<p>The effect of direction thrombin inhibition on acute deep vein thrombosis (DVT) stability has not been defined and could contribute to pulmonary embolism (PE) risk. Direct thrombin inhibitors (DTIs) effectively inhibit free and clot-bound thrombin, which could potentiate thrombus instability through disruption of platelet, fibrin, and FXIIIa stabilizing mechanisms. This could manifest as increased thrombus embolization. A clinically relevant mouse model of DVT stability could further our understanding of venous thrombosis pathophysiology and define the effect of direct thrombin inhibition on PE. We hypothesized that acute DTI administration would decrease acute DVT stability and potentially increase PE risk. Platelets were labeled <em>in vivo</em>, femoral vein thrombosis was induced using FeCl₃, and lepirudin (8U/g) was administered <em>after</em> clot formation. Using intravital videomicroscopy (IVM), real time embolization was quantified as a measurement of thrombus stability. Thrombus stability increased in the control group and decreased in the lepirudin-treated group over two hours. The decrease in α₂-antiplasmin (α₂-AP) content within lepirudin-treated thrombi, compared to control thrombi, could possibly contribute to the observed decrease in thrombus stability. Continued growth and embolization established the dynamic nature of formed thrombi. In both groups, emboli were detected in the pulmonary artery circulation. Therefore, we successfully developed a mouse model of venous thrombus stability, which imitated the clinical progression of DVT to PE. DTI administration in the acute DVT setting could decrease thrombus stability, demonstrated through increased embolization and PE. This model could be useful in examining the effect of other antithrombotics and risk factors settings on DVT stability.</p> / Master of Science (MSc)

Background: Venous thromboembolism (VTE), comprising the conditions of deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common acute cardiovascular event associated with increased long-term morbidity, functional disability, all-cause mortality, and high rates of recurrence. Major advances in identification, prophylaxis, and treatment over the past 3-decades have likely changed its clinical epidemiology. However, there are little published data describing contemporary, population-based, trends in VTE prevention and management. Objectives: To examine recent trends in the epidemiology of clinically recognized VTE and assess the risk of recurrence after a first acute episode of VTE. Methods: We used population-based surveillance to monitor trends in acute VTE among residents of the Worcester, Massachusetts, metropolitan statistical area (WMSA) from 1985 through 2009, including in-hospital and ambulatory settings. Results: Among 5,025 WMSA residents diagnosed with acute PE and/or lower-extremity DVT between 1985 and 2009 (mean age = 65 years), 46% were men and 95% were white. Age- and sex-adjusted annual event rates (per 100, 000) of clinically recognized acute first-time and recurrent VTE was 142 overall, increasing from 112 in 1985/86 to 168 in 2009, due primarily to increases in PE occurrence. During this period, non-invasive diagnostic VTE testing increased, vi while treatment shifted from the in-hospital (chiefly with warfarin and unfractionated heparin) to out-patient setting (chiefly with low-molecular-weight heparins and newer anticoagulants). Among those with community-presenting first-time VTE, subsequent 3-year cumulative event rates of key outcomes decreased from 1999 to 2009, including all-cause mortality (41% to 26%), major bleeding episodes (12% to 6%), and recurrent VTE (17% to 9%). Active-cancer (with or without chemotherapy), a hypercoagulable state, varicose vein stripping, and Inferior vena cava filter placement were independent predictors of recurrence during short- (3-month) and long-term (3-year) follow-up after a first acute episode of VTE. We developed risk score calculators for VTE recurrence based on a 3-month prognostic model for all patients and separately for patients without active cancer. Conclusions: Despite advances in identification, prophylaxis, and treatment between 1985 and 2009, the disease burden from VTE in residents of central Massachusetts remains high, with increasing annual events. Declines in the frequency of major adverse outcomes between 1999 and 2009 were reassuring. Still, mortality, major bleeding, and recurrence rates remained high, suggesting opportunities for improved prevention and treatment. Clinicians may be able to use the identified predictors of recurrence and risk score calculators to estimate the risk of VTE recurrence and tailor outpatient treatments to individual patients.

Hintergrund: Leptin ist ein unabhängiger kardiovaskulärer Risikofaktor und scheint prothrombotische Effekte zu besitzten. Adiponectin hingegen scheint vor Thrombosen zu schützen. Wir untersuchten deswegen die Bedeutung dieser beiden Adipozytokine bei Patienten mit einer akuten Lungenembolie. Durchführung: Im Rahmen einer prospektiven Fall-Kontroll-Studie schlossen wir zwischen 2003 und 2006 97 Patienten mit gesichterter Lungenembolie und 40 Patienten mit dem Ausschluß einer Lungenembolie ein. Die Lungenembolie-Patienten wurden bezüglich eines komplizierten Verlaufs innerhalb der ersten 30 Tage nach dem Ereignis (Tod, Katecholaminebedarf, Reanimation, Intubation, Hypotonie) sowie bezüglich des Langzeit-Überlebens beobachtet. Ergebnisse: Bei Patienten mit Lungenembolie ist ein höherer Leptinspiegel ein prognostischer Parameter für eine niedrigere 30-Tages-Komplikationsrate und ein besseres Langzeit-Überleben. Patienten mit einer Lungenembolie weisen signifikant höhere Adiponectinwerte als Patienten ohne Lungenembolie auf. Eine prognostische Bedeutung hat Adiponectin bei Patienten mit einer Lungenembolie nicht. Schlußfolgerung: Niedrige Leptinspiegel sind bei Patienten mit einer akuten Lungenembolie ein unabhängiger prognostischer Parameter für einen komplizierten 30-Tages-Verlauf und eine erhöhte Mortalität im Langzeit-Verlauf. Lungenembolie-Patienten weisen eine Hyperoadiponectinämie auf, dies könnten Ausdruck einer kardialen Sekretion und Wirkung des Asiponectins infolge der Lungenembolie sein.

No description available.

La maladie thrombo-embolique veineuse est une entité hétérogène avec des formes cliniques de présentation et de pronostic variables. Compte tenu de l'évolution démographique de la population, de la grande diffusion d'outils diagnostiques fiables et de l'impact de la thromboprophylaxie, il nous a paru nécessaire de réactualiser les connaissances sur ce sujet. Trois études épidémiologiques ont permis les analyses de ce travail. Pour les sujets âgés en soins de suite lors d'une étude de type coupe transversale avec évaluation de type avant/après, nous avons montré que les patients âgés avaient des facteurs spécifiques comme l'immobilisation prolongée, le grand âge (plus de 80 ans), la présence d'escarres et la dépendance estimée par l'indice IADL. Le bénéfice de la prévention est hautement probable dans cette population car nous avons trouvé un taux de thromboses asymptomatiques de 15% avec une réduction d'un tiers après une action de sensibilisation à la thromboprophylaxie. Par contre, le bénéfice de la compression doit être évalué chez la personne âgée. L'étude Optimev a étudié les facteurs de risque, les méthodes diagnostiques et le pronostic des différentes formes cliniques de MTEV (de la thrombose superficielle à l'embolie pulmonaire). Pendant 15 mois, des médecins vasculaires hospitaliers et libéraux ont saisi grâce à un cahier d'observation électronique, les facteurs de risque, les examens complémentaires et le traitement mis en place auprès de 8256 patients avec suspicion clinique de MTEV. Un suivi téléphonique à 3 mois, 6 mois, un an et trois ans a été effectué. Le suivi des TVP distales (n=787), proximales (n=598), TVP avec EP (n=371), EP sans TVP (n=130) et des contrôles (n=2404) montre que la mortalité à 3 mois des EP sans TVP est proche de celle des contrôles (4%) alors que celle des patients EP avec TVP est de 13%. Les TVP distales sont la forme la plus fréquente de MTE ( 56,8% vs 43,2% pour les proximales), leurs facteurs de risque sont plus souvent transitoires et elles récidivent tout autant que les proximales, même si leur mortalité est plus faible. Parmi les TVP distales, les thromboses musculaires sont comparables aux thromboses des troncs jambiers. Le diagnostic d'élimination de TVP par écho-Doppler a été validé pour les patients externes et pour la première fois chez des patients hospitalisés. Optimev a également permis de valider une règle clinique simple de probabilité de TVP du membre supérieur. Ce travail permet de mieux comprendre la signification des formes cliniques diagnostiquées actuellement et leur pronostic à court terme. Les perspectives pour cette étude portent sur les éléments pronostiques de ces différentes formes cliniques mais aussi la relation avec les pathologies ischémiques artérielles. Summary

Submitted by THALITA LEONE ALVES ROCHA null (thalarocha@hotmail.com) on 2016-04-18T15:51:39Z No. of bitstreams: 1 dissertação thalita final.pdf: 794073 bytes, checksum: 8f42b335b8638b50194b64ede638c446 (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-04-19T16:16:26Z (GMT) No. of bitstreams: 1 rocha_tla_me_bot.pdf: 794073 bytes, checksum: 8f42b335b8638b50194b64ede638c446 (MD5) / Made available in DSpace on 2016-04-19T16:16:26Z (GMT). No. of bitstreams: 1 rocha_tla_me_bot.pdf: 794073 bytes, checksum: 8f42b335b8638b50194b64ede638c446 (MD5) Previous issue date: 2016-02-29 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / As metaloproteinases de matriz extracelular (MMPs) podem limitar a vasodilatação pulmonar e os efeitos inotrópicos positivos promovidos pela adrenomedulina durante a hipertensão pulmonar. O presente estudo teve por objetivo avaliar os efeitos da administração combinada da doxiciclina (inibidor não seletivo das MMPs) e da adrenomedulina sobre as alterações hemodinâmicas observadas durante a embolia pulmonar aguda em ovinos. Alterações hemodinâmicas e respiratórias foram mensuradas em ovinos anestesiados, pré-tratados com doxiciclina (10 mg/kg por via intravenosa), submetidos à EPA induzida pela injeção intravenosa (IV) de microesferas de silicone (500 mg) e posteriormente tratados com solução salina (grupo Dox+PE) ou adrenomedulina (50 ng/kg/min) (grupo Dox+PE+Adm). Os resultados deste estudo foram comparados com grupos históricos recentemente publicados por nosso grupo de pesquisa, realizados sob as mesmas condições experimentais, onde foram utilizados ovinos anestesiados não submetidos a qualquer intervenção (grupo Sham) ou submetidos à EPA e tratados com solução salina (grupo PE) ou com adrenomedulina (50 ng/kg/min) (grupo PE+Adm). Doxiciclina não produziu efeitos adicionais sobre as diminuições significativas no índice de resistência vascular pulmonar e aumento no índice cardíaco (ambos em 25%) observadas com o uso da adrenomedulina (grupo PE+Adm). A administração da adrenomedulina (grupo PE+Adm e Dox+PE+Adm) diminuiu significativamente a pressão arterial média e o índice de resistência vascular sistêmica, levando a uma hipotensão sistêmica moderada. Reduções significativas na pressão parcial de oxigênio arterial foram observadas após a doxiciclina e a EPA, que não foram afetadas pela administração da adrenomedulina. Estes resultados demonstram que a administração combinada da doxiciclina e adrenomedulina não traz benefícios hemodinâmicos adicionais quando comparada ao uso isolado da adrenomedulina, sugerindo que está combinação não se apresenta vantajosa durante a EPA induzida por microesferas. / Matrix metalloproteinases (MMPs) may limit severely the pulmonary vasodilatory and inotropic effects of adrenomedullin during pulmonary hypertension. Hemodynamic and respiratory changes were measured in anesthetized bovine pre-treated with doxycycline (10 mg/kg intravenously), subjected to APE induced by intravenous injection of silicone microspheres (500 mg) and subsequently treated with physiological saline (Dox+PE group) or adrenomedullin (50 ng / kg / min) (Dox+PE+ Adm group). The results were compared with historical group recently published by our research group, carried out under the same experimental conditions, where anesthetized sheep were used not subjected to any intervention (Sham group) or subjected to APE, and treated with physiological saline (PE group) or with adrenomedullin (50 ng / kg / min) (PE+Adm Group). Doxycycline produced no effect on significant temporal decreases in pulmonary vascular resistance index and increases in cardiac index (both by 25%) observed with adrenomedullin. The administration of adrenomedullin significantly decreased mean arterial pressure and systemic vascular resistance index, leading to a moderate systemic hypotension. Significant decreases in arterial oxygen partial pressure were observed after doxycycline or APE, but these changes were not affected by adrenomedullin. These results demonstrate that the combined administration of doxycycline and adrenomedullin does not provide additional hemodynamic benefits when compared to isolated use of adrenomedullin, suggesting that this combination does not appear advantageous for the APE-induced microspheres. / FAPESP: 2012/12.291-7

Orientador: Carlos Alan Candido Dias Junior / Resumo: As metaloproteinases de matriz extracelular (MMPs) podem limitar a vasodilatação pulmonar e os efeitos inotrópicos positivos promovidos pela adrenomedulina durante a hipertensão pulmonar. O presente estudo teve por objetivo avaliar os efeitos da administração combinada da doxiciclina (inibidor não seletivo das MMPs) e da adrenomedulina sobre as alterações hemodinâmicas observadas durante a embolia pulmonar aguda em ovinos. Alterações hemodinâmicas e respiratórias foram mensuradas em ovinos anestesiados, pré-tratados com doxiciclina (10 mg/kg por via intravenosa), submetidos à EPA induzida pela injeção intravenosa (IV) de microesferas de silicone (500 mg) e posteriormente tratados com solução salina (grupo Dox+PE) ou adrenomedulina (50 ng/kg/min) (grupo Dox+PE+Adm). Os resultados deste estudo foram comparados com grupos históricos recentemente publicados por nosso grupo de pesquisa, realizados sob as mesmas condições experimentais, onde foram utilizados ovinos anestesiados não submetidos a qualquer intervenção (grupo Sham) ou submetidos à EPA e tratados com solução salina (grupo PE) ou com adrenomedulina (50 ng/kg/min) (grupo PE+Adm). Doxiciclina não produziu efeitos adicionais sobre as diminuições significativas no índice de resistência vascular pulmonar e aumento no índice cardíaco (ambos em 25%) observadas com o uso da adrenomedulina (grupo PE+Adm). A administração da adrenomedulina (grupo PE+Adm e Dox+PE+Adm) diminuiu significativamente a pressão arterial média e o índice ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Matrix metalloproteinases (MMPs) may limit severely the pulmonary vasodilatory and inotropic effects of adrenomedullin during pulmonary hypertension. Hemodynamic and respiratory changes were measured in anesthetized bovine pre-treated with doxycycline (10 mg/kg intravenously), subjected to APE induced by intravenous injection of silicone microspheres (500 mg) and subsequently treated with physiological saline (Dox+PE group) or adrenomedullin (50 ng / kg / min) (Dox+PE+ Adm group). The results were compared with historical group recently published by our research group, carried out under the same experimental conditions, where anesthetized sheep were used not subjected to any intervention (Sham group) or subjected to APE, and treated with physiological saline (PE group) or with adrenomedullin (50 ng / kg / min) (PE+Adm Group). Doxycycline produced no effect on significant temporal decreases in pulmonary vascular resistance index and increases in cardiac index (both by 25%) observed with adrenomedullin. The administration of adrenomedullin significantly decreased mean arterial pressure and systemic vascular resistance index, leading to a moderate systemic hypotension. Significant decreases in arterial oxygen partial pressure were observed after doxycycline or APE, but these changes were not affected by adrenomedullin. These results demonstrate that the combined administration of doxycycline and adrenomedullin does not provide additional hemodynamic benefits when compared to iso... (Complete abstract click electronic access below) / Mestre

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

Background: Guidelines recommend the use of multiple pharmacologic agents and/or mechanical compressive devices for prevention of venous thromboembolism, but preference for any specific agent is no longer given in regard to safety or efficacy. Objective: To compare postoperative bleeding rates in patients receiving enoxaparin, rivaroxaban, or aspirin for thromboprophylaxis after undergoing elective total hip arthroplasty or total knee arthroplasty. Methods: This retrospective cohort analysis evaluated patients who received thromboprophylaxis with either enoxaparin, rivaroxaban, or aspirin. All data were collected from the electronic medical record. The primary outcome was any postoperative bleeding. Results: A total of 1244 patients were included with 366 in the aspirin, 438 in the enoxaparin, and 440 in the rivaroxaban arms. Those who received aspirin or enoxaparin were less likely to experience any bleeding compared to those patients who received rivaroxaban (P <.05). There was also a lower rate of major bleeding in these groups, but the differences were not significant. Conclusions: Aspirin and enoxaparin conferred similar bleeding risks, and both exhibited less bleeding than patients who received rivaroxaban.

Background: The Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) 1 to 4 trials compared rivaroxaban 10 mg daily with commonly used doses of enoxaparin and demonstrated similar rates of VTE and bleeding. Objective: To evaluate bleeding events between patients who received enoxaparin or rivaroxaban for prevention of venous thromboembolism (VTE) following total hip arthroplasty (THA) or total knee arthroplasty (TKA). Methods: Retrospective cohort that compared patients undergoing THA and TKA who received enoxaparin (enoxaparin) with those who received rivaroxaban (rivaroxaban) and also with those who received enoxaparin in the RECORD 1 to 4 trials (enoxaparin RECORD). The primary outcome was any postoperative bleeding, defined as a composite of major and clinically relevant nonmajor bleeding based on the definitions in the RECORD 1 to 4 trials. Results: There was a lower rate of any postoperative bleeding (2.2% vs 6.8%, P = 0.004) in patients who received enoxaparin compared with rivaroxaban, and bleeding rates between the enoxaparin group and the enoxaparin RECORD groups were similar (2.2% vs 2.5%, P = 0.085). Major bleeding in the enoxaparin group (0.2%) was not significantly different from that in the rivaroxaban group (1.4%, P = 0.12) or the RECORD group (0.2%, P = 0.93). Clinically relevant nonmajor bleeding was also lower in the enoxaparin group compared with the rivaroxaban group (2.0% vs 5.5%, P = 0.012). Conclusions: The use of enoxaparin for VTE prophylaxis following THA and TKA was associated with a lower rate of the primary outcome (any postoperative bleeding) compared with the use of rivaroxaban in a similar cohort of patients.