempo real foram realizados com o intuito de investigar mutações nos genes da protrombina (G20210A) e do fator V de Leiden (G1691A). Resultados: O principal achado deste estudo foi a maior ocorrência de Trombose Venosa Profunda (TVP) em pacientes com fator V de Leiden e hiperhomocisteinemia. Não houve associação entre Lesão Medular por TVP, Tromboembolismo Venoso (TEV) e trombofilia. Não houve também relação com lúpus anticoagulante e anti-cardiolipina. Conclusões: Houve importante diferença na incidência de TVP em pacientes com Lesão Medular, tanto aguda quanto crônica (após um ano da lesão). A investigação de trombofilia deve ter como base os fatores clínicos, fatores de risco para TVP e história familiar de trombose / Objective: Evaluate the impact of risk factors in the development of thromboembolic events in patients with spinal cord injury. Design: Observational, prospective and cross study. Eligible patients (n=100) had spinal injury (SI) by spinal cord injury (SCI), older than 18 years of age. The degree of motor and sensory lesion was evaluated based on ASIA Impairment Scale (AIS). Blood samples were collected for coagulation exams, hemogram, laboratory and biochemical analyses. Ultrasonography analyzes were performed from deep and superficial venous systems of lower limbs. Quantitative real-time PCR experiments were performed in order to investigate mutations in the prothrombin (G20210A) and Leiden factor V (G1691A) genes. Results: The main finding of this study was the higher occurrence of Deep Venous Thromboembolism (DVT) in patients with Leiden factor V and hyper homocysteinemia. There was no association between SI for DVT, venous thromboembolism (VT) and thrombophilia. Also, there was no relation between lupus anticoagulant and anti-cardiolipin. Conclusions: There is an important difference in the incidence of DVT in patients with SI by acute SCI and after 1 year. The conduct of the investigation for thrombophilia should be based on clinical factors, risk factors for DVT and family history of thrombosis

INTRODUÇÃO: Após a embolia pulmonar cerca de 1 a 3% dos pacientes desenvolvem embolismo crônico seguido de elevação da pressão da artéria pulmonar e aumento da resistência vascular pulmonar (RVP) e o aumento contínuo da pressão vascular leva ao remodelamento das pequenas artérias. Considerando estes dados, o objetivo deste estudo foi avaliar o aumento da reatividade da artéria pulmonar após a inalação de óxido nítrico, após à tromboendarterectomia (PTE) em comparação ao pré-operatório. MÉTODOS: Foram inclusos neste estudo vinte pacientes com idade entre 18 e 68 anos, submetidos à tromboendarterectomia no período de janeiro de 2005 a julho de 2008. Todos os pacientes no período pré-operatório foram submetidos a cateterização cardíaca direita, com medida da pressão pulmonar, entre as duas pressões, potência cardíaca e resistência vascular pulmonar. Estes mesmos pacientes foram submetidos à inalação de óxido nítrico (NO) por dez minutos e nova medida de todas as variáveis foi realizada. Três meses após a tromboendarterectomia, treze pacientes passaram por novos exames, antes e após a inalação de NO. Foi avaliada a reatividade pela comparação estatística dos parâmetros hemodinâmicos, antes e após a inalação do NO. Nós também consideramos o teste positivo de acordo com o critério clássico (redução 20% na PAPm e PVR após inalação de NO) e redefinimos o critério (PAPm diminuindo para 40 mmHg ou menos após inalação com NO, com um redução maior que 10 mmHg). RESULTADOS: A análise estatística usada para análise dos dados paramétricos foi o teste student t e para dados não paramétricos utilizou-se o Wilcoxcon Signed Ranks. Significância estatística 5%. Considerando somente os pacientes que completaram os testes hemodinâmicos (n=13), de acordo com o critério clássico seis indivíduos apresentaram resposta positiva ao NO inalado antes PTE, enquanto nove pacientes tiveram resposta positiva após PTE. A diferença entre pré-PTE e pós-PTE não foi estatísticamente significante (p=0,375). Assim, os critérios foram redefinidos. Dois pacientes tiveram resposta positiva na pré-PTE e outros quatro foram positivos na pós-PTE. Nenhuma diferença estatística foi observada entre pré-PTE e pós-PTE respondedores (p=0,688). CONCLUSÕES: Neste estudo, não foi observado aumento da reatividade ao NO inalado em comparação aos testes pré-operatórios / INTRODUCTION: After pulmonary embolism, 1 to 3% of these patients develop a chronic embolism, with elevated pulmonary artery pressure and increased pulmonary vascular resistance (PVR). The continuous elevated pressure leads to the remodeling of the small arteries. The objective of this study is to determinate if there is an increase in the responsiveness to the inhaled nitric oxide, in the post-thromboendaterectomy test, in comparison to the preoperative test. METHODS: The study includes twenty patients, age 18 to 68, submitted to thromboendarterctomy, between January 2005 and December 2007. All patients, in the preoperative period, were submitted to right cardiac catheterization, with the measurement of the pulmonary pressures, wedge pressure, cardiac output and PVR. Afterwards, they inhaled 20 ppm of nitric oxide (NO) for ten minutes, with a new measurement of all variables. Three months after thromboendarterectomy, thirteen patients underwent a new measurement, before and after nitric oxide inhalation. We analyzed the reactivity of the pulmonary artery, considering the statistical changes in the hemodinamical parameters. We also considered a positive test according to classical criterion (reduction 20% in PAPm and PVR after NO inhalation) and redefined criterion (PAPm falling to 40 mmHg or less, after inhaled NO, with a drop higher than 10 mmHg). RESULTS:The statistical analyze used the Student-t test for parametrical data and the Wilcoxon Signed Ranks for non parametrical data. Statistical significance 5%.Regardling only the patients who complete both hemodynamic tests (n = 13), according to the classical criterion, six subjects had positive response to inhaled NO before PTE while nine patients had positive response after PTE. The difference between pre-PTE and post-PTE was not statistical significant: p = 0,375. Concernig the redefined criterion, two subjects had positive response in pre-PTE test and four subjects had positive response in post-PTE test, with no statistically significant difference between pre-PTE and post-PTE responders (p = 0,688). CONCLUSIONS: In this study, we could not find, in the postoperative test, a greater reactivity to inhaled NO, in comparison to the preoperative test

A partir des données de deux études de cohortes hospitalières françaises (MEVE etFARIVE), nous nous sommes intéressés aux facteurs de risque de récidive de maladieveineuse thromboembolique (MVTE).Nous avons confirmé un excès de risque de récidive de MVTE chez les hommescomparés aux femmes et montré que cette relation dépendait en partie de l’âge, de lamutation du FV Leiden et de la prise d'hormones au premier événement. Une analyse enfonction du sexe a mis en évidence que l’âge, l’obésité et des niveaux élevés de D-dimèresaugmentaient significativement le risque de récidive de MVTE chez les femmes. Par ailleurs,contrairement aux estrogènes oraux, les estrogènes transdermiques seuls ou combinés à laprogestérone micronisée n'exposaient pas les femmes ménopausées à un risque accru derécidive de MVTE. Chez les hommes, la mutation du facteur V Leiden, un antécédent familialde maladie artérielle et un premier événement idiopathique étaient des facteurs de risqueindépendants de récidive.L'identification de profils de risque différents en fonction du sexe pourrait permettreune meilleure stratification du risque de récidive de MVTE. Ces résultats devraientcontribuer à améliorer la prise en charge de la maladie par une évaluation individuelle de ladurée optimale du traitement anticoagulant. De plus, une bonne sécurité d’emploi desestrogènes transdermiques seuls ou combinés à la progestérone micronisée ouvre desperspectives cliniques intéressantes dans le traitement des troubles sévères de laménopause chez des patientes avec un antécédent personnel de MVTE.Mots / Based on data from two French hospital cohort studies, we investigated the riskfactors for recurrent venous thromboembolism (VTE).We confirmed the higher risk of recurrent VTE among men compared with womenand we suggested that this relation depended on age, Factor V Leiden mutation andhormone-related first event. A sex-specific analysis showed that advancing age, obesity andelevated D-dimer significantly increased the risk of recurrent VTE in women. Moreover, oralbut not transdermal estrogens, were associated with a higher risk of recurrent VTE amongpostmenopausal women. In men, factor V Leiden mutation, family history of arterial diseaseand an idiopathic first event were independent risk factors for VTE recurrence.The identification of sex-specific risk factors provides a new insight to riskstratification for VTE recurrence. These results could improve the prevention of this diseaseby an individual assessment of the optimal duration of anticoagulation therapy. In addition,our results provide first evidence supporting the safety of transdermal estrogens alone orcombined with micronized progesterone with respect to VTE recurrence risk. These datacould have important clinical implications for women with personal history of VTE whorequire hormone therapy for severe postmenopausal symptoms.

<p>For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE).</p><p>Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT).</p><p>The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication.</p><p>The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.</p>