Introduction: La stratégie diagnostique de l’EP au cours de la grossesse est incertaine du fait du manque d’études solides d’un point de vue méthodologique, et du risque lié à l’irradiation des examens diagnostiques (angioscanner thoracique et scintigraphie pulmonaire). L’enjeu est donc de valider des stratégies performantes d’une part, et d’identifier des marqueurs cliniques permettant de réduire le recours aux examens irradiants d’autre part. Notre premier objectif a été d’identifier les pièges au cours de la stratégie diagnostique de l’EP (baisse de la performance du dosage des D‐dimères, des scores de probabilité clinique et de l’imagerie) au cours de la grossesse. Le deuxième objectif a été de comparer les performances diagnostiques et les risques des deux examens d’imagerie de référence que constituent la scintigraphie pulmonaire et l’angioscanner thoracique. Le troisième objectif a été de valider une stratégie diagnostique permettant une réduction du recours aux examens irradiants (ajustement du taux de D-dimères sur la probabilité clinique). Le dernier objectif a été de mettre en place un programme de recherche centré sur le poids des antécédents familiaux de MVTE, paramètre lui aussi susceptible de réduire le recours aux examens paracliniques. Conclusion : Au terme de ces analyses, nous avons développé un programme de validation d’une stratégie diagnostique de l’EP chez la femme enceinte ; en outre, l’identification d’un ajustement du taux de D‐dimères sur la probabilité clinique ainsi que, en termes de perspective, sur les antécédents familiaux de MVTE a le potentiel de conduire à des stratégies diagnostiques moins irradiantes et plus performantes chez les femmes enceintes ayant une suspicion d’EP. / Introduction : The diagnostic strategy for PE during pregnancy is uncertain due to the lack of high quality studies and the risk of radiation exposure with computed tomography pulmonary angiography (CTPA) and ventilationperfusion (V-Q) lung scan. The challenge is to validate diagnostic strategies, and to identify predictive factors to reduce the number of additional imaging tests with radiation exposure.First, we aim to identify pitfalls during the diagnostic strategy of PE (the D-dimer assay threshold, clinical probability scores, imaging) during pregnancy. Second, our objective was to compare the diagnostic efficiency of CTPA and (V-Q) lung scan during pregnancy.Third, our objective was to validate a diagnostic strategy wich reduces the number of imaging tests (adjustment of the D-dimer level on the clinical probability). Finally, the last objective was to set up a research program focused on the weight of the family history of MVTE, that may also reduce the need of additional tests. Conclusion : We identified an ongoing validation protocol with a new diagnostic algorithm in pregnant patients withPE suspicion ; Furthermore, identifying a D-dimer level adjustement as well as a family history of VTE can lead tomore effective diagnostic stragegies with less radiation exposure for pregnant women with suspected PE.

Comme dans tout cancer, l'association entre myélome multiple et maladie thrombo-embolique veineuse est bien établie. Son incidence au cours du myélome est en moyenne de 10 à 20%. Elle semble plus élevée en cas de myélome de novo et lors de l’utilisation de traitements immunomodulateurs comme le thalidomide. Pourtant, la part de surcroît du risque de thrombose dû à ce traitement n’est pas encore très bien définie. Tout d’abord, nous avons réalisé un bilan de ces pathologies afin de délimiter le champ d’étude grâce à une revue de la littérature. Nous avons ensuite évalué l’incidence de la maladie thrombo-embolique veineuse, identifié les facteurs de risque thrombotique et évalué le classement en groupe de risque des patients présentant un myélome et traités par immunomodulateur grâce à une étude observationnelle, multicentrique, prospective, de la prise en charge des myélomes par les hématologues en France. Par la suite, nous avons réalisé l’analyse médico-économique du seul essai randomisé réalisé à ce jour sur la thrombophylaxie chez les malades présentant un myélome multiple traités par thalidomide en première ligne. Cette étude montre un gain de qualité de vie associé à des économies majeures lors de la prévention de la thrombose par aspirine plutôt que par héparine. Enfin nous avons réalisé 2 études médicales utilisant la génération de thrombine, test biologique de recherche. La première a été effectuée afin d’essayer de prédire les patients qui vont présenter une thrombose. La deuxième a pour but de rechercher l’existence d’une résistance à l’héparine aux doses habituelles utilisées dans cette pathologie / The association between multiple myeloma and venous thromboembolic disease is well established. This incidence in myeloma is on average from 10 to 20%. It appears to be higher in newly diagnosed myeloma and immunomodulatory drugs such as thalidomide might significantly increase the risk. However, the risk of thrombosis due to these treatments is not yet well defined. First, we performed a review of these diseases in order to delimit the field of this study through a literature review. Then, we evaluated the incidence of venous thromboembolic disease in patients with myeloma and treated with immunomodulatory, identified the thrombotic risk factors and evaluated the thrombotic risk assessment based on the physicians choice, through an observational, multicenter, prospective French study. Moreover, we performed the medico-economic analysis of the only randomized trial conducted to date on the thrombophylaxis in patients with multiple myeloma treated with thalidomide in the first line of chemotherapy. This analysis showed a gain in quality of life associated with significant cost savings in the prevention of thrombosis by aspirin rather than heparin. Finally we performed two medical studies using thrombin generation test, a global assay that measures the overall tendency of a plasma sample to form thrombin. The first study was conducted to predict patients who will have thrombosis. The second is performed to know if a heparin resistance with the usual doses in this pathology, exists

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.

<p>Acute thrombo-embolic occlusion of the superior mesenteric artery (SMA) with intestinal infarction is a lethal disease, difficult to diagnose in time, with unknown incidence and cause-specific mortality. The aim of this thesis was to characterize the disease and to develop diagnostic methods. </p><p>Two laboratory studies were conducted on patients with suspected acute SMA occlusion. A pilot-study showed that the fibrinolytic marker D-dimer was elevated in six patients with the disease. In the subsequent study including 101 patients, D-dimer was the only elevated coagulation marker in nine patients with the disease. In a prospective study 24 patients (median age 84 years) were identified, of whom four were diagnosed at autopsy, despite an autopsy-rate of 10%. One-fourth were initially nursed in non-surgical wards. Length of the intestinal infarction was a predictor for death. An analysis of patients from the three studies showed that D-Dimer was elevated in all 16 tested patients with the disease.</p><p>Sixty patients with acute SMA occlusion underwent intestinal revascularisation and were registered in the Swedish Vascular Registry (SWEDVASC). One-year survival-rate was 40%. Previous vascular surgery was a negative risk-factor.</p><p>A population-based study was conducted in Malmö, based on an autopsy-rate of 87%. Among 270 patients with the disease, 2/3 were diagnosed only at autopsy and 1/2 were managed in non-surgical wards. The incidence was 8.6 per 100000 person years. The age-standardized incidence increased exponentially without gender differences. The diagnosis was the cause of death in 1.2% among octogenarians and beyond. Thrombotic occlusions were located proximally within the SMA and associated with extensive intestinal infarctions. Synchronous embolism, often multiple, occurred in 2/3 of the patients with embolic occlusions.</p><p>Conclusions: A normal D-dimer at presentation most likely excludes the diagnosis. Acute SMA occlusion was more frequent than previously estimated from clinical series. The patients were often nursed in non-surgical wards.</p>

Acute thrombo-embolic occlusion of the superior mesenteric artery (SMA) with intestinal infarction is a lethal disease, difficult to diagnose in time, with unknown incidence and cause-specific mortality. The aim of this thesis was to characterize the disease and to develop diagnostic methods. Two laboratory studies were conducted on patients with suspected acute SMA occlusion. A pilot-study showed that the fibrinolytic marker D-dimer was elevated in six patients with the disease. In the subsequent study including 101 patients, D-dimer was the only elevated coagulation marker in nine patients with the disease. In a prospective study 24 patients (median age 84 years) were identified, of whom four were diagnosed at autopsy, despite an autopsy-rate of 10%. One-fourth were initially nursed in non-surgical wards. Length of the intestinal infarction was a predictor for death. An analysis of patients from the three studies showed that D-Dimer was elevated in all 16 tested patients with the disease. Sixty patients with acute SMA occlusion underwent intestinal revascularisation and were registered in the Swedish Vascular Registry (SWEDVASC). One-year survival-rate was 40%. Previous vascular surgery was a negative risk-factor. A population-based study was conducted in Malmö, based on an autopsy-rate of 87%. Among 270 patients with the disease, 2/3 were diagnosed only at autopsy and 1/2 were managed in non-surgical wards. The incidence was 8.6 per 100000 person years. The age-standardized incidence increased exponentially without gender differences. The diagnosis was the cause of death in 1.2% among octogenarians and beyond. Thrombotic occlusions were located proximally within the SMA and associated with extensive intestinal infarctions. Synchronous embolism, often multiple, occurred in 2/3 of the patients with embolic occlusions. Conclusions: A normal D-dimer at presentation most likely excludes the diagnosis. Acute SMA occlusion was more frequent than previously estimated from clinical series. The patients were often nursed in non-surgical wards.

Acute occlusion of the superior mesenteric artery (SMA) is a condition associated with high mortality and morbidity. The aim of this thesis is to evaluate diagnostic and therapeutic approaches for acute SMA occlusion. In a prospective study of patients with suspected intestinal ischemia, no biomarker was sufficiently accurate to detect this condition. In a second retrospective study, pancreatic amylase and troponin-I were elevated in a substantial proportion of patients with verified SMA occlusion. In an experimental animal model of acute SMA occlusion, microarray studies of ischemic small bowel wall were used to characterize the mRNA response to ischemia. Thrombospondin, Monocyte Chemoattractant Protein 1 and Gap Junction Alpha 1 were consistently up-regulated in all pigs with intestinal ischemia. Genes encoding previously proposed biomarkers for intestinal ischemia were either up-regulated, such as lactate dehydrogenase and creatine kinase, or down-regulated, such as intestinal fatty acid binding protein and glutathione S-transferase. In a study of the role of computed tomography in the diagnosis of SMA occlusion, it was shown that computed tomography with intravenous contrast was associated with improved survival. A retrospective analysis of all acute SMA revascularizations in Sweden 1999-2006 revealed that D-dimer was elevated in all 35 measured cases.  Endovascular surgery was associated with better outcome than open surgery, both in short and in long term. The presence of postoperative short bowel syndrome was a strong independent risk-factor for decreased long-term survival. Conclusions: Data affirm that D-dimer may serve as an exclusion test for acute SMA occlusion, whereas elevated troponin-I and pancreatic amylase are potential diagnostic pitfalls. Contrast-enhanced computed tomography of the visceral arteries seems to be the best diagnostic method. Endovascular surgery is an option to open surgery in selected cases, and was associated with favourable outcome.

L’identification des facteurs de risque de la maladie thromboembolique veineuse (MVTE) est un enjeu pour la prévention de la maladie et de sa récidive. Nous avons montré chez l’homme que le cumul des facteurs de risque cardiovasculaires d’athérosclérose (FRCV) est associé à la MVTE non provoquée, à sa gravité et au risque de récidive. Le vieillissement, FRCV et facteur de risque de MVTE, induit chez le rat une dysfonction endothéliale de la veine fémorale liée aux cyclooxygénases (COX), associée à la génération de prostanoïdes au profil pro-thrombogène. Chez le rat obèse ZSF1 jeune, le cumul des FRCV induit une dysfonction endothéliale veineuse précoce liée aux COX-1 et 2. Un traitement par Ω-3 chez le rat vieillissant permet de moduler le métabolisme de l’acide arachidonique pour générer des prostanoïdes moins délétères COX-2-dépendants pouvant réduire le risque thrombogène, faisant des Ω-3 un traitement adjuvant potentiel de la MVTE. / Identification of risk factors for venous thromboembolism (VTE) is a major concern for the prevention of the disease and its recurrence. We have shown in humans that the cumulative cardiovascular risk factors (CVFR) for atherosclerosis were associated with unprovoked VTE, its severity and the risk of recurrence. Aging, CVRF and VTE risk factor, induced an endothelial dysfunction in the rat femoral vein involving cyclooxygenases (COX) associated with potential pro-thrombogenic prostanoids generation. In the young obese ZSF1 rat, cumulative CVRF induced early venous endothelial dysfunction related to COX-1 and 2. Omega-3 treatment in aging rats modulates arachidonic acid pathway leading to COX-2-mediated formation of less deleterious prostanoids, associated with a decreased thrombogenic risk, making omega-3 a potential adjuvant treatment for VTE.

Hemostasis, thrombosis, and inflammation are tightly interconnected processes which may give rise to thrombo-inflammation, involved in infectious and non-infectious acute and chronic diseases, including cardiovascular diseases (CVD). Traditionally, due to its hemostatic role, blood coagulation is isolated from the inflammation, and its critical contribution in the progressing CVD is underrated, until the full occlusion of a critical vessel occurs. Underlying vascular injury exposes extracellular matrix to deposit platelets and inflammatory cells. Platelets being key effector cells, bridge all the three key processes (hemostasis, thrombosis, and inflammation) associated with thrombo-inflammation. Under physiological conditions, platelets remain in an inert state despite the proximity to the endothelium and other cells which are decorated with glycosaminoglycan (GAG)-rich glycocalyx (GAGs). A pathological insult to the endothelium results in an imbalanced blood coagulation system hallmarked by increased thrombin generation due to losses of anticoagulant and cytoprotective mechanisms, i.e., the endothelial GAGs enhancing antithrombin, tissue factor pathwayinhibitor (TFPI) and thrombomodulin-protein C system. Moreover, the loss of GAGs promotes the release of mediators, such as von Willebrand factor (VWF), platelet factor 4 (PF4), and P-selectin, both locally on vascular surfaces and to circulation, further enhancing the adhesion of platelets to the affected sites. Platelet-neutrophil interaction and formation of neutrophil extracellular traps foster thrombo-inflammatory mechanisms exacerbating the cardiovascular disease course. Therefore, therapies which not only target the clotting mechanisms but simultaneously or independently convey potent cytoprotective effects hemming the inflammatory mechanisms are expected to provide clinical benefits. In this regard, we review the cytoprotective protease activated protein C (aPC) and its strong anti-inflammatory effects thereby preventing the ensuing thrombotic complications in CVD. Furthermore, restoring GAGlike vasculo-protection, such as providing heparin-proteoglycan mimetics to improve regulation of platelet and coagulation activity and to suppress of endothelial perturbance and leukocyte-derived pro-inflammatory cytokines, may provide a path to alleviate thrombo-inflammatory disorders in the future. The vascular tissue-modeled heparin proteoglycan mimic, antiplatelet and anticoagulant compound (APAC), dual antiplatelet and anticoagulant, is an injury-targeting and locally acting arterial antithrombotic which downplays collagen- and thrombin-induced and complement-induced activation and protects from organ injury.