CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / The therapeutic use of Varfarin, the most common oral anticoagulant it is indicated in many cases, including the atrial fibrillation, cardiac valvular prostheses and venous trombolic disease. Many discussions still exist related to the suspension or not before tooth extraction. People who are for itâs suspension agree that it may increase the risk of hemorrhage, however the ones who prefer to maintain itâs use refer the high risk of tromboembolism. Due to the controversy related to the cronic use of oral anticoagulant before tooth extraction and what to use to control bleeding after extraction, we decided to perform a one center randomized clinical trial study to compare the effectiveness of the hemostasis using soaked gauze with tranexamic acid at 4,8% and plain gauze and the use of collagen sponge (HemosponÂ), using it inside the tooth socket after extraction. The sample was made of 84 surgical procedures performed in 38 patients who were under anticoagulant treatment and who needed at least one tooth extraction. The trial was divided in three groups regarding the method used to reach hemostasis after tooth extraction. In group I we used compression with soaked gauze with tranexamic acid at 4,8%; in group II we used collagen sponge (HemosponÂ) inside the socket while in group III we compressed the socket with dry gauze for 8 minutes. There were two cases of post surgical bleeding, being one from group I and one from group II. The data collected was evaluated thru SPSS 1.5 (Statistic Package of Social Science) program. All the statistical analysis performed were considered significantly when p was less than 5%. We used the Qui square X2 Test, Fisher Exact Test e Analysis of Variance (ANOVA) to verify the variables of the data. There was no statistically significant difference between the groups, related to bleeding (p>0,05). The compression with dry gauze and suture, compression with soaked gauze with trenaxamic acid at 4.8% and suture and the use of collagen sponge (HemosponÂ) in the tooth socket hold with suture showed similar efficacy to the control of post extraction bleeding in patients who are under anticoagulant treatment. / A terapÃutica com varfarina, o anticoagulante oral mais utilizado, està indicada em mÃltiplas situaÃÃes, incluindo a fibrilaÃÃo atrial, prÃteses valvulares cardÃacas e o tromboembolismo venoso. DiscussÃes ainda existem sobre a indicaÃÃo ou nÃo da sua interrupÃÃo prÃvia a realizaÃÃo de exodontias. Aqueles que defendem a parada de sua administraÃÃo baseiam tal decisÃo no risco aumentado de hemorragias, enquanto os que acreditam na manutenÃÃo da terapia ressaltam o risco de tromboembolismo. Em virtude das controvÃrsias acerca da realizaÃÃo de exodontias em pacientes que fazem uso crÃnico de anticoagulantes orais, alÃm da dÃvida de que mÃtodo empregar no controle do sangramento pÃs-exodontia, decidimos realizar um estudo do tipo ensaio clÃnico, unicÃntrico, randomizado com o objetivo de comparar a efetividade hemostÃtica local da compressÃo com gaze embebida ou nÃo em Ãcido tranexÃmico à 4,8% com o emprego da esponja de colÃgeno (HEMOSPONÂ) no interior do alvÃolo pÃs-exodontia. A amostra foi constituÃda por 84 procedimentos cirÃrgicos realizados em 38 pacientes sob terapia anticoagulante que necessitavam de pelo menos uma extraÃÃo dentÃria. A amostra foi dividida em trÃs grupos a depender do mÃtodo hemostÃtico local empregado para o controle do sangramento apÃs a extraÃÃo dentÃria. No grupo I utilizou-se a compressÃo com gaze embebida em Ãcido tranexÃmico a 4,8%; no grupo II introduziu-se no interior do alvÃolo uma esponja de colÃgeno (HemosponÂ); enquanto no grupo III, a compressÃo com gaze seca por 8 minutos foi o mÃtodo empregado. Em dois casos foi observado sangramento pÃs-operatÃrio sendo um paciente do grupo I e outro do grupo II. Os dados coletados foram consolidados e avaliados por meio do programa SPSS 15.0 (Statistic Package of Social Science). Todas as anÃlises estatÃsticas efetuadas foram consideradas significativas quando valor de p foi menor que 5%. Utilizou-se os testes Qui-Quadrado (XÂ), Teste Exato de Fisher e AnÃlise de VariÃncia (ANOVA) para verificar as diferenÃas entre as variÃveis. NÃo houve diferenÃa estatisticamente significante entre os grupos com relaÃÃo à ocorrÃncia de hemorragias (p-valor>0,05). A compressÃo com gaze seca associado à sutura, a compressÃo com gaze embebida com Ãcido tranexÃmico a 4,8% associada a sutura e o emprego da esponja de fibrina (HemosponÂ) intra-alveolar associado a sutura mostraram eficÃcia semelhante no controle do sangramento pÃs-exodontia em pacientes sob terapia anticoagulante.

[Truncated abstract] Cardiac surgery involving cardiopulmonary bypass is a complex procedure that results in significant changes to blood coagulation, fibrinolytic biochemistry, platelet number and function, and the vasculature. These are due to pharmacological agents which are administered, haemodilution and contact of the blood with artificial surfaces. Consequently there are significant risks of thrombosis and haemorrhage associated with this procedure. The research presented in this thesis utilises in vitro, in vivo, and a novel ex vivo model to investigate the nature of the haemostatic defect induced by cardiopulmonary bypass. The components studied include the drugs heparin, protamine sulphate, and aprotinin, different types of bypass circuitry (including heparin bonded circuits) and procedures such as acute normovolaemic haemodilution. Patient variables, such as Factor V Leiden, are also studied. Each of these components is assessed for the effects on a number of laboratory measures of haemostasis including activated partial thromboplastin time, prothrombin time, activated protein C ratio, antithrombin concentration, heparin concentration, thrombin-antithrombin complex formation, prothrombin fragment 1+2 formation, markers of platelet surface activation and secretion, activated clotting time, haemoglobin concentration and coagulation factor assays.

The aim of this thesis was to explore variations in stroke prevention and the effect of prevention on outcome. The studies were based on patients registered in the Swedish Stroke Register between 2001 and 2009 and although used to different extents in each paper, additional information was retrieved through linkage to The National Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Total Population Register. Cardiovascular risk factors were prevalent among ischemic stroke (IS) patients; however, they were not always prescribed the drugs recommended, and increasing age was an important negative predictor (Paper I). After IS, the rate of hemorrhage in patients prescribed antiplatelet agents (2.4 per 100 person-years) was double to results from randomized controlled trails, but was similar for patients prescribed warfarin (2.5 per 100 person-years).  Age ≥75 years and previous hemorrhage were associated with a moderately increased risk of future hemorrhage (Paper II). Among IS patients with atrial fibrillation, one-third was prescribed warfarin and two-thirds were prescribed antiplatelets. After adjustment for a propensity score (used to adjust for the non-randomized design), warfarin was associated with a reduced risk of death (0.67; 95% CI, 0.63-0.71) (Paper III). The rate of subsequent hemorrhagic stroke was 0.4 per 100 person-years and the risk did not change (HR 1.04; 95% CI, 0.73-1.48) when later years of the 2000s (inclusion period 2005-8: follow-up until 2009) was compared with earlier years (inclusion period 2001-4: follow-up until 2005) (Paper IV, cohort). Although the risk of first-ever hemorrhagic stroke more than doubled with warfarin than without, the risk did not change between 2006 and 2009 (Paper IV, case-control). In summary, the prescription of secondary preventive drugs varies with age, even though cardiovascular risk factors are prevalent in all ages. The risk of death and hemorrhage are affected by the type of antithrombotic prescribed. Therefore, it is important individual’s stroke and bleeding risks in stroke prevention are assessed.

INTRODUCCIÓN: La heparina no fraccionada (HNF) se utiliza en el tratamiento del ictus desde varias décadas como fármaco anticoagulante. Los ensayos clínicos aleatorizados no han demostrado eficacia de este tratamiento, por lo que se desaconseja su uso. Sin embargo estos estudios tienen numerosas limitaciones como un excesivo retraso en el inicio del tratamiento, la vía de administración del fármaco y la falta de monitorización. En los últimos años se han descrito numerosas propiedades antiinflamatorias de la HNF que podrían ser beneficiosas en la isquemia cerebral aguda. OBJETIVOS: establecer un modelo animal de tratamiento continuo con HNF que permita mantener una heparinemia dentro de los márgenes terapéuticos deseados y determinar si la HNF administrada de la manera adecuada es neuroprotectora en un modelo de isquemia-reperfusión cerebral focal en rata, estudiar si hay mecanismos antiinflamatorios involucrados en este efecto neuroprotector, analizar marcadores séricos de inflamación en pacientes con ictus para determinar si existe un efecto antiinflamatorio al usar HNF y desarrollar un ensayo clínico aleatorizado comparando la HNF con la aspirina en el tratamiento del ictus isquémico agudo para evaluar la superioridad de este tratamiento. MÉTODOS Y RESULTADOS: Evaluamos la farmacocinética de la HNF en diferentes grupos de rata mediante reactivos cromógenos y encontramos que la dosis que mantenía una heparinemia constante de 0.3 a 0.6 U/mL fue un bolus de 200 U/kg seguido de una perfusión intraperitoneal de 70 U/kg/h. Mediante la técnica de oclusión endoluminal de la arteria cerebral media determinamos que la HNF iniciada a las 3 horas de la isquemia reducía el volumen de infarto cerebral en un 46% respecto al grupo control. Este efecto neuroprotector se acompañó de una elevación de los niveles plasmáticos de IL-10, de una mayor expresión de hemooxigenasa-1, y de una menor expresión de VCAM-1. En pacientes con isquemia cerebral agudo, encontramos una mayor respuesta de fase aguda (leucocitos totales, porcentaje de polimorfonucleares y velocidad de sedimentación globular) en los tratados con aspirina que en los que recibieron HNF. La reacción de fase aguda fue menor que presentaban una recuperación completa al alta. Además se demostró una asociación positiva entre el uso de HNF y la recuperación completa, sobre todo en el ictus no lacunar. En otro estudio el aumento de VCAM-1 sérica a las 48 horas se asoció de forma independiente con una peor recuperación a los 6 meses. Los niveles de VCAM-1 sérica fueron 1.24 veces mayores en los pacientes tratados con aspirina. Por último, realizamos un ensayo aleatorizado, el estudio RAPID, comparando la eficacia de la aspirina y de la HNF en el ictus isquémico no lacunar de menos de 12 horas de evolución. El estudio se cerró prematuramente con 67 pacientes incluidos. La HNF demostró un perfil de seguridad igual al de la aspirina. CONCLUSIONES: La HNF administrado de forma adecuada es neuroprotectora en el modelo de isquemia-reperfusión cerebral focal de rata, ya que reduce en un 46% el volumen de infarto. La acción neuroprotectora de la HNF está mediada por mecanismos antiinflamatorios, como el incremento de la IL-10 plasmática, el aumento de la expresión de la hemooxigenasa-1 y la inhibición de la inducción de la VCAM-1. En pacientes con ictus tratados con HNF se observa una menor respuesta de fase aguda y niveles séricos más bajos de VCAM-1. Esta disminución de marcadores inflamatorios se asoció con una mejor recuperación funcional.La medicina basada en la evidencia no tiene, en estos momentos, datos suficientes para evaluar la eficacia y seguridad del tratamiento con HNF en las primeras 12 horas tras un ictus isquémico no lacunar. No obstante, el estudio RAPID aporta que el perfil de seguridad de la HNF puede ser similar al de la aspirina y una mayor eficacia en la prevención de recurrencias tempranas.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 1977.

Thesis (M.S.)--University of Michigan, 1977.