<p>Unfractionated heparin (UFH) is used as an adjunct during thrombolytic therapy. However, its use is associated with many clinical limitations, such as the inability to inhibit fibrin-bound coagulation factors, increasing the potential for sustained procoagulant activity. We have developed a covalent conjugate of antithrombin (AT) and heparin (ATH) with superior anticoagulant properties to those of UFH. Some advantages of ATH include enhanced inhibition of surface-bound enzymes and its ability to reduce the overall size and mass of clots <em>in vivo</em>. However, the potential interactions of UFH or ATH with the components of the fibrinolytic pathway are not well understood. Therefore, our study utilized discontinuous second order rate constant (<em>k₂</em>) assays to determine rates of inhibition of plasmin (Pn) in the presence or absence of fibrin by AT+UFH <em>vs.</em> ATH. In addition, we monitored the rates of Pn generation in a system comprised of preformed fibrin clots with the aim of evaluating the inhibitory effect of AT+UFH or ATH in this more native system. The <em>k₂</em>values for the inhibition of Pn without fibrin were 5.74x10⁶±0.278x10⁶ and 6.39x10⁶±0.588x10⁶ for AT+UFH and ATH, respectively (p=0.36). In the presence of fibrin, the <em>k₂</em>values decreased to 1.45x10⁶±0.0971x10⁶ for AT+UFH and 3.07x10⁶±0.192x10⁶for ATH (<em>p</em></p> / Master of Science (MS)

<p>We evaluated, in patients with ST-elevation myocardial infarction (STEMI) treated with thrombolytics, admission Troponin T (tnT), ST-segment resolution and admission N-terminal pro-brain natriuretic peptide (NT-proBNP) for early risk stratification as well as time delays and outcome in real life patients according to prehospital or in-hospital thrombolytic treatment. Also, baseline characteristics, treatments and outcome in patients enrolled in the ASSENT-2 trial in Sweden and in patients not enrolled were evaluated. </p><p>TnT (n=881) and NT-proBNP (n=782) on admission and ST-resolution at 60 minutes (n=516) in patients from the ASSENT-2 and ASSENT-PLUS trials were analysed. Elevated levels of NT-proBNP and tnT on admission were both independently related to one-year mortality. However, when adding information on ST-resolution (</≥50%) 60 minutes after initiation of thrombolytic treatment, tnT no longer contributed independently to mortality prediction. High and low risk patients were best identified by a combination of NT-proBNP and ST-resolution at 60 minutes.</p><p>We investigated consecutive STEMI patients included in the RIKS-HIA registry between 2001 and 2004, if they were ambulance transported and had received prehospital (n=1690) or in-hospital (n=3685) thrombolytic treatment. Prehospital diagnosis and thrombolysis reduced the time to thrombolysis by almost one hour, were associated with better left ventricular function and fewer complications and reduced the adjusted one-year mortality by 30% compared with in-hospital thrombolysis. </p><p>Prospective data from the RIKS-HIA registry on STEMI patients treated with thrombolytics were linked to data on trial participants in the ASSENT-2 trial of thrombolytic agents and used for direct comparisons. Patients treated with thrombolytics and not enrolled in a clinical trial at trial hospitals (n=2048) had higher risk characteristics, more early complications and twice as high adjusted one-year mortality compared to those enrolled (n=729). One major reason for the difference in outcome appeared to be the selection of less critically ill patients to the trial.</p>

We evaluated, in patients with ST-elevation myocardial infarction (STEMI) treated with thrombolytics, admission Troponin T (tnT), ST-segment resolution and admission N-terminal pro-brain natriuretic peptide (NT-proBNP) for early risk stratification as well as time delays and outcome in real life patients according to prehospital or in-hospital thrombolytic treatment. Also, baseline characteristics, treatments and outcome in patients enrolled in the ASSENT-2 trial in Sweden and in patients not enrolled were evaluated. TnT (n=881) and NT-proBNP (n=782) on admission and ST-resolution at 60 minutes (n=516) in patients from the ASSENT-2 and ASSENT-PLUS trials were analysed. Elevated levels of NT-proBNP and tnT on admission were both independently related to one-year mortality. However, when adding information on ST-resolution (&lt;/≥50%) 60 minutes after initiation of thrombolytic treatment, tnT no longer contributed independently to mortality prediction. High and low risk patients were best identified by a combination of NT-proBNP and ST-resolution at 60 minutes. We investigated consecutive STEMI patients included in the RIKS-HIA registry between 2001 and 2004, if they were ambulance transported and had received prehospital (n=1690) or in-hospital (n=3685) thrombolytic treatment. Prehospital diagnosis and thrombolysis reduced the time to thrombolysis by almost one hour, were associated with better left ventricular function and fewer complications and reduced the adjusted one-year mortality by 30% compared with in-hospital thrombolysis. Prospective data from the RIKS-HIA registry on STEMI patients treated with thrombolytics were linked to data on trial participants in the ASSENT-2 trial of thrombolytic agents and used for direct comparisons. Patients treated with thrombolytics and not enrolled in a clinical trial at trial hospitals (n=2048) had higher risk characteristics, more early complications and twice as high adjusted one-year mortality compared to those enrolled (n=729). One major reason for the difference in outcome appeared to be the selection of less critically ill patients to the trial.

No description available.

Les ultrasons focalisés permettent d’effectuer des traitements thérapeutiques ciblés dans le corps humain. Dans le domaine des applications cardiovasculaires, ils permettent de détruire des caillots sanguins susceptibles de se former dans le système vasculaire. Dans ce cas, les mécanismes de thrombolyse sont largement liés à la cavitation ultrasonore, dont la dynamique complexe reste un obstacle à l’élaboration d’un dispositif thérapeutique. Dans le cadre de cette thèse, un système permettant le contrôle temporel de l’activité de cavitation en régime pulsé a été développé puis caractérisé. Ce dispositif utilise un transducteur focalisé et un hydrophone avec une boucle de rétroaction pour réguler l’activité de cavitation. Alors qu’en régime non régulé l’activité de cavitation a un caractère très aléatoire, le système de régulation mis au point permet d’atteindre un niveau de cavitation souhaité de manière très reproductible et avec une bonne stabilité temporelle. L’application de ce dispositif à la thrombolyse ultrasonore a été testée in vitro sur des caillots de sang humain. Au dispositif précédent a été ajouté un système permettant de déplacer le caillot sanguin au niveau du foyer, ainsi qu’un conduit permettant de compter le nombre de fragments libérés par la destruction du caillot. En comparaison des essais en régime non régulé, les essais en régime régulé ont montré une excellente efficacité thrombolytique et une très bonne reproductibilité, tout en diminuant les intensités acoustiques utilisées pour lyser les caillots sanguins. En parallèle des essais in vitro, une campagne de thrombolyse ultrasonore in vivo a été mise en place afin de réaliser des essais sur un modèle animal d’ischémie aiguë de membre inférieur. Un dispositif ultrasonore extracorporel in vivo guidé par échographie et monté sur un bras robotisé 6 axes a été développé. Un modèle ovin de thrombose artérielle a également été développé. Les tests ont permis de valider, d’une part, la faisabilité du modèle de caillot artériel et, d’autre part, le concept de thrombolyse extracorporelle purement ultrasonore basée sur la cavitation inertielle régulée / Focused ultrasound can be used for therapeutic applications in the human body. In cardiovascular applications, they can destroy blood clots formed in the vascular system. In this case, thrombolysis mechanisms are related to ultrasonic cavitation, but the complex dynamics remains an obstacle to the development of a therapeutic device. In this thesis, a system for the temporal control of the pulsed cavitation activity has been developed and characterized. This device uses a focused transducer and a hydrophone with a feedback loop for regulating the cavitation activity. While cavitation activity has a random behaviour in non-regulated conditions, the control system developed achieves a desired level of cavitation with very reproducibly and with good temporal stability. The application of this device to the ultrasound thrombolysis was tested in vitro on human blood clots. In the previous device was added a system for moving the blood clot at the focal point, and a tube for counting the number of fragments released by the destruction of the clot. In comparison to uncontrolled regime, tests showed an excellent thrombolytic efficacy and a very good reproducibility, with reduced acoustic intensities. In parallel to the in vitro tests, ultrasound thrombolysis was tested in vivo on an animal model of acute limb ischemia. An extracorporeal ultrasound device, guided by ultrasound and mounted on a robotic arm, has been developed for in vivo investigation. An ovine model of arterial thrombosis has also been developed. Tests were used to validate the feasibility of the model of arterial clots and to validate in vivo the concept of purely ultrasonic extracorporeal thrombolysis based on inertial cavitation regulation system

Tid till behandling är livsviktigt för människor som får en stroke. På olika platser i världen har man därför sett värdet i att införskaffa en specialambulans för stroke (stroke-ambulans) som har specialutrustning och specialpersonal som kan utföra intravenös behandling (trombolys). Då det är uppenbart att dess involvering i vården skulle hjälpa åtminstone en viss andel patienter används ofta ingen utvecklad metod eller analys av var och hur denna stroke-ambulans ska placeras. Genom att noggrant undersöka läget i Skåne län om hur denna placeringen kan gå till, är vårt mål att genom vår metod, som bygger på optimering av förväntade transporttider, upplysa beslutstagare om olika perspektiv man bör ta hänsyn till. Vår metod kan användas över olika geografiska områden.Vi föreslår en optimeringsmetod som utgår från två olika perspektiv: effektivitet och jämlikhet. Metoden visar att beroende på vilket perspektiv man väljer, kan den optimala placeringen för ett givet område variera kraftigt. Det är därför viktigt att beslutstagare av placering för stroke-ambulanser har tydliga och väl genomtänkta mål. Dessa mål bör även innefatta de lokala sjukhusens mål när det kommer till förbättring av behandlingstiden för strokepatienter, s.k. door-to-needle-time (DTN) då dessa i vissa fall kan göra större förbättringar än vad en införskaffning av en stroke-ambulans skulle göra. / Tid till behandling är livsviktigt för människor som får en stroke. På olika platser i världen har man därför sett värdet i att införskaffa en specialambulans för stroke (stroke-ambulans) som har specialutrustning och specialpersonal som kan utföra intravenös behandling (trombolys). Då det är uppenbart att dess involvering i vården skulle hjälpa åtminstone en viss andel patienter används ofta ingen utvecklad metod eller analys av var och hur denna stroke-ambulans ska placeras. Genom att noggrant undersöka läget i Skåne län om hur denna placeringen kan gå till, är vårt mål att genom vår metod, som bygger på optimering av förväntade transporttider, upplysa beslutstagare om olika perspektiv man bör ta hänsyn till. Vår metod kan användas över olika geografiska områden.Vi föreslår en optimeringsmetod som utgår från två olika perspektiv: effektivitet och jämlikhet. Metoden visar att beroende på vilket perspektiv man väljer, kan den optimala placeringen för ett givet område variera kraftigt. Det är därför viktigt att beslutstagare av placering för stroke-ambulanser har tydliga och väl genomtänkta mål. Dessa mål bör även innefatta de lokala sjukhusens mål när det kommer till förbättring av behandlingstiden för strokepatienter, s.k. door-to-needle-time (DTN) då dessa i vissa fall kan göra större förbättringar än vad en införskaffning av en stroke-ambulans skulle göra. / The time to treatment is vital for people who suffer from a stroke. Therefore, in different places in the world, the value of acquiring a specially developed ambulance for a stroke (i.e., a Mobile Stroke Unit, MSU) with special equipment and specialists who can perform intravenous treatment (thrombolysis) has been identified. Since it is clear that an MSU’s involvement in health care would aid at least a certain proportion of the patients, the MSU is often purchased and placed without any developed method or analysis of where and how this MSU is to be placed. By carefully examining the situation in Skåne Municipality of how this placement could be performed, we will inform decision makers about different perspectives that should be taken into consideration, including other areas than Skåne.Our optimization method showed that depending on what perspective you are investing, efficiency or equality, the optimal placement for any given area can vary greatly. It is therefore importantthat decision-makersofMSUpurchaseshaveclearandwell-thought-outgoals.These goals should also include the goals of the local hospitals when it comes to improving the treatment time for stroke patients, door-to-needle (DTN), as the DTN may in some cases make greater improvements than a purchase of an MSU would. / The time to treatment is vital for people who suffer from a stroke. Therefore, in different places in the world, the value of acquiring a specially developed ambulance for a stroke (i.e., a Mobile Stroke Unit, MSU) with special equipment and specialists who can perform intravenous treatment (thrombolysis) has been identified. Since it is clear that an MSU’s involvement in health care would aid at least a certain proportion of the patients, the MSU is often purchased and placed without any developed method or analysis of where and how this MSU is to be placed. By carefully examining the situation in Skåne Municipality of how this placement could be performed, we will inform decision makers about different perspectives that should be taken into consideration, including other areas than Skåne.Our optimization method showed that depending on what perspective you are investing, efficiency or equality, the optimal placement for any given area can vary greatly. It is therefore importantthat decision-makersofMSUpurchaseshaveclearandwell-thought-outgoals.These goals should also include the goals of the local hospitals when it comes to improving the treatment time for stroke patients, door-to-needle (DTN), as the DTN may in some cases make greater improvements than a purchase of an MSU would.

Objective: A malignant profile of early brain ischemia has been demonstrated in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) trial. Patients with a malignant profile had a low chance for an independent functional outcome despite thrombolysis within 3–6 h. We sought to determine whether CT angiography (CTA) could identify a malignant imaging profile within 3 h from symptom onset. Methods: We studied consecutive patients (04/02–09/07) with anterior circulation stroke who received CTA before intravenous thrombolysis within 3 h. We assessed the Alberta Stroke Program Early CT Score (ASPECTS) on CTA source images (CTASI). Intracranial thrombus burden on CTA was assessed with a novel 10-point clot burden score (CBS). We analyzed percentages independent (modified Rankin Scale score ≤2) and fatal outcome at 3 months and parenchymal hematoma rates across categorized combined CTASI-ASPECTS + CBS score groups where 20 is best and 0 is worst. Results: We identified 114 patients (median age 73 years [interquartile range 61–80], onset-to-tPA time 129 min [95–152]). Among 24 patients (21%) with extensive hypoattenuation on CTASI and extensive thrombus burden (combined score ≤10), only 4% (1/24) were functionally independent whereas mortality was 50% (12/24). In contrast, 57% (51/90) of patients with less affected scores (combined score 11–20) were functionally independent and mortality was 10% (9/90; p < 0.001). Parenchymal hematoma rates were 30% (7/23) vs. 8% (7/88), respectively (p = 0.008). Conclusion: CTA identifies a large hyperacute stroke population with high mortality and low likelihood for independent functional outcome despite early thrombolysis. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

L'accès aux thérapeutiques de reperfusion (thrombolyse/thrombectomie) dans les délais recommandés constitue l'enjeu principal de la prise en charge de l'accident vasculaire cérébral (AVC) à la phase aiguë. Actuellement, seuls 20% des patients éligibles en bénéficient, en raison de difficultés à identifier l'AVC et de délais de prise en charge prolongés. La filière de soins optimale pour l'AVC à la phase aiguë comprend l'appel au 15 dès la survenue des symptômes et un transfert direct du patient en unité neurovasculaire (UNV). Cependant, une 1ère étude menée dans le Rhône en 2006-2007 (AVC 69) avait objectivé que la filière de soins passait par les urgences dans 80% des cas et que seuls 10% des patients éligibles étaient thrombolysés. Les principaux retards identifiés dans la prise en charge concernaient au niveau préhospitalier, l'identification de l'AVC et l'appel au 15 par le patient ou les témoins, et au niveau intrahospitalier, le parcours de soins dans les services d'urgences, l'obtention de l'imagerie cérébrale et le transfert en UNV. Pour répondre à ces problématiques, nous avons mis en place un programme visant à améliorer la prise en charge de l'AVC en région Rhône-Alpes. Notre travail de thèse rapporte 3 projets menés au sein de ce programme : Le premier projet ciblait la phase préhospitalière. Il a permis d'évaluer la perception de l'AVC au sein de la population générale, afin de proposer une campagne d'information pertinente. Nous avons étudié l'impact de cette campagne dans le Rhône sur l'appel au 15 et les connaissances de la population sur l'AVC. Le second projet a évalué une intervention multifacettes de formation des professionnels des services d'urgences dont l'objectif était de diminuer les délais de prise en charge intrahospitaliers et améliorer l'accès à la thrombolyse. Le troisième projet a porté sur l'étude de la validité des bases de données médico-administratives hospitalières pour identifier les AVC, en vue de l'utilisation de ces bases à des fins épidémiologiques ou pour la construction d'indicateurs de suivi de la performance. Les interventions déployées au sein du programme ont permis d'améliorer le recours à l'appel au 15 et le taux de thrombolyse, néanmoins l'ampleur des effets observés reste limitée et aucun effet sur les délais n'a pu être mis en évidence. Un approfondissement des mécanismes d'action des interventions est nécessaire pour pouvoir proposer des interventions plus efficaces / The main issue in the management of acute stroke is access to reperfusion strategies (ie thrombolysis or thrombectomy) within the recommended time window. Currently, fewer than 1 in 2 eligible patients are receiving this treatment, partly because of difficulties in stoke identification and extended treatment delays. The optimal care pathway for acute stroke includes immediately calling emergency medical services (EMS) at symptoms onset followed by a direct transfer to the stroke unit (SU). However, a previous study carried out in 2006-2007 in the Rhône region (AVC69) pointed out that 80% of patients were managed in the emergency unit and only 10% of eligible patients were thrombolysed. Delays in management were identified at different stages: at the prehospital level, for stroke identification and the EMS call, and at the inhospital level with inefficicent processes in emergency units, delays in cerebral imaging obtaining and for SU transfert. To address these problems, we have set up a program to improve stroke management in the Rhône-Alpes region. Our work reports 3 projects carried out within this program: The first project identified stroke representations in the general population in order to design a relevant information campaign. Then, we studied the impact of this campaign on the number of EMS call for stroke suspicion and on population's knowledge about stroke. In the second project, we developed and evaluated a multifaceted training intervention for emergency units professionals aimed at reducing inhospital management times and improving access to thrombolysis. The third project analyzed the validity of hospital medico-administrative databases to identify strokes, in anticipation of the use of these databases for epidemiological studies or for the construction of performance indicators. Interventions within the program improved the EMS call and thrombolysis rate, but the magnitude of observed effects remained limited and no effect on management times could be observed. A deeper understanding of the mechanisms of intervention is needed to further design more effective interventions

Dans nombre d’applications thérapeutiques des ultrasons, il peut être intéressant d’augmenter l’activité de cavitation inertielle tout en limitant au maximum les intensités utilisées : ceci permet de maximiser les effets mécaniques des ultrasons au niveau des tissus visés tout en minimisant les échauffements des tissus environnants. L’étude expérimentale présentée ici ² porte sur la modification des seuils de cavitation inertielle et de l’activité de cavitation au-delà du seuil lorsqu’un signal bifréquentiel comportant deux composantes fréquentielles proches est utilisé. Le caractère non linéaire de la modification du seuil est démontré. Ainsi, des réductions significatives de l’intensité nécessaire à l’obtention de cavitation inertielle peuvent être obtenues dans des milieux où les seuils sont élevés. De plus, l’évolution de l’activité de cavitation lorsque l’intensité ultrasonore est augmentée au-delà du seuil montre qu’avec une excitation bifréquentielle, de fortes activités de cavitation peuvent être atteintes pour des intensités plus proches du seuil. Ce point présente un double intérêt sur le plan de l’application pratique, puisque cela signifie une meilleure séparation des régimes cavitant et non cavitant et permet de réduire encore, par rapport à une excitation monofréquentielle, les intensités requises pour atteindre une activité de cavitation donnée. Des essais sur modèle de caillots sanguins ont permis de valider in vitro l’efficacité de cette excitation bifréquentielle pour la thrombolyse purement ultrasonore. / Enhancing cavitation activity using lower acoustic intensities is interesting to a variety of therapeutic applications, where the mechanical effects of cavitation are required with minimal heating of surrounding tissues. The present experimental work is focused on the modification of the inertial cavitation threshold and on the cavitation activity beyond the threshold where an excitation signal made of two neighbouring frequency components is used. A significant reduction of the acoustic intensity required to trigger cavitation can be obtained in a medium with a strong cavitation threshold. Moreover, comparing the evolution of the cavitation activity beyond the threshold where mono- and bi-frequency excitations are used, it is shown, in the latter case, that strong activities can be reached with intensities closer to the threshold value. This fact would offer a dual-benefit in terms of therapeutic applications, as it enables a better separation between the cavitating and non-cavitating regime and allows lower intensities to be used to attain a given cavitation activity. The evolution of the bifrequency threshold as function of the external parameters shows that the mechanisms involved are nonlinear. Experiments on in vitro blood clot models have validated the efficiency of this bifrequency excitation for purely ultrasound thrombolysis

End stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Despite the advances in both Cardiovascular disease (CVD) management and renal replacement therapy (RRT), there still is a major burden of cardiovascular mortality and morbidity in the chronic kidney disease (CKD) population. Declining renal function itself represents a continuum of cardiovascular risk and in those individuals who survive to reach ESRD, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Pro-thrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) the time taken to form an occlusive platelet rich thrombus and thrombolytic status (time taken to lyse such thrombus) as assessed by measuring Lysis Time (LT), may identify vulnerable patients. The aim of this study was to assess overall thrombotic status in ESRD and relate this to cardiovascular and peripheral thrombotic risk. Small sub studies were also planned to establish the effect of RRT modality on the thrombotic status.