No description available.

No description available.

No description available.

No description available.

Chronic venous insufficiency is the term used to describe lower limb venous disease causing symptoms in the leg, which include swelling, lipodermatosclerosis and ulceration. The underlying processes for the development of these symptoms are venous reflux, deep venous occlusion or both, which in turn result in venous hypertension. This thesis is focussed on the former process only, as deep venous occlusion is usually managed conservatively at the institutions in which this research took place.

Background: Venous insufficiency is very common and causes significant quality of life (QoL) impairment. Conventional open surgery featuring junction ligation, stripping of the axial vein and phlebectomy is known to offer significant benefits over conservative management; resulting in improved QoL. Additionally this treatment has been shown to be highly cost-effective. Despite these advantages, surgery is associated with significant post-operative morbidity; in the form of pain and immobility, even in the absence of complications. Additionally, in the long term; high recurrence rates have marred these promising early results, eventually returning patients to their pre-operative state. Unsurprisingly recurrence is unpopular with patients and patient satisfaction has been observed to be disappointingly low. At the end of the 20th century, new minimally invasive endovenous interventions were developed. Rapidly gaining popularity; it was hoped that they could address some of the limitations of surgery. Following initial cases series; the endothermal technique of endovenous laser ablation (EVLA) appeared to have the highest technical efficacy with a good safety record. Objectives: Three studies were performed with the aim of perfecting the ablative procedure and evaluating it against the gold standard of conventional surgery. Study 1 was designed to establish the optimal management of saphenous tributaries and perforators following ablation of the saphenous axis. Study 2 was designed to directly compare the outcomes of EVLA with surgery to establish whether EVLA can match the effectiveness of surgery, whilst addressing its limitations. Study 3 was designed to explore the association between the magnitude of energy delivered during EVLA, procedural safety and periprocedural morbidity; in the context of evidence suggesting lower recanalisation rates following more aggressive use of laser energy. Methods: Studies 1 and 2 were randomised clinical trials. Participants had primary, symptomatic, unilateral venous insufficiency, with isolated saphenofemoral junction incompetence, leading to reflux into the great saphenous vein (GSV). Study 1 randomised 50 patients to EVLA alone (Control) or EVLA with concomitant ambulatory phlebectomies (EVLTAP). Study 2 randomised 280 patients equally into groups receiving either surgery or EVLA. Outcomes were: QoL, Venous Clinical Severity Score (VCSS), technical success, requirement for secondary procedures, pain scores, time taken to return to normal function, recurrent varicose veins on clinical examination, patterns of reflux on duplex ultrasound examination, and the effect of recurrence on quality of life. Assessments were at 1, 6, 12 and 52 weeks after the procedure. Study 3 used linear and logistic regression models to study the effect of energy delivery on outcome. The models controlled for age, gender, BMI, pre-operative QoL and vein dimension. The outcomes were QoL, complications, recovery time, pain scores and analgesia requirements. The sample size calculation established that 115 patients would be required to detect any significant relationship. Results: Study 1: EVLTAP took longer, but significantly decreased the requirement for subsequent interventions. There was no impairment in immediate post-procedural pain or QoL with EVLTAP. Median (IQR) Venous Clinical Severity Score (VCSS) at 3 months was lower (better) for EVLTAP than for Control (0 (0-1) versus 2 (0-2); P < 0.001), with lower (better) disease specific QoL (Aberdeen Varicose Vein Questionnaire (AVVQ) scores) at 6 weeks (7.9 (4.1-10.7) versus 13.5 (10.9-18.1); P < 0.001) and 3 months (2.0 (0.4-7.7) versus 9.6 (2.2-13.8); P = 0.015). At 1 year, there were no differences in VCSS or AVVQ scores. Study 2: Both groups had significant improvements in VCSS after treatment (P < 0.001), which resulted in improved disease-specific QoL (AVVQ, P < 0.001) and quality-adjusted life year (QALY) gain (P < 0.001). The pain and disability following surgery impaired normal function, with a significant decline in five of eight SF-36 domains (P < 0.001 to P = 0.029). Periprocedural QoL was relatively preserved following EVLA, leading to a significant difference between the two treatments in pain scores (P < 0.001), six of eight SF-36 domains (P = 0.004 to P = 0.049) and QALYs (P = 0.003). As a result, surgical patients took longer to return to work and normal activity (14 versus 3 days; P < 0.001). Complications were rare. Initial technical success was greater following EVLA: 99.3 versus 92.4% (P = 0.005). Surgical failures related mainly to an inability to strip the above-knee GSV. The clinical recurrence rate at 1 year was lower after EVLA: 4.0 versus 20.4% (P < 0.001). The number of patients needed to treat with EVLA rather than surgery to avoid one recurrence at 1 year was 6.3 (95 per cent confidence interval 4.0 to 12.5). 12 of 23 surgical recurrences were related to an incompetent below-knee GSV and ten to neovascularisation. Of five recurrences after EVLA, two were related to neoreflux in the groin tributaries and one to recanalisation. Clinical recurrence was associated with worse QoL (AVVQ scores) (P < 0.001). Study 3: 232 patients were included. The mean (range) age was 50 (18-83) years. 63% were women. The mean (range) energy delivery was 89.8 (44.5-158.4) Jcm-1. There was no significant effect on any outcome related to increasing energy delivery. Conclusions: Concomitant phlebectomy with EVLA prolonged the procedure, but reduced the need for secondary procedures and significantly improved quality of life and the severity of venous disease. This supports a recommendation that phlebectomy is performed routinely in conjunction with EVLA. EVLA was as effective as surgery for varicose veins, but importantly had lower periprocedural morbidity as evidenced by less negative impact on early post-intervention QoL and furthermore clinical recurrence rates were also significantly lower than observed following conventional surgery. This suggests that EVLA with phlebectomy is superior to conventional surgery in the management of primary superficial venous insufficiency. Study 3 clearly confirms that EVLA is a safe procedure and that for the range of energies studied, there was no evidence demonstrating an increase in complication rates or the periprocedural morbidity of EVLA. These findings support the adoption of EVLA and concomitant phlebectomy as the gold standard treatment for primary superficial venous insufficiency.

Le syndrome des anticorps antiphospholipides (SAPL) est caractérisé par une atteinte auto-immune systémique à l’origine d’événements cliniques thrombotiques ou obstétricaux en présence d’anticorps antiphospholipides (aPL) persistants sur 2 prélèvements. Ce travail de thèse s’est intéressé à des manifestations cliniques et des tests biologiques dont le but est d’évaluer le risque thrombotique dans ce syndrome. En premier lieu, le risque de valvulopathie associé aux aPL chez les patients lupiques a été étudié. L’existence d’une telle association faisait l’objet d’une controverse non résolue. En ayant recours à une revue systématique de la littérature et à une méta-analyse d’études observationnelles, les fréquences des valvulopathies chez les patients lupiques en fonction de la présence ou non d’aPL ont été comparées. Le résultat principal est, qu’en présence d’aPL chez les patients lupiques, ce risque est multiplié par 3. En second lieu, la valeur pronostique sur le risque de thrombose des thromboses veineuses superficielles (TVS) a été étudiée chez les patients atteints d’un SAPL. Une étude de cohorte prospective monocentrique a montré que la présence d’un antécédent de TVS était prédictive du risque de thrombose ultérieure. D’autre part, l’apport de nouveaux marqueurs biologiques, les anticorps spécifiquement dirigés contre le domaine I de la [bêta]2-Glycoprotéine I ainsi que les paramètres de thrombinographie prenant en compte la sensibilité à la protéine C activée ont été étudiés. Les résultats montrent que ces 2 tests sont prédictifs du risque thrombotique incident. Enfin, les données de qualité de vie d’une cohorte multicentrique de patients atteints de lupus et/ou porteurs d’aPL, ont été analysées. Les résultats montrent que la présence d’un antécédent de thrombose artérielle était associée à une altération de toutes les dimensions de la qualité de vie évaluée par un auto-questionnaire généraliste (MOS-SF36) en comparaison à des patients atteints de maladie auto-immune sans ce type de thrombose. Ces résultats pourront avoir un impact significatif dans la réflexion sur l’évolution des critères de classification de ce syndrome / Antiphospholipid syndrome (APS) is characterized by an auto-immune disorder with thrombotic and obstetrical morbidity in the presence of persistant antiphospholipid antibodies (aPL). This work studied clinical manifestations and laboratory assays for the determination of thrombotic risk in APS patients. Firstly, the risk of heart valve disease associated with aPL in systemic lupus erythematosus (SLE) patients was studied. Since 20 years, data regarding this association yielded conflicting results. A systematic review and a meta-analysis were performed to compare frequencies of heart valve disease in SLE patients with and without aPL. Main result concluded that the presence of aPL in SLE patients is associated with a 3-fold increased risk for heart valve disease in comparison with SLE patients without these antibodies. Secondly, prognostic significance of superficial vein thrombosis (SVT) was studied in APS patients. A prospective cohort study was performed and showed that SVT was predictive of thrombotic events overtime in this population. Moreover, the contribution of new laboratory assays were studied (antibodies directed against the domain I of [beta]2-Glycoprotein I and thrombin generation assay assessing sensitivity to activated protein C). Results demonstrated that these two assays were predictive of thrombotic events in APS patients. Finally, health-related quality of life was assessed in a multicentric cohort study of patients with aPL and/or SLE. Results showed that the presence of a history of arterial thrombosis was significantly associated with an impairment of all dimensions scores assessed by the MOS-SF36 questionnaire in comparison with patients with an auto-immune disease but without arterial thrombosis. This work provides new insights in the field of APS and may have an impact in the evolution leading to new classification criteria for definite APS.

La thrombose est le plus important processus pathologique sous-jacent à de nombreuses maladies cardiovasculaires, qui sont responsables d’une mortalité élevée dans le monde entier. Dans cette thèse, la conception assistée par ordinateur de nouveaux agents antithrombotiques capables d’inhiber deux types de récepteurs situés à la surface des plaquettes a été appliquée. Le premier - αIIbβ3 - est responsable de l’interaction des plaquettes activées avec le fibrinogène pour former des caillots, tandis que le second – le thromboxane A2 – est responsable de l’activation des plaquettes par l’un des agonistes excrétés par les plaquettes activées. Afin d’atteindre cet objectif, différents types de modèles ont été développés en utilisant les informations expérimentales disponibles et la structure des complexes protéine-ligand, comprenant des modèles QSAR, des pharmacophores 3D basés sur la structure de la protéine ou du ligand, des pharmacophores 2D, des modèles basés sur la forme et sur le champ moléculaire. L’ensemble des modèles développés ont été utilisés en criblage virtuel. Cette étude a abouti sur la suggestion de nouveaux antagonistes potentiels des récepteurs αIIbβ3 et thromboxane A2. Les antagonistes de αIIbβ3 suggérés pouvant se lier soit à la forme ouverte soit à la forme fermée du récepteur ont été synthétisés et testés expérimentalement. L’expérience montre qu’ils font preuve d’une forte activité; de plus, certains des composés conçus théoriquement sont plus efficaces que le Tirofiban, qui est un médicament commercialisé. Les antagonistes recommandés du récepteur thromboxane A2 ont déjà été synthétisés mais les tests biologiques n’ont pas encore été complétés. / Thrombosis is the most important pathological process underlying many cardiovascular diseases, which are responsible for high mortality worldwide. In this theses the computer-aided design of new anti-thrombotic agents able to inhibit two types of receptors located on the surface of the platelets has been applied. The first one - αIIbβ3 - is responsible for the interaction of activated platelets with fibrinogen to form clots, whereas the second one - thromboxane A2 - is responsible for platelet activation by one of agonists excreted by activated platelets. To achieve this, different types of models have been developed using experimentally available information and structure of protein-ligand complexes. This concerns: QSAR models, structure-based and ligand-based 3D pharmacophore models, 2D pharmacophore models, shape-based and molecular field-based models. The ensemble of the developed models were used in virtual screening. This study resulted in suggestion of new potential antagonists of αIIbβ3 and thromboxane A2 receptors. Suggested antagonists of αIIbβ3 able to bind either open or closed form of the receptor have been synthesized and tested experimentally. Experiments show that they display high activity; moreover some of theoretically designed compounds are more efficient than Tirofiban – the commercialized drug molecule. The recommended antagonists of thromboxane A2 receptor have been already synthesized but biological tests have not been completed yet.