Venous thromboembolism (VTE) is a common disease with a myriad of presentation. It is often difficult to diagnosis with symptoms which are shared with many other disorders. Because of the overlap in symptomatology with other pathologies it is both commonly overlooked when present and commonly considered when absent. The threshold for investigating suspected VTE has dropped over time, in part due to a greater awareness of the disease among clinicians, but also because of the greater availability of diagnostic tests which are both accurate at positively diagnosing VTE and are patient friendly. This has resulted in a mushrooming of the number of diagnostic tests being performed for suspected VTE in radiology departments. As such radiology provides a window into the disease in a way that no other speciality can. All branches of medicine having their share of VTE patients but radiology provides a unique opportunity to study VTE patients as, no matter from which speciality they arise when the disease is suspected, they will almost inevitably end up undergoing a definitive radiological test. There is much still to learn about VTE however developments in modern imaging and computerised databases have advanced our understanding of this common disease. The window that radiology provides into VTE has contributed towards those advances.

Orientador: Joyce Maria Anichino-Baizzacchi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-17T00:05:28Z (GMT). No. of bitstreams: 1 Alessio_AlineMorandi_D.pdf: 8973520 bytes, checksum: 3a7a6ff893220f5bdd3d1d52da276f91 (MD5) Previous issue date: 2010 / Resumo: As células endoteliais participam da hemostasia com efeitos pró e antitrombóticos, que podem ser estimulados por uma lesão endotelial. A presença de células endoteliais na circulação pode ser considerada um novo marcador de integridade vascular, como já descrito em várias patologias tais como: doenças cardiovasculares, doenças infecciosas, doenças imunes, transplantes, anemia falciforme. Os objetivos do nosso estudo foram: padronizar a identificação e quantificação das células endoteliais circulantes (CECs) e das células endoteliais progenitoras (CEPs) em um grupo de pacientes com trombose venosa profunda (TVP) ao diagnóstico (aguda, 1ª coleta) e após no mínimo 6 meses (2ª coleta), em um grupo de TVP crônica e em um grupo controle; padronizar um modelo animal de TVP induzida por lesão endotelial para avaliar as CECs e CEPs no sangue periférico e no trombo venoso. O grupo de TVP aguda foi composto por 9 pacientes [F: 7; M: 2; 45 anos (26 - 54 anos)], sendo recrutados 6 indivíduos para uma 2ª coleta [F: 5; M: 1; 47,5 anos (27 - 55 anos)], no grupo de TVP crônica foram incluídos 10 pacientes [F: 6; M: 4; 44,5 anos (28 - 56 anos)] e no grupo controle 11 voluntários [F: 9; M: 2; 29 anos (21 - 52 anos)]. A identificação das CECs e CEPs no sangue periférico foi realizada por citometria de fluxo. No modelo animal, a TVP foi induzida por lesão endotelial com uma solução de FeCl3 a 15%. Após a indução da TVP as CECs e CEPs foram avaliadas no sangue periférico nos tempos: 15 minutos, 30 minutos, 45 minutos, 1 hora, 24 horas, 48 horas e 72 horas. O trombo venoso formado na veia cava inferior (VCI) foi avaliado pela coloração de Verhoff van Gienson e a presença de CECs e CEPs por imunofluorescência. Houve uma diferença estatística no número das CECs (P=0.001, CD31+CD144+CD45dimCD133-; P<0.001, CD31+CD146+CD45dimCD133-; P=0.002, CD31+VEGFR2+CD45dimCD133-) entre os grupos estudados, com um aumento importante nos pacientes com TVP aguda. Os grupos de TVP crônica e TVP 2ª coleta mostraram um aumento significativo de CECs em relação aos controles. Não houve diferença estatística no número das CEPs (CD34+VEGFR2+CD45dimCD133-) entre os grupos estudados, porém observou-se um aumento no grupo de TVP aguda. No modelo animal, a oclusão total da VCI foi verificada entre 15 minutos e 1 hora. Após 24 horas ocorreu uma diminuição progressiva da área do trombo formado [85,4% (24h); 65,4% (48h); 51,3% (72h)], e não foram observadas CECs e CEPs no mesmo. No sangue periférico, no tempo de 48 horas houve um aumento importante de CECs e CEPs quando comparado com os outros tempos estudados (P=0.001, Sca1-VEGFR2+CD45dim; P=0.004, CD34-VEGFR2+CD45dim; P<0.001,Sca1+VEGFR2+CD45dim; P<0.001, CD34+VEGFR2+CD45dim). Os resultados observados em camundongos e humanos sugerem que as CEPs podem ser recrutadas da medula óssea para a circulação, participando do processo de reparo endotelial. O aumento de CECs na fase em que se inicia o processo de recanalização no modelo animal, sugere que apesar da lesão endotelial inicial, as mesmas somente são liberadas quando o fluxo começa a ser restabelecido. Neste estudo concluímos que as CECs podem constituir um marcador de dano vascular. / Abstract: Endothelial cells participate in hemostasia and have pro and anti -thrombotic effects which can be stimulated by an endothelial lesion. The presence of endothelial cells in circulation can be considered a novel marker of vascular integrity, as described in several pathologies, such as: cardiovascular disease, infectious disease, immune diseases, transplants, and sickle cell anemia. The aims of our study were to: standardize the identification and quantification of circulating endothelial cells (CECs) and progenitor endothelial cells (EPCs) in a group of patients with Deep Vein Thrombosis (DVT) at diagnosis (acute, 1st collection) and after a minimum of six months (2nd collection), in a group with chronic DVT and in a control group; standardize an animal model with DVT induced by endothelial lesion in order to evaluate CECs and EPCs in peripheral blood and in venous thrombosis. The group of DVT was composed of 9 patients [F: 7; M: 2; 45 years old (y.o.) (26 - 54 y.o.)], of which six individuals were recruited for the 2nd collection [F: 5; M: 1; 47.5 y.o. (27 - 55 y.o.)]; in the chronic DVT group 10 patients were included [F: 6; M: 4; 44.5 y.o. (28 - 56 y.o.)]; and in the control group 11 volunteers were included [F: 9; M: 2; 29 y.o. (21 - 52 y.o.)]. The identification of CECs and EPCs in peripheral blood was carried out by flow cytometry. DVT was induced in the animal model by endothelial lesion using a FeCl3 solution at 15%. After DVT induction, CECs and EPCs were evaluated in peripheral blood at: 15 minutes, 30 minutes, 45 minutes, 1 hour, 24 hours, 48 hours and 72 hours. The venous thrombus formed in the inferior cava vein (ICV) was evaluated using Verhoff van Gienson stain and the presence of CECs and EPCs was evaluated using immunofluorescence. There was a statistical difference in the number of CECs (P=0.001, CD31+CD144+CD45dimCD133-; P<0.001, CD31+CD146+CD45dimCD133-; P=0.002, CD31+VEGFR2+CD45dimCD133-) between the groups studied, with a significant increase in acute DVT patients. The chronic DVT and 2nd collection DVT groups demonstrated a significant increase in CECs in relation to the controls. There was no statistical difference in the number of EPCs (CD34+VEGFR2+CD45dimCD133-) among the groups studied, however an increase in the acute DVT group was observed. In the animal model, total ICV occlusion was observed between 15 minutes and 1 hour. After 24 hours a progressive decrease in the area of the formed thrombus occurred [85.4% (24h); 65.4% (48h); 51.3% (72h)], and no CECs or CEPs were observed. After 48hours, there was a significant increase in CECs and EPCs in peripheral blood when compared to other periods studied (P=0.001, Sca1-VEGFR2+ CD45dim; P=0.004, CD34-VEGFR2+CD45dim; P<0.001, Sca1+VEGFR2+CD45dim; P<0.001, CD34+VEGFR2+CD45dim). The results observed in mice and human beings suggest that EPCs can be recruited to circulation from the bone marrow, participating in a process of endothelial repair. The increase of CECs during the phase when the re-channeling process begins in the animal model, suggests that despite the initial endothelial lesion, CECs are liberated when the flow is reestablished. In the present study we concluded that CECs can represent a vascular damage marker. / Doutorado / Medicina Experimental / Doutor em Ciências

Orientador: Nelci Fenalti Hoehr, Joyce M. Anichino-Baizzacchi / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T11:11:48Z (GMT). No. of bitstreams: 1 Alessio_AlineMorandi_M.pdf: 5240817 bytes, checksum: f759b9c995ffcb5198175f672d2a40aa (MD5) Previous issue date: 2005 / Resumo: o estrógeno atua na hemostasia promovendo efeitos pró e antitrombóticos, sua ação ocorre através de sua ligação a receptores nucleares específicos, denominados receptores 'alfa' e 'beta' do estrógeno (RE). A presença de polimorfismos nos genes que codificam o RE poderia modular a resposta do estrógeno, assim como a transcrição de genes e conseqüentemente a expressão. Existem fatores de risco adquiridos para a trombose venosa profunda (TVP) que estão associados a alterações do nível de estrógeno como: gravidez, puerpério, uso de anticoncepcional oral (ACO) e a terapia de reposição hormonal. Os objetivos deste estudo foram de associar polimorfismos nos genes dos RE 'alfa' e 'beta' em controles e mulheres e homens com TVP e avaliar a influência deles na atividade da proteína C (PC), proteína S (PS), antitrombina e concentração de fibrinogênio. Nas mulheres sob o uso de ACO, o genótipo AA do polimorfismo G1730A e, nas mulheres grávidas, os genótipos AA e GA do polimorfismo G1082A, ambos no gene do RE-~, podem ter um efeito protetor para o risco de TVP. Porém, o genótipo GG do polimorfismo G1730A tem uma influência no aumento da atividade da PS nas mulheres do grupo controle total e nas mulheres sob o uso de ACO; e os genótipos AA e AG do polimorfismo A351G no gene do RE-'alfa' , e o genótipo GG do polimorfismo G1082A tem um efeito no aumento da concentração de fibrinogênio nas mulheres grávidas. Contudo, a mutação G20210A no gene da protrombina, o fator V de Leiden e os polimorfismos do RE- foram fatores preditores de trombose venosa. Apesar da miscigenação brasileira, a PC apresentou diminuída em mulheres AITo-descendente. Nossos resultados sugerem que polimorfismos no gene dos RE-'beta' têm uma influência maior no risco para TVP. A contribuição deste trabalho é de grande importância, pois nenhum estudo associou o risco de TVP com os polimorfismos dos RE-'beta' / Abstract: Estrogen acts in haemostasis promoting pro and antithrombotic effects. Its action occurs through linking the specific nuclear receptors called 'alfa' and 'beta' estrogen receptor (ER). Polymorphisms in the genes that codify the ER a and ~could modulate estrogen response, as well as gene transcription and expression. There are acquired risk factors for deep venous thrombosis (DVT) that can alter the estrogen levels. These factors are oral contraceptives (OC), hormonal replacement therapy, pregnancy, and puerperium. The objectives of this study were to associate the polymorphisms in the genes of the a and ~ER in controls, women and rnen with DVT, and to evaluate the influence of these polyrnorphisms in protein C, protein S (PS), in antithrombin activity and fibrinogen concentration. Women under OC use with the AA genotype ofthe G1730A polyrnorphism, and pregnant women with the AA and GA genotypes of the G1082A polymorphism, both in the ER-~ gene, could have a protective effect for DVT risk. However, GG genotype of the G1730A polymorphisrn has an influence in the increase of the PS activity in women of the total control group and women under OC use; and the AA and AG genotypes of the A351G polymorphism in the ER-a gene, and the GG genotype of the G1O82A polymorphism have an effect in the increase of the fibrinogen leveI in pregnant women. However, the G20210A rnutation in the prothrombin gene, the Leiden V factor and the polymorphisms in the ER-'alfa' gene were predictor factors of venous thrombosis. Despite Brazilian miscegenation, PC activity was lower in Afro-descendent women. Our results suggest that the polymorphisrns in the ER-'beta' gene have a higher influence for DVT risk. The contribution of this study is of great importance, as no study has associated DVT risk with the ER polymorphisms yet / Mestrado / Patologia Clinica / Mestre em Ciências Médicas

No description available.

La maladie veineuse thromboembolique (MVTE) est un problème de santé publique (plus de 100000 cas par an en France). Elle regroupe deux entités cliniques : la thrombose veineuse profonde (TVP) des membres inférieurs et l’embolie pulmonaire (EP). La TVP correspond à la formation inadaptée d’un thrombus veineux (appelé aussi caillot sanguin) dans les veines profondes (poplitées, fémorales, iliaques). Un thrombus est principalement constitué de globules rouges et de plaquettes dans un réseau de fibrine. La complication majeure d’une TVP est la survenue d’une EP, c’est-à-dire que le thrombus s’est détaché de la paroi veineuse, ou s’est fragmenté, et est entraîné par la circulation sanguine jusqu’à une artère pulmonaire. Cette complication a un taux de mortalité assez élevée autour de 10000 à 20000 cas mortels par an en France. La survenue d’une TVP est multifactorielle associant des facteurs génétiques et acquis pouvant être répartis en trois catégories : la stase veineuse, l’altération de la paroi d’une veine et une hypercoagulabilité. En analysant la structure du thrombus, notre projet vise à identifier le facteur principal responsable de la TVP et à évaluer le risque d’EP. Pour caractériser sa structure, nous disposons de deux modes d’imagerie acoustique : l’échographie et l’élastographie (carte de dureté). Nous proposons d’extraire des descripteurs de ces images acoustiques par deux approches, l’une basée sur les ondelettes (le scattering operator) et l’autre sur les statistiques d’ordre supérieur (les multicorrélations). Ces descripteurs sont ensuite analysées par diverses techniques de classification (analyse en composantes principales, k-moyennes, classification spectrale) pour retrouver la cause principale des TVP ou la présence d’EP. / Venous thromboembolism (VTE) is an important public health issue (over 100000 individuals in France per year). VTE is a combination of a deep venous thrombosis (DVT) and a pulmonary embolism (PE). DVT is an inappropriate formation of a thrombus (also called blood clot) in one of the deep veins of the body, usually in the leg (popliteal, femoral, iliac). There are mainly three components in a thrombus: platelets, red blood cells and a mesh of fibrins. The main complication of a DVT is a pulmonary embolism (PE) which occurs when a thrombus breaks loose and travels to the lungs. PE affects an estimated 10000 - 20 000 individuals just in France per year. Three physiopathological mechanisms cancontribute, isolated or combined, to the development of a DVT: venous stasis, endothelial injury and hypercoagulability. Our project is aiming to relate the thrombus structure, its main triggering factor and the risk of a PE. To characterize the thrombus structure, we are collecting ultrasonography (echogenicity) and elastography (stiffness) of human thrombus. We propose to extract features from these to kind of ultrasound images using two approaches: one basedon wavelets (the scattering operator) and another based on high order statistics (multicorrelations). Then, the obtained features are analysed using several classification technics (principal component analysis, k-means, spectral clustering) to find the main cause of the DVT or the presence of PE.

L’acquisition par MDCT et la reconstruction en coupes épaisses de 1.25 mm permettent l’analyse des artères pulmonaires jusqu’à leur 5ème ordre. L’angiographie thoracique par TDM permet de proposer des critères pronostiques de survie des patients atteints d’EP sévère. Le VD/VGd et le diamètre de la veine azygos en sont les meilleurs prédicteurs. En tenant compte de Dmax, de tmax, de l’homogénéité de l’opacification vasculaire et de la différence minimale nécessaire, le délai optimal pour l’acquisition de la vénographie par TDM se situe entre 210 et 240 sec. pour les veines infrapoplitées et entre 180 et 300 sec. pour les veines supra-poplitées. Pour une vénographie par TDM en mode séquentiel, une acquisition caudo-craniale débutant 210 sec. après l’injection du produit de contraste iodé pourrait permettre la détection optimale des caillots. En mode hélicoïdal, le sens de l’acquisition n’est pas déterminant. Malgré la possible amélioration de la détection des caillots artériels pulmonaires par MDCT, cette technique n’a pas permis de déceler plus d’EP sans TVP que le SDCT. En revanche, puisque le MDCT a permis de détecter plus de TVP sans EP que le SDCT, la vénographie par TDM en MDCT apporte une valeur ajoutée au SDCT. Par ailleurs, en MDCT, la vénographie par TDM diminue de 29% la proportion d’examens indéterminés obtenus par la seule réalisation de l’angiographie thoracique par TDM. Que ce soit en SDCT ou en MDCT, cette étude suggère l’utilité de combiner les deux examens. Chez les patients suspects d’EP, la vénographie par TDM doit s’étendre des mollets aux crêtes iliaques. Bien qu’une EP existe chez une majorité de patients atteints de TVP et vice versa, la charge en caillots dans un compartiment n’indique pas nécessairement la charge en caillots dans l’autre. / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

No description available.

L’accident thromboembolique veineux, tel que la thrombose veineuse profonde (TVP) ou thrombophlébite des membres inférieurs, est une pathologie vasculaire caractérisée par la formation d’un caillot sanguin causant une obstruction partielle ou totale de la lumière sanguine. Les embolies pulmonaires sont une complication mortelle des TVP qui surviennent lorsque le caillot se détache, circule dans le sang et produit une obstruction de la ramification artérielle irriguant les poumons. La combinaison d’outils et de techniques d’imagerie cliniques tels que les règles de prédiction cliniques (signes et symptômes) et les tests sanguins (D-dimères) complémentés par un examen ultrasonographique veineux (test de compression, écho-Doppler), permet de diagnostiquer les premiers épisodes de TVP. Cependant, la performance de ces outils diagnostiques reste très faible pour la détection de TVP récurrentes. Afin de diriger le patient vers une thérapie optimale, la problématique n’est plus basée sur la détection de la thrombose mais plutôt sur l’évaluation de la maturité et de l’âge du thrombus, paramètres qui sont directement corrélées à ses propriétés mécaniques (e.g. élasticité, viscosité). L’élastographie dynamique (ED) a récemment été proposée comme une nouvelle modalité d’imagerie non-invasive capable de caractériser quantitativement les propriétés mécaniques de tissus. L’ED est basée sur l’analyse des paramètres acoustiques (i.e. vitesse, atténuation, pattern de distribution) d’ondes de cisaillement basses fréquences (10-7000 Hz) se propageant dans le milieu sondé. Ces ondes de cisaillement générées par vibration externe, ou par source interne à l’aide de la focalisation de faisceaux ultrasonores (force de radiation), sont mesurées par imagerie ultrasonore ultra-rapide ou par résonance magnétique. Une méthode basée sur l’ED adaptée à la caractérisation mécanique de thromboses veineuses permettrait de quantifier la sévérité de cette pathologie à des fins d’amélioration diagnostique. Cette thèse présente un ensemble de travaux reliés au développement et à la validation complète et rigoureuse d’une nouvelle technique d’imagerie non-invasive élastographique pour la mesure quantitative des propriétés mécaniques de thromboses veineuses. L’atteinte de cet objectif principal nécessite une première étape visant à améliorer les connaissances sur le comportement mécanique du caillot sanguin (sang coagulé) soumis à une sollicitation dynamique telle qu’en ED. Les modules de conservation (comportement élastique, G’) et de perte (comportement visqueux, G’’) en cisaillement de caillots sanguins porcins sont mesurés par ED lors de la cascade de coagulation (à 70 Hz), et après coagulation complète (entre 50 Hz et 160 Hz). Ces résultats constituent les toutes premières mesures du comportement dynamique de caillots sanguins dans une gamme fréquentielle aussi étendue. L’étape subséquente consiste à mettre en place un instrument innovant de référence (« gold standard »), appelé RheoSpectris, dédié à la mesure de la viscoélasticité hyper-fréquence (entre 10 Hz et 1000 Hz) des matériaux et biomatériaux. Cet outil est indispensable pour valider et calibrer toute nouvelle technique d’élastographie dynamique. Une étude comparative entre RheoSpectris et la rhéométrie classique est réalisée afin de valider des mesures faites sur différents matériaux (silicone, thermoplastique, biomatériaux, gel). L’excellente concordance entre les deux technologies permet de conclure que RheoSpectris est un instrument fiable pour la mesure mécanique à des fréquences difficilement accessibles par les outils actuels. Les bases théoriques d’une nouvelle modalité d’imagerie élastographique, nommée SWIRE (« shear wave induced resonance dynamic elastography »), sont présentées et validées sur des fantômes vasculaires. Cette approche permet de caractériser les propriétés mécaniques d’une inclusion confinée (e.g. caillot sanguin) à partir de sa résonance (amplification du déplacement) produite par la propagation d’ondes de cisaillement judicieusement orientées. SWIRE a également l’avantage d’amplifier l’amplitude de vibration à l’intérieur de l’hétérogénéité afin de faciliter sa détection et sa segmentation. Finalement, la méthode DVT-SWIRE (« Deep venous thrombosis – SWIRE ») est adaptée à la caractérisation de l’élasticité quantitative de thromboses veineuses pour une utilisation en clinique. Cette méthode exploite la première fréquence de résonance mesurée dans la thrombose lors de la propagation d’ondes de cisaillement planes (vibration d’une plaque externe) ou cylindriques (simulation de la force de radiation par génération supersonique). DVT-SWIRE est appliquée sur des fantômes simulant une TVP et les résultats sont comparés à ceux donnés par l’instrument de référence RheoSpectris. Cette méthode est également utilisée avec succès dans une étude ex vivo pour l’évaluation de l’élasticité de thromboses porcines explantées après avoir été induites in vivo par chirurgie. / The venous thromboembolism such as the lower limb deep venous thrombosis (DVT) is a vascular pathology characterized by a blood clot formation that induces partial or total vessel lumen occlusion. Pulmonary embolism is a fatal complication of DVT where the clot detaches from the wall, circulates in the blood flow, and produces an obstruction of pulmonary arterial branches. The combination of clinical prediction rules (signs or symptoms) and blood tests (D-dimer testing) coupled to venous ultrasonography (i.e. compression ultrasonography, color Doppler) allows an accurate diagnosis of first DVT. Nevertheless, such clinical tools present poor results to detect recurrent thrombotic events. Then, in order to guide patients towards optimal therapy, the problem is no more to detect the presence of thrombus, but to evaluate its maturity and its age, which are correlated to their mechanical properties (e.g. elasticity, viscosity). The dynamic elastography (DE) has been recently proposed as a novel non-invasive imaging modality capable to characterize the quantitative mechanical properties of tissues. The DE is based on the analysis of acoustical parameters (i.e. velocity, attenuation, wave pattern) of low frequency (10-7000 Hz) shear waves propagating within the probed medium. Such shear waves generated by external vibration, or remotely using ultrasound beam focalisation (radiation force), were tracked using ultra-fast ultrasound or magnetic resonance imaging. A method based on DE and adapted to mechanical characterization of venous thrombosis may allow the quantification of diseases severity in order to improve the final diagnosis. This thesis presents the works related to the development and complete validation of a novel non-invasive elastography imaging method for the quantitative and reliable estimation of mechanical properties of venous thrombosis. In order to fulfil the main objective, it is first necessary to improve knowledge about mechanical behaviours of blood clot (coagulated blood) subjected to a dynamic solicitation similar to DE. The shear storage (elastic behaviour, G’) and loss (viscous behavior, G’’) moduli of porcine blood clots are measured by DE during the blood coagulation kinetics (at 70 Hz) and after completely coagulation (between 50 Hz and 160 Hz). These results are the first dynamic behaviour measurements of blood clots in such wide frequency range. The subsequent step consists in introducing an innovative reference instrument (« gold standard »), called RheoSpectris, dedicated to measure the hyper-frequency viscoelasticity (between 10 Hz and 1000 Hz) of materials and biomaterials. This tool is indispensable to validate new dynamic elastography techniques. A comparative study between RheoSpectris and classical rheometry is performed to validate the measurements on different materials (silicon, thermoplastic, biomaterials, gel). The excellent agreement between both technologies allows to conclude that RheoSpectris is a reliable instrument for mechanical measurements at high frequencies, which is not always possible with current tools. The theoretical basis of a novel elastographic imaging modality, labelled SWIRE (« shear wave induced resonance dynamic elastography ») is presented and validated on vascular phantoms. Such approach allows the characterization of mechanical properties of a confined inclusion (e.g. blood clot) from its resonance (displacement amplification) due to the propagation of judiciously oriented shear waves. SWIRE has also the advantage to amplify the vibration amplitude within the heterogeneity to help for its detection and segmentation. Finally, the method DVT-SWIRE ((« Deep venous thrombosis – SWIRE ») is adapted to the quantitative elasticity estimation of venous thrombosis in the context of clinical use. DVT-SWIRE exploits the first resonance frequency measured within the thrombosis during the plane (vibration of rigid plate) or cylindrical (simulating supersonic radiation force generation) shear waves propagation. The technique is applied on DVT phantoms and the results are compared to those given by the RheoSpectris reference instrument. This method is also used successfully in an ex vivo study for the elasticity assessment of explanted porcine thrombosis surgically induced in vivo.

Venous disease will affect 1-3% of the western world at some point in their lives, yet there are few effective treatments for the venous system [1]. One such disease is chronic venous insufficiency (CVI), a painful and debilitating illness that affects the superficial and deep vein valves of the legs. When the valves become incompetent they allow reflux and subsequent pooling of blood. Current clinical therapies are only moderately; and therefore, the need for a better solution remains. Prosthetic venous valves were constructed from a novel hydrogel biomaterial patented by Georgia Tech. The valves had flexible cusps similar to normal, anatomic venous valves. The purpose of this work was to evaluate the thrombotic potential of the GT venous valve in an in vitro study and to design a percutaneous delivery system. In vitro thrombosis model provides an appropriate intermediate step between valve development and in vivo analysis, which is necessary to determine the biocompatibility of the prosthetic device. The flow system was modified from a one-pass, flow-through thrombosis assay using whole blood [2] to mimic pulsatile physiologic conditions. Cessation of flow indicated thrombotic obstruction. Histological analysis was performed using H and E staining and Carstairs stain (specific for platelets). A group of valves were lined with Dacron to confirm the thrombotic potential of the system. All Dacron valves were occluded by thrombus connecting the polymer fibers with adherent platelets. Whole blood perfused through the GT prosthetic valves exhibited no thrombosis or platelet adherence. All GT valves were patent and competent after blood perfusion. H and E staining revealed no thrombus deposition on the GT vein valves. A percutaneous delivery system was designed after evaluating the GT valves for their compressibility and plastic deformation over time. Appropriate stents, catheters and sheaths were selected. As designed, this system will be utilized in an ovine trial of the valve. Due to the low in vitro thrombotic potential and strong history of PVA as a medical implant material, positive trial results are expected. With successful animal and human trials this valve can provide a potential intervention for the 7 million people suffering from CVI.

L’accident thromboembolique veineux, tel que la thrombose veineuse profonde (TVP) ou thrombophlébite des membres inférieurs, est une pathologie vasculaire caractérisée par la formation d’un caillot sanguin causant une obstruction partielle ou totale de la lumière sanguine. Les embolies pulmonaires sont une complication mortelle des TVP qui surviennent lorsque le caillot se détache, circule dans le sang et produit une obstruction de la ramification artérielle irriguant les poumons. La combinaison d’outils et de techniques d’imagerie cliniques tels que les règles de prédiction cliniques (signes et symptômes) et les tests sanguins (D-dimères) complémentés par un examen ultrasonographique veineux (test de compression, écho-Doppler), permet de diagnostiquer les premiers épisodes de TVP. Cependant, la performance de ces outils diagnostiques reste très faible pour la détection de TVP récurrentes. Afin de diriger le patient vers une thérapie optimale, la problématique n’est plus basée sur la détection de la thrombose mais plutôt sur l’évaluation de la maturité et de l’âge du thrombus, paramètres qui sont directement corrélées à ses propriétés mécaniques (e.g. élasticité, viscosité). L’élastographie dynamique (ED) a récemment été proposée comme une nouvelle modalité d’imagerie non-invasive capable de caractériser quantitativement les propriétés mécaniques de tissus. L’ED est basée sur l’analyse des paramètres acoustiques (i.e. vitesse, atténuation, pattern de distribution) d’ondes de cisaillement basses fréquences (10-7000 Hz) se propageant dans le milieu sondé. Ces ondes de cisaillement générées par vibration externe, ou par source interne à l’aide de la focalisation de faisceaux ultrasonores (force de radiation), sont mesurées par imagerie ultrasonore ultra-rapide ou par résonance magnétique. Une méthode basée sur l’ED adaptée à la caractérisation mécanique de thromboses veineuses permettrait de quantifier la sévérité de cette pathologie à des fins d’amélioration diagnostique. Cette thèse présente un ensemble de travaux reliés au développement et à la validation complète et rigoureuse d’une nouvelle technique d’imagerie non-invasive élastographique pour la mesure quantitative des propriétés mécaniques de thromboses veineuses. L’atteinte de cet objectif principal nécessite une première étape visant à améliorer les connaissances sur le comportement mécanique du caillot sanguin (sang coagulé) soumis à une sollicitation dynamique telle qu’en ED. Les modules de conservation (comportement élastique, G’) et de perte (comportement visqueux, G’’) en cisaillement de caillots sanguins porcins sont mesurés par ED lors de la cascade de coagulation (à 70 Hz), et après coagulation complète (entre 50 Hz et 160 Hz). Ces résultats constituent les toutes premières mesures du comportement dynamique de caillots sanguins dans une gamme fréquentielle aussi étendue. L’étape subséquente consiste à mettre en place un instrument innovant de référence (« gold standard »), appelé RheoSpectris, dédié à la mesure de la viscoélasticité hyper-fréquence (entre 10 Hz et 1000 Hz) des matériaux et biomatériaux. Cet outil est indispensable pour valider et calibrer toute nouvelle technique d’élastographie dynamique. Une étude comparative entre RheoSpectris et la rhéométrie classique est réalisée afin de valider des mesures faites sur différents matériaux (silicone, thermoplastique, biomatériaux, gel). L’excellente concordance entre les deux technologies permet de conclure que RheoSpectris est un instrument fiable pour la mesure mécanique à des fréquences difficilement accessibles par les outils actuels. Les bases théoriques d’une nouvelle modalité d’imagerie élastographique, nommée SWIRE (« shear wave induced resonance dynamic elastography »), sont présentées et validées sur des fantômes vasculaires. Cette approche permet de caractériser les propriétés mécaniques d’une inclusion confinée (e.g. caillot sanguin) à partir de sa résonance (amplification du déplacement) produite par la propagation d’ondes de cisaillement judicieusement orientées. SWIRE a également l’avantage d’amplifier l’amplitude de vibration à l’intérieur de l’hétérogénéité afin de faciliter sa détection et sa segmentation. Finalement, la méthode DVT-SWIRE (« Deep venous thrombosis – SWIRE ») est adaptée à la caractérisation de l’élasticité quantitative de thromboses veineuses pour une utilisation en clinique. Cette méthode exploite la première fréquence de résonance mesurée dans la thrombose lors de la propagation d’ondes de cisaillement planes (vibration d’une plaque externe) ou cylindriques (simulation de la force de radiation par génération supersonique). DVT-SWIRE est appliquée sur des fantômes simulant une TVP et les résultats sont comparés à ceux donnés par l’instrument de référence RheoSpectris. Cette méthode est également utilisée avec succès dans une étude ex vivo pour l’évaluation de l’élasticité de thromboses porcines explantées après avoir été induites in vivo par chirurgie. / The venous thromboembolism such as the lower limb deep venous thrombosis (DVT) is a vascular pathology characterized by a blood clot formation that induces partial or total vessel lumen occlusion. Pulmonary embolism is a fatal complication of DVT where the clot detaches from the wall, circulates in the blood flow, and produces an obstruction of pulmonary arterial branches. The combination of clinical prediction rules (signs or symptoms) and blood tests (D-dimer testing) coupled to venous ultrasonography (i.e. compression ultrasonography, color Doppler) allows an accurate diagnosis of first DVT. Nevertheless, such clinical tools present poor results to detect recurrent thrombotic events. Then, in order to guide patients towards optimal therapy, the problem is no more to detect the presence of thrombus, but to evaluate its maturity and its age, which are correlated to their mechanical properties (e.g. elasticity, viscosity). The dynamic elastography (DE) has been recently proposed as a novel non-invasive imaging modality capable to characterize the quantitative mechanical properties of tissues. The DE is based on the analysis of acoustical parameters (i.e. velocity, attenuation, wave pattern) of low frequency (10-7000 Hz) shear waves propagating within the probed medium. Such shear waves generated by external vibration, or remotely using ultrasound beam focalisation (radiation force), were tracked using ultra-fast ultrasound or magnetic resonance imaging. A method based on DE and adapted to mechanical characterization of venous thrombosis may allow the quantification of diseases severity in order to improve the final diagnosis. This thesis presents the works related to the development and complete validation of a novel non-invasive elastography imaging method for the quantitative and reliable estimation of mechanical properties of venous thrombosis. In order to fulfil the main objective, it is first necessary to improve knowledge about mechanical behaviours of blood clot (coagulated blood) subjected to a dynamic solicitation similar to DE. The shear storage (elastic behaviour, G’) and loss (viscous behavior, G’’) moduli of porcine blood clots are measured by DE during the blood coagulation kinetics (at 70 Hz) and after completely coagulation (between 50 Hz and 160 Hz). These results are the first dynamic behaviour measurements of blood clots in such wide frequency range. The subsequent step consists in introducing an innovative reference instrument (« gold standard »), called RheoSpectris, dedicated to measure the hyper-frequency viscoelasticity (between 10 Hz and 1000 Hz) of materials and biomaterials. This tool is indispensable to validate new dynamic elastography techniques. A comparative study between RheoSpectris and classical rheometry is performed to validate the measurements on different materials (silicon, thermoplastic, biomaterials, gel). The excellent agreement between both technologies allows to conclude that RheoSpectris is a reliable instrument for mechanical measurements at high frequencies, which is not always possible with current tools. The theoretical basis of a novel elastographic imaging modality, labelled SWIRE (« shear wave induced resonance dynamic elastography ») is presented and validated on vascular phantoms. Such approach allows the characterization of mechanical properties of a confined inclusion (e.g. blood clot) from its resonance (displacement amplification) due to the propagation of judiciously oriented shear waves. SWIRE has also the advantage to amplify the vibration amplitude within the heterogeneity to help for its detection and segmentation. Finally, the method DVT-SWIRE ((« Deep venous thrombosis – SWIRE ») is adapted to the quantitative elasticity estimation of venous thrombosis in the context of clinical use. DVT-SWIRE exploits the first resonance frequency measured within the thrombosis during the plane (vibration of rigid plate) or cylindrical (simulating supersonic radiation force generation) shear waves propagation. The technique is applied on DVT phantoms and the results are compared to those given by the RheoSpectris reference instrument. This method is also used successfully in an ex vivo study for the elasticity assessment of explanted porcine thrombosis surgically induced in vivo.