Au décours d'une première embolie pulmonaire (EP), certains patients présentent un syndrome post EP : un tiers des patients ont une obstruction persistante de la vascularisation pulmonaire, associée à la persistance d'une dyspnée et une limitation des performances à l'effort. Certains patients présenteront une récidive d'EP ou, plus rarement, une hypertension pulmonaire, dont les séquelles perfusionnelles sont un critère diagnostique indispensable. Le rôle et la physiopathologie des séquelles perfusionnelles au cours du syndrome post EP est incomprise. Ce travail a mis en évidence l'existence d'un risque majoré de récidive d'EP (odds ratio 1,9) chez les patients présentant des séquelles perfusionnelles >10% à la vascularisation pulmonaire. L'analyse des propriétés fonctionnelles du fibrinogène purifié à partir du plasma de patients suivis pour une première EP améliore la prédiction de séquelles perfusionnelles confirmant le rôle clé de celui-ci dans la physiopathologie de la maladie. Ainsi, une forte proportion de chaine Bβ porteuse d'un seul résidu acide sialique majore le risque de séquelles. L'étude des cellules endothéliales circulantes à la phase aigüe et après une EP montre que les patients qui développeront des séquelles mobilisent peu de cellules endothéliales, témoignant d'une forte altération des processus de réparation de l'endothélium pulmonaire. L'interaction de la fibrine avec les progéniteurs endothéliaux dans cette anomalie de la régulation est possible : les progéniteurs expriment le récepteur VLDLr dont l'épitope β15-42 de la fibrine est un ligand impliqué dans la régulation du cycle cellulaire et l'inhibition de l'angiogenèse. / Pulmonary vascular sequels after pulmonary embolism: prognosis, prediction and physiopathologyAbstract: Post Pulmonary Embolism (PE) syndrome is not rare after PE: one third of the patients presents residual pulmonary vascular obstruction (RPVO) traducing sequels associated with increased dyspnea and impaired exercise capacity. Some of these patients will suffer PE recurrence or, more rarely, chronic thromboembolic pulmonary hypertension, whose one the diagnosis criteria is persistent perfusion defect. Prognosis value and mechanisms underlying vascular sequels are still unclear. The present work shows that RPVO > 10% after a first PE is associated with an increased risk for venous thromboembolism recurrence (odds ratio 1.9). Secondly, fibrinogen properties were investigated in PE patients. Patients with RPVO >10% presented more monosialiated Bβchain form. Prediction models for RPVO that include fibrinogen analysis were more accurate than those without fibrinogen data; This results highlights the key role of fibrin in the pathophysiology of chronic venous thromboembolism. Interestingly, the present work shows that patient who will present RPVO had an impaired endothelial cells mobilization. Compared to patients without RPVO, patients with RPVO had lower circulating endothelial cells at the acute phase of PE. This endothelial dysfunction is probably triggered by endothelial progenitors that expressed the very low density lipoprotein receptor (VLDLr), implicated in the inhibition of angiogenesis and able to bind the β15-42 N terminal sequence of the fibrin Bβ chain.

Bakgrund: Lungemboli är den allvarligaste diagnosen av venös tromboembolism. Poliklinisk behandling istället för traditionell slutenvård kan erbjudas för patienter med LE som inte löper risk för plötslig död och allvarliga komplikationer. Men poliklinisk behandlingsmodell kräver att korrekt medicinsk behandling i hemmet och korrekt medicinsk uppföljning kan säkerställas. Det saknas dock kunskap avseende sjuksköterskor och läkares erfarenheter av polikliniskt omhändertagande av patienter med lungemboli. Syfte: Syftet var att belysa sjuksköterskors och läkares erfarenheter av polikliniskt omhändertagande av patienter med lungemboli Metod: En kvalitativ studie med 12 semistrukturerade intervjuer som analyserades induktivt enligt innehållsanalys.  Resultat: Utifrån analysen av intervjuerna framkom att det strukturerade omhändertagandet ledde till en känsla av kompetens där man kände att man kunde erbjuda denna patientgrupp en god och säker vård. Dessutom var det angeläget att arbeta på ett personcentrerat sätt med hänsyn till de individuella egenskaper och förutsättningar patienter hade och ha förmåga att bemöta deras oro och funderingar med respekt och empati. En viktig del utgjorde även insatser för att främja hos patienter delaktighet i egenvård. Slutsats: Sjuksköterskors och läkares erfarenheter tyder på att en välfungerande poliklinisk struktur skapar förutsättningar för en god och säker vård.  Enligt sjuksköterskor och läkare ligger fokus i möten med polikliniska patienter inte enbart på den medicinska behandlingen utan även på fysiska och psykiska påfrestningar som LE har orsakat. / Background: Pulmonary embolism is the most serious diagnosis of venous thromboembolism. Outpatient treatment instead of traditional inpatient care can be offered for patients with LE who are not at risk of sudden death and serious complications. But the outpatient treatment model requires that proper medical treatment at home and proper medical follow-up can be ensured. However, knowledge regarding nurses’ and physicians’ experiences of outpatient care is lacking of outpatient care for patients with pulmonary embolism.Purpose:The purpose was to illuminate nurses’ and physicians’ experiences of outpatient care of patients with pulmonary embolism.  Method: A qualitative study with 12 semi-structured interviews analysed inductively according to content analysis.  Results: Based on the analyse of the interviews it emerged that the structured outpatient care led to a feeling of competence to be able to offer this patient group good and safe care. In addition, it was important to work in a person-centered way, taking into account the individual characteristics and conditions patients had and to be able to respond to their concerns and questions with respect and empathy. Efforts to promote patients' involvement in self-care also constituted an important part.Conclusion:  The experiences of nurses and physicians indicate that a well-functioning outpatient structure creates the conditions for good and safe care. According to nurses and physicians, the focus in meetings with outpatients is not only on the medical treatment but also on the physical and psychological strains that LE has caused.

Venous thromboembolism (VTE), defined as deep vein thrombosis and/or pulmonary embolism is the second leading cause of mortality in cancer patients, second only to cancer itself. A number of reports suggest that circulating extracellular vesicles (EVs) may be increased in cancer patients with VTE. The aim of this study was to examine circulating EVs in high-risk ambulatory cancer patients, determine if levels are associated with hematological outcomes (VTE, major bleeding event), and to assess the impact of prophylactic antithrombotic therapy (Apixaban). We hypothesized that elevated levels of circulating large EVs will be predictive of cancer associated VTE and/or bleeding events and that treatment with Apixaban will reduce EV levels and incidence of cancer VTE. Plasma samples from patients at baseline, and 90-days follow-up from the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer patients (AVERT) trial were investigated. Total EVs were quantified by their pro-coagulant activity using the Zymuphen MP-Activity kit. Platelet, endothelial and tissue-factor EV levels were quantified by flow cytometry. We observed that circulating EVs exhibited significant associations with sex, age, and cancer type, however we did not observe any relationships with clinical outcomes. Thus, it appears that circulating EVs may not have a role in risk stratification for VTE in in high-risk ambulatory cancer patients.

Le syndrome d’embolie de liquide amniotique (SELA) est une complication rare et souvent catastrophique de l’accouchement chez la femme caractérisée classiquement par une hypotension sévère, un arrêt cardiorespiratoire et une coagulation intra-vasculaire disséminée. Malheureusement, sa physiopathologie est encore mal connue. Le rôle des kinines n’a notamment pas été étudié. L’objectif de notre projet était de développer un modèle animal de SELA et d’étudier le rôle éventuel des kinines dans ce syndrome. Douze lapines en fin de gestation ont été incluses dans l’étude. Pour chacune d’entre-elles, le liquide amniotique était aspiré de chaque sac amniotique après une laparotomie. Six lapines recevaient un bolus de liquide amniotique injecté via la veine auriculaire alors que les six autres recevaient un bolus de saline. Parallèlement, les effets in vitro de liquide amniotique sur la coagulation étaient évalués par thrombelastographie (TEG) et comparés aux effets de la saline. L’injection de liquide amniotique n’a pas permis de reproduire les signes cliniques de SELA, n’a pas entrainé la génération de bradykinine, et n’a pas eu d’effet sur le temps de prothrombine, le temps de thromboplastine partielle activée, et l’activité du facteur VIII de. Une thrombocytopénie sévère et transitoire a cependant été notée 5 minutes après l’injection de liquide amniotique. De plus, en additionnant in vitro de liquide amniotique au sang on a observé un tracé de TEG hypercoagulable comparé à celui obtenu avec la saline. Le modèle n’ayant pas pu reproduire le SELA, le rôle des kinines dans ce syndrome reste à déterminer. / Amniotic fluid embolism (AFE) is a rare but catastrophic complication of parturition characterized by severe hypotension, cardiovascular collapse, and massive consumptive coagulopathy. Its pathophysiology remains obscure. In particular, the potential role of bradykinin in hypotension is unknown. The objective of this study was to develop a suitable animal model of AFE and to study the effects of amniotic fluid injection on bradykinin release in this model. Twelve rabbits in late gestation (25 days) were used. For each rabbit, amniotic fluid was collected from foetal amniotic sacs by laparotomy. For six rabbits, the amniotic fluid was then injected as a bolus via the left auricular vein, whereas the six other rabbits received saline (control group). In parallel, the in vitro effects of amniotic fluid on coagulation was assessed by thrombelastography (TEG) and compared to the effects of saline. Injection of amniotic fluid did not reproduce clinical signs of AFE, did not provoke bradykinin generation and had no effect on prothrombin time, the activated partial thromboplastin time, nor Factor VIII activity. However, a significant thrombocytopenia was observed five minutes after amniotic fluid administration. This thrombocytopenia resolved within 60 minutes. In vitro addition of amniotic fluid to blood resulted in accelerated clotting on TEG tracings as compared to the effect of saline. As we were not able to reproduce AFE with our model, the role of kinins in this syndrome remains to be determined.

Nesta tese, buscou-se avaliar se a tomografia computadorizada de duplaenergia pós-contraste (TCDE) é capaz de detectar diferenças regionais da perfusão pulmonar em um modelo animal suíno incluindo variações de decúbito, lesão alveolar e oclusão da artéria pulmonar com balão, comparando estes resultados com os obtidos pela perfusão de primeira passagem com a tomografia computadorizada dinâmica (TCD). Dez suínos landrace foram divididos em Grupos A (N = 5, controle) e B (N = 5). Animais do Grupo B foram submetidos ao protocolo de lesão alveolar induzida por ventilação mecânica (LPIV). O volume sanguíneo perfundido e o fluxo sanguíneo pulmonar foram, respectivamente, estimados pela TCDE (%VSPTCDE) e pela TCD (FSPTCD), em diversas condições experimentais: posição supina versus prona, presença versus ausência de LPIV, presença ou ausência de oclusão da artéria pulmonar. A correlação entre %VSPTCDE e FSPTCD foi moderada (R = 0,60) com ampla variabilidade (intervalo 0,35-0,91) entre animais. %VSPTCDE e FSPTCD demonstraram padrões similares de heterogeneidade da perfusão pulmonar nas diferentes condições experimentais. Entretanto, reduções do %VSPTCDE causadas pela oclusão com balão foram em média -29,32 %, enquanto reduções do FSPTCD foram em média -86,78 % (p < 0,001). Estimativas quantitativas do VSPTCDE tiveram um erro médio de +4.3 ml/100g em comparação com o FSPTCD, com limites de concordância de 95 % entre -16,6 ml/100g e 25,1 ml/100g. A TCDE póscontraste é capaz de prover estimativas semiquantitativas que refletem a heterogeneidade regional da perfusão pulmonar causada por mudanças de decúbito, lesão alveolar e oclusão da artéria pulmonar com balão, apresentando moderada correlação com a perfusão de primeira passagem pela TCD / We aimed to evaluate whether contrast-enhanced dual-energy CT (DECT) detects regional pulmonary perfusion changes in a swine model of acute lung injury, with variations in decubitus and transient occlusion of the pulmonary artery, comparing these results with those obtained with dynamic CT perfusion (DynCT). Ten landrace swine were assigned to Groups A (N = 5, control) and B (N = 5). Group B was subjected to ventilator-induced lung injury (VILI). Perfused blood volume and pulmonary blood flow were quantified by DECT (PBVDECT) and DynCT (PBFDynCT), respectively, under different settings: supine versus prone, and with/without balloon occlusion of a pulmonary artery (PA) branch. Correlation of regional PBVDECT versus PBFDynCT was moderate (R = 0.60) with high variability (range 0.35-0.91) among the animals. Regional pulmonary perfusion changes assessed by %PBVDECT agreed with PBFDynCT in response to decubitus changes, lung injury and balloon occlusion in the multivariate analysis. However, reductions in %PBVDECT caused by balloon occlusion were in average -29.32 %, whereas reductions in PBFDynCT were in average -86.78 % (p < 0.001). Quantitative estimates of PBVDECT had a mean bias of +4.3 ml/100g in comparison with PBVDynCT, with 95 % confidence intervals between -16.6 ml/100g and 25.1 ml/100g. Semiquantitative contrastenhanced DECT reflects regional changes in perfusion caused decubitus changes, acute lung injury, and balloon occlusion of the PA, with moderate correlation in comparison with DynCT

INTRODUÇÃO: A hipertensão pulmonar tromboembólica crônica (HPTEC) é uma doença vascular pulmonar progressiva, cuja incidência varia de 0,56% a 3,2% em indivíduos com embolia pulmonar aguda (EPA) recorrente. Apesar do avanço nas opções de tratamento para HPTEC, a tromboendarterectomia pulmonar (TEAP) continua sendo padrão ouro, levando a melhora hemodinâmica e aumento da sobrevida. OBJETIVOS: Avaliar o impacto que mudanças técnicas intraoperatórias implementadas tiveram na evolução dos pacientes submetidos à TEAP em relação à morbimortalidade imediata e tardia, e também sobre o desenvolvimento do ato operatório. MÉTODOS: Estudo retrospectivo em portadores de HPTEC, submetidos à TEAP, no período de janeiro/2007 a maio/2016, divididos em 3 grupos, de acordo com intervenções implementadas. A 1ª intervenção consistiu em mudanças na circulação extracorpórea (CEC) e no tempo de parada circulatória total (PCT), e a 2ª intervenção incluiu alterações na CEC, técnicas anestésica e cirúrgica. A avaliação dos dados incluiu análise univariada para associações entre intervenções com variáveis de morbimortalidade e técnica operatória. O modelo de regressão multivariado foi aplicado para validar se as melhorias resultaram das intervenções implementadas. A análise de sobrevida foi feita por Kaplan-Meier. RESULTADOS: Foram avaliados 102 indivíduos, 62,8% mulheres, idade média de 49,1±14,8 anos, 65,7% estavam em classe funcional III-IV (NYHA). A avaliação hemodinâmica demonstrou hipertensão pulmonar importante, com valores médios elevados de pressão média na artéria pulmonar (PmAP; G1=52,9±14,45mmHg; G2=53,2±12,4mmHg; G3=53,3±12,5mmHg, p=0,992) e resistência vascular pulmonar (RVP; G1=828,4±295,13 dynas.s.cm-5; G2=838,9±428,4 dynas.s.cm-5; G3=969±417,3 dynas.s.cm-5, p=0,313). Os pacientes submetidos à TEAP mostraram aumento do tempo total de CEC entre os grupos (G1=192,3±39,4min; G2=251,7±33,4min; G3=298,2±40,2min, p < 0,001), como resultado da padronização dos tempos de esfriamento (G1=47,9±18,5min; G2=66,9±5,9min; G3=70,6±3,7min, p < 0,001), aquecimento (G1=66,8±17,7min; G2=87,2±8,1min; G3=107,7±23,5min, p < 0,001) e reperfusão (G1=25,5±7,6min; G2=20,7±8,4 min; G3=18,6±9,4min, p=0,007). A diminuição do número de operações com mais de 2 PCT (G1= 89%; G2= 60%; G3: 55%, p=0,002) foi decorrente do aumento da duração média de cada PCT (G1=15,5±2,9min; G2=17,8±1,7min; G3=19,2±2,0min, p < 0,001). Complicações pós-operatórias foram observadas em 88,5% dos pacientes, havendo redução significativa das complicações cirúrgicas (p=0,035), infecciosas (p=0,017) e neurológicas com sintomas permanentes (p=0,048) na comparação entre os 3 grupos. No seguimento após a alta, 85% estavam em classe funcional I-II (NYHA), sem melhora hemodinâmica significativa entre os grupos. Após a análise multivariada, o G3 apresentou 4,7 menos chances de complicação cirúrgica que G1 (p=0,034) e tempo de aquecimento menor que 83 minutos aumentou 4 vezes a chance de complicação infecciosa (p=0,002). A redução da mortalidade hospitalar e da sobrevida não foi significativa entre os grupos. CONCLUSÕES: Em relação à morbimortalidade imediata e tardia, o impacto das intervenções foi evidenciado pela redução das complicações neurológicas com sintomas permanentes, complicações cirúrgicas e infecciosas. Em relação ao ato operatório, o impacto foi evidenciado pelo aumento dos tempos totais de CEC, de esfriamento, de aquecimento, tempo médio das PCT, redução nos números de PCT e no tempo total de reperfusão / INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disease which incidence varies from 0.56% to 3.2% in individuals with recurrent acute pulmonary embolism (APE). Despite advances in treatment options for CTEPH, pulmonary endarterectomy (PE) remains a gold standard, leading to hemodynamic improvement and increased survival. OBJECTIVES: Evaluate the impact of intraoperative technical changes on the evolution of patients submitted to PE related to immediate and late morbimortality, as well as on the development of the operative procedure. METHODS: Retrospective study of patients with CTEPH, submitted to PE, between January 2007 and May 2016, divided into 3 groups, according to the implemented interventions. The first intervention consisted of changes in cardiopulmonary bypass (CPB) and total circulatory arrest time (CAT), and the second intervention included changes in CPB, anaesthetic and surgical techniques. The data analysis included a univariate analysis for associations between interventions with morbidity variables and operative technique. The multivariate regression model was applied to validate whether the improvements resulted from the interventions implemented. Survival analysis was performed using Kaplan-Meier. RESULTS: We evaluated 102 individuals, 62.8% were women, mean age was 49.1 ± 14.8 years, and 65.7% were in functional class III-IV (NYHA). The hemodynamic evaluation showed significant pulmonary hypertension, with mean values of mean pulmonary artery pressure (mPAP, G1 = 52.9 ± 14.45 mmHg, G2 = 53.2 ± 12.4 mmHg, G3 = 53.3 ± 12.5 mmHg, p = 0.992) and pulmonary vascular resistance (PVR, G1 = 828.4 ± 295.13 dynas.s.cm-5, G2 = 838.9 ± 428.4 dynas.s.cm-5, G3 = 969 ± 417.3 dynas.s.cm-5, p = 0.313). The patients submitted to PE showed an increase in the total CPB time between the groups (G1 = 192.3 ± 39.4min, G2 = 251.7 ± 33.4min, G3 = 298.2 ± 40.2min, p < 0.001), as a result of the standardization of cooling times (G1 = 47.9 ± 18.5min, G2 = 66.9 ± 5.9min, G3 = 70.6 ± 3.7min, p < 0.001), heating (G1 = 66.8 ± 17.7min, G2 = 87.2 ± 8.1min, G3 = 107.7 ± 23.5min, p < 0.001) and reperfusion (G1 = 25.5 ± 7.6min, G2 = 20.7 ± 8.4 min, G3 = 18.6 ± 9.4min, p = 0.007). The decrease in the number of operations with more than 2 CAT (G1 = 89%, G2 = 60%, G3: 55%, p = 0.002) was due to the increase in the average duration of each CAT (G1 = 15.5 ± 2, 9min, G2 = 17.8 ± 1.7min, G3 = 19.2 ± 2.0min, p < 0.001). Postoperative complications were observed in 88.5% of the patients, with a significant reduction in surgical (p = 0.035), infectious (p = 0.017) and neurological complications with permanent symptoms (p = 0.048) in the comparison between the three groups. In the post-discharge follow-up, 85% were in functional class I-II (NYHA), with no significant hemodynamic improvement between groups. After the multivariate analysis, G3 presented 4.7 less chance of surgical complication than G1 (p = 0.034) and warming time less than 83 minutes increased 4 times the chance of infectious complication (p = 0.002). The reduction in hospital mortality and survival was not significant between the groups. CONCLUSIONS: Regarding immediate and late morbimortality, the impact of interventions was evidenced by the reduction of neurological complications with permanent symptoms, surgical and infectious complications. Regarding the operative event, the impact was evidenced by the increase in total CPB, cooling, heating, mean CAT time, CAT reduction and total reperfusion time

Introdução: A doença tromboembólica é um distúrbio complexo multicausal com sinais e sintomas inespecíficos, confundindo-se com outras enfermidades. Devido à sua gravidade buscam-se estratégias objetivando obter um diagnóstico precoce. O teste de dosagem do dímero - D plasmático parece ser uma alternativa para exclusão do diagnóstico de tromboembolismo venoso agudo. Objetivo: Avaliar o valor do teste de dosagem de dímero - D plasmático, utilizando o método Enzyme Linked Fluorescent Assay (ELFA), na rotina diagnóstica de tromboembolismo venoso agudo. Métodos: Em 89 pacientes com sinais e sintomas sugestivos de tromboembolismo pulmonar e/ou trombose venosa profunda foram realizadas dosagens do dímero - D pela técnica ELFA no equipamento VIDAS® - BioMérieux. Foram calculados os valores da sensibilidade, especificidade, valores preditivos positivo e negativo e acurácia do teste, bem como a curva ROC da amostra estudada. Todos os pacientes foram submetidos a exame por imagem para confirmação do evento tromboembólico agudo. Foi calculado o índice kappa para analisar o resultado do teste dímero - D versus resultados de exames por imagem. Resultados: Entre os 89 pacientes estudados (média de idade 54,3 anos; 51 mulheres), 36 (40,4%) apresentaram TEV e 53 não apresentaram trombose aguda (59,6%). Entre os pacientes sem trombose aguda 15 (28,3%) apresentaram resultado de dímero - D negativo. Todos pacientes com trombose apresentaram resultado de dímero - D positivo. O teste apresentou sensibilidade de 100%; especificidade de 28,3%; valor preditivo positivo de 48,6%; valor preditivo negativo de 100% e exatidão de 57,3%. A ASC para a amostra total estudada foi igual a 0,734, indicando que o teste é um bom preditor de trombose aguda. O valor do índice kappa para a amostra total foi igual a 0,24 (p<0,001), indicando uma concordância fraca entre dímero - D e diagnóstico confirmatório de trombose. Conclusão: A dosagem do dímero - D pelo método ELFA foi capaz de excluir o diagnóstico de tromboembolismo venoso agudo nessa amostra estudada. Os resultados obtidos nessa amostra estudada permitiram concluir que o uso do teste dímero - D em pacientes com suspeita de tromboembolismo venoso revelou alta sensibilidade no diagnóstico dessa enfermidade. / Introduction: The thromboembolic disease is a multicausal complex disturb with signals and symptoms that confusing itself with other diseases. Because its gravity strategies search objecting to get a faster diagnosis. The measure plasmatic D dimer test seems to be an alternative for exclusion of the diagnostic of acute venous thromboembolism. Objectives: To evaluate the value of the measure plasmatic D dimer test, using the method Enzyme Linked Fluorescent Assay (ELFA), in the diagnostic of acute venous thromboembolism. Methods: In 89 patients with signals and symptoms suggestive of pulmonary thromboembolism and/or deep vein thrombosis had been carried through measure D dimer by technique ELFA equipment VIDAS® - BioMérieux. The values of sensibility, accuracy specificity, predictive values positive and negative and of the test had been calculated, as well as curve ROC of the sample studied. All the patients had been submitted the image exams for the confirmation of the acute thromboembolism event. It was calculated kappa ratio to compare D dimer test results with image exams results. Results: Between 89 studied patients (mean of age 54.3 years; 51 women), 36 (40.4%) they had presented and 53 had not presented acute thrombosis (59.6%). It enters the patients without acute thromboembolism 15 (28.3%) had presented resulted negative of D dimer. All patients with thrombosis had presented resulted positive of D dimer. The test presented 100% sensibility; 28.3% of specificity; positive predictive value was 48.6%; 100% of negative predictive value and accuracy value was 57.3%. The area under the curve (AUC) to total sample studied was 0.734, it was showed that the test have a good prediction to acute thrombosis. The kappa ratio value was 0.24 (p<0.001) showing a bad concordat n to thrombosis diagnostic. Conclusion: The measure of D dimer by method ELFA was able to exclude the diagnostic of acute venous thromboembolism in this sample studied. The results obtained in this sample studied let to conclude that the D dimer test in patients with suspected of acute thromboembolism presented high sensibility to diagnostic of this disease.

Nesta tese, buscou-se avaliar se a tomografia computadorizada de duplaenergia pós-contraste (TCDE) é capaz de detectar diferenças regionais da perfusão pulmonar em um modelo animal suíno incluindo variações de decúbito, lesão alveolar e oclusão da artéria pulmonar com balão, comparando estes resultados com os obtidos pela perfusão de primeira passagem com a tomografia computadorizada dinâmica (TCD). Dez suínos landrace foram divididos em Grupos A (N = 5, controle) e B (N = 5). Animais do Grupo B foram submetidos ao protocolo de lesão alveolar induzida por ventilação mecânica (LPIV). O volume sanguíneo perfundido e o fluxo sanguíneo pulmonar foram, respectivamente, estimados pela TCDE (%VSPTCDE) e pela TCD (FSPTCD), em diversas condições experimentais: posição supina versus prona, presença versus ausência de LPIV, presença ou ausência de oclusão da artéria pulmonar. A correlação entre %VSPTCDE e FSPTCD foi moderada (R = 0,60) com ampla variabilidade (intervalo 0,35-0,91) entre animais. %VSPTCDE e FSPTCD demonstraram padrões similares de heterogeneidade da perfusão pulmonar nas diferentes condições experimentais. Entretanto, reduções do %VSPTCDE causadas pela oclusão com balão foram em média -29,32 %, enquanto reduções do FSPTCD foram em média -86,78 % (p < 0,001). Estimativas quantitativas do VSPTCDE tiveram um erro médio de +4.3 ml/100g em comparação com o FSPTCD, com limites de concordância de 95 % entre -16,6 ml/100g e 25,1 ml/100g. A TCDE póscontraste é capaz de prover estimativas semiquantitativas que refletem a heterogeneidade regional da perfusão pulmonar causada por mudanças de decúbito, lesão alveolar e oclusão da artéria pulmonar com balão, apresentando moderada correlação com a perfusão de primeira passagem pela TCD / We aimed to evaluate whether contrast-enhanced dual-energy CT (DECT) detects regional pulmonary perfusion changes in a swine model of acute lung injury, with variations in decubitus and transient occlusion of the pulmonary artery, comparing these results with those obtained with dynamic CT perfusion (DynCT). Ten landrace swine were assigned to Groups A (N = 5, control) and B (N = 5). Group B was subjected to ventilator-induced lung injury (VILI). Perfused blood volume and pulmonary blood flow were quantified by DECT (PBVDECT) and DynCT (PBFDynCT), respectively, under different settings: supine versus prone, and with/without balloon occlusion of a pulmonary artery (PA) branch. Correlation of regional PBVDECT versus PBFDynCT was moderate (R = 0.60) with high variability (range 0.35-0.91) among the animals. Regional pulmonary perfusion changes assessed by %PBVDECT agreed with PBFDynCT in response to decubitus changes, lung injury and balloon occlusion in the multivariate analysis. However, reductions in %PBVDECT caused by balloon occlusion were in average -29.32 %, whereas reductions in PBFDynCT were in average -86.78 % (p < 0.001). Quantitative estimates of PBVDECT had a mean bias of +4.3 ml/100g in comparison with PBVDynCT, with 95 % confidence intervals between -16.6 ml/100g and 25.1 ml/100g. Semiquantitative contrastenhanced DECT reflects regional changes in perfusion caused decubitus changes, acute lung injury, and balloon occlusion of the PA, with moderate correlation in comparison with DynCT

La Maladie Thrombo-Embolique Veineuse (MTEV) est une maladie dont les facteurs de risque sont à la fois environnementaux et génétiques. Les facteurs de risque génétiques bien établis sont les déficits en anti-thrombine, en protéine S, en protéine C, la mutation du Facteur V de Leiden (FVL), la mutation du Facteur (F) II G20210A, ainsi que le gène ABO dont les allèles A1 et B augmentent le risque de MTEV par rapport aux allèles A2 et O. Alors qu’une part importante de l’héritabilité de la MTEV reste inexpliquée, les études contemporaines se heurtent à un manque de puissance pour découvrir de nouveaux facteurs génétiques dont les effets sont de plus en plus faibles. En vue d’augmenter la puissance de détection de nouveaux gènes de susceptibilité à la MTEV, j’ai recherché les déterminismes génétiques de deux de ses phénotypes intermédiaires : les taux d’activité plasmatique du FVIII et les taux d’antigénémie de sa protéine de transport, le Facteur de von Willebrand (vWF). Dans un premier temps, j’ai réalisé une analyse de liaison des taux de FVIII et de vWF à partir d’un échantillon de cinq grandes familles franco-canadiennes (totalisant 255 personnes) recrutées via un cas de MTEV avec mutation FVL. Quatre régions liées aux taux de FVIII et/ou vWF ont été identifiées. L’une de ces régions correspondait au locus du gène ABO déjà connu pour influencer les taux de FVIII et vWF. La recherche de gènes candidats au sein des autres signaux de liaison s’est effectuée par l’étude in silico d’une analyse d’association pangénomique de la MTEV incluant 419 cas et 1228 témoins. Deux gènes candidats ont été identifiés : STAB2 et BAI3. J’ai ensuite réalisé des études d’associations de cinq polymorphismes de BAI3. L’un d’entre eux était d’une part associé à une élévation des taux de vWF (résultat obtenu dans un échantillon de 108 familles nucléaires en bonne santé et reproduit dans un échantillon de 916 patients non apparentés atteints de MTEV), et d’autre part associé au risque de survenue de MTEV parmi les sujets non porteurs de mutations FVL et FII de deux échantillons cas-témoins (respectivement 916 cas et 801 témoins, et 250 cas et 607 témoins). Quant à STAB2, durant le courant de ma thèse, deux de ces polymorphismes ont été décrits comme associés aux taux de FVIII et vWF au cours d’une vaste étude d’association pangénomique (GWAS) menée par le consortium CHARGE rassemblant 23 600 personnes. Dans un second temps, j’ai réalisé une méta-analyse de trois GWAS des taux de FVIII et vWF. Ces analyses avaient été conduites avec l’échantillon des cinq grandes familles franco-canadiennes et deux échantillons de 972 et 570 patients atteints de MTEV. Elles étaient ajustées sur les polymorphismes du gène ABO permettant de distinguer les allèles A1, A2, B et O, dans l’optique d’augmenter la puissance des analyses en diminuant la variance résiduelle des phénotypes. Aucun polymorphisme n’était associé ni aux taux de vWF ni à ceux de FVIII après prise en compte de la correction de Bonferroni pour tests multiples (p<10-7). Cependant, parmi les onze gènes qui présentaient des polymorphismes associés aux taux de vWF ou de FVIII avec une significativité p<10-5, de manière intéressante se trouvait STAB2. Cette étude a de plus permis de confirmer les associations nouvellement découvertes de polymorphismes situés dans les gènes VWF, STXBP5 et STX2. / The Venous Thromboembolism (VTE) risk factors are environmental and genetic. The well established risk factors are anti-thrombin, protein C, protein S deficiency, Factor V Leiden and factor II mutation and ABO gene, with A1 and B allele increasing the risk of VTE. While an important part of VTE heritability remains unexplained, contemporary studies fail to discover new susceptibility genes with weaker effects. In order to increase the discovery power, I searched for genetic geterminism of two intermediary phenotypes of VTE : Factor VIII plasmatic activity (FVIII) and von Willebrand factor antigenemia (vWF)First, I performed a linkage study of FVIII and vWF from a sample of 5 large pedigrees (N=255). Four loci have been identified. One included ABO gene. I searched for candidate genes located in the others loci by studying in silico results from o Genome Wide Association Study (GWAS) of the VTE including 419 cases and and 1228 controls. témoins. Two candidate genes were identified : STAB2 et BAI3. Then I performed association studies of five SNPs in BAI3 with FVIII and vWF. One of them was associated to vWF (in a sample of 108 nuclear families and 916 VTE patients), and associated to VTE in two case-controls samples (respectively 916 cases and 801 controls, and 250 cases et 607 controls).Second, I performed a meta-analysis of three GWAS of FVIII and vWF from the same 5 pedigrees and two samples of VTE (N=972 and 570) adjusted on ABO blood group. No polymorphisms were significant after Bonferoni correction (p<10-7). Nevertheless, among 11 genes carrying polymorphisms with a p<10-5, interestingly was STAB2. Futhermore, this study allowed to confirm newly discoverd association with VWF, STXBP5 et STX2.

Le syndrome d’embolie de liquide amniotique (SELA) est une complication rare et souvent catastrophique de l’accouchement chez la femme caractérisée classiquement par une hypotension sévère, un arrêt cardiorespiratoire et une coagulation intra-vasculaire disséminée. Malheureusement, sa physiopathologie est encore mal connue. Le rôle des kinines n’a notamment pas été étudié. L’objectif de notre projet était de développer un modèle animal de SELA et d’étudier le rôle éventuel des kinines dans ce syndrome. Douze lapines en fin de gestation ont été incluses dans l’étude. Pour chacune d’entre-elles, le liquide amniotique était aspiré de chaque sac amniotique après une laparotomie. Six lapines recevaient un bolus de liquide amniotique injecté via la veine auriculaire alors que les six autres recevaient un bolus de saline. Parallèlement, les effets in vitro de liquide amniotique sur la coagulation étaient évalués par thrombelastographie (TEG) et comparés aux effets de la saline. L’injection de liquide amniotique n’a pas permis de reproduire les signes cliniques de SELA, n’a pas entrainé la génération de bradykinine, et n’a pas eu d’effet sur le temps de prothrombine, le temps de thromboplastine partielle activée, et l’activité du facteur VIII de. Une thrombocytopénie sévère et transitoire a cependant été notée 5 minutes après l’injection de liquide amniotique. De plus, en additionnant in vitro de liquide amniotique au sang on a observé un tracé de TEG hypercoagulable comparé à celui obtenu avec la saline. Le modèle n’ayant pas pu reproduire le SELA, le rôle des kinines dans ce syndrome reste à déterminer. / Amniotic fluid embolism (AFE) is a rare but catastrophic complication of parturition characterized by severe hypotension, cardiovascular collapse, and massive consumptive coagulopathy. Its pathophysiology remains obscure. In particular, the potential role of bradykinin in hypotension is unknown. The objective of this study was to develop a suitable animal model of AFE and to study the effects of amniotic fluid injection on bradykinin release in this model. Twelve rabbits in late gestation (25 days) were used. For each rabbit, amniotic fluid was collected from foetal amniotic sacs by laparotomy. For six rabbits, the amniotic fluid was then injected as a bolus via the left auricular vein, whereas the six other rabbits received saline (control group). In parallel, the in vitro effects of amniotic fluid on coagulation was assessed by thrombelastography (TEG) and compared to the effects of saline. Injection of amniotic fluid did not reproduce clinical signs of AFE, did not provoke bradykinin generation and had no effect on prothrombin time, the activated partial thromboplastin time, nor Factor VIII activity. However, a significant thrombocytopenia was observed five minutes after amniotic fluid administration. This thrombocytopenia resolved within 60 minutes. In vitro addition of amniotic fluid to blood resulted in accelerated clotting on TEG tracings as compared to the effect of saline. As we were not able to reproduce AFE with our model, the role of kinins in this syndrome remains to be determined.