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Balali_Pargol_MSc thesis_Neuroscience department_2023Sep / Background: Cerebral microbleeds are asymptomatic neuroimaging markers of small vessel disease (SVD), visualized as small hypointensities on blood-sensitive magnetic resonance imaging (MRI) sequences. Patients with ischemic stroke and microbleeds are at a higher risk of future ischemic stroke and intracranial hemorrhage. Antithrombotic therapies, the mainstay treatment of secondary stroke prevention, are associated with an increased risk of bleeding. This raises concerns surrounding the net benefit of antithrombotic therapies in these hemorrhage-prone patients. The overarching aim of this thesis is to determine the safety of antithrombotic treatments in patients with hemorrhage-prone SVD marked by microbleeds on MRI or prior intracerebral hemorrhage (ICH). I aimed to characterize the association between baseline microbleeds and the risk of future clinical outcomes in patients with ischemic stroke and whether there exists treatment effect modification of different anticoagulants on clinical outcomes according to microbleeds presence, location, and number. Methods: We performed post hoc analyses on two multicenter previously conducted randomized trials in patients with non-cardioembolic ischemic stroke. For the PACIFIC-STROKE trial, we used multivariable regression models to determine the contribution of microbleeds to the risk of new microbleeds, hemorrhagic transformation (HT), ischemic stroke, intracranial hemorrhage, and death. We assessed the treatment effect of asundexian, a factor XIa inhibitor, vs. placebo on these clinical outcomes, stratified by microbleeds presence, location, and number. I was trained on standardized rating of microbleeds on MRI, achieved excellent interrater reliability, and rated all DATAS-II participant MRIs. I used multivariable logistic regression models to identify the association between microbleeds and HT and 90-day excellent functional outcome. I assessed the interaction between treatment with dabigatran, a direct thrombin inhibitor, vs. aspirin and microbleeds for these outcomes. Separately, I performed a review of the literature and wrote an editorial discussing the optimum timing of antiplatelet re-initiation after ICH. Results: The PACIFIC-STROKE post hoc analyses showed that microbleeds are associated with a 1.6-fold and 4.4-fold higher risk of HT and new microbleeds, respectively. The DATAS-II exploratory analyses demonstrated no association between the risk of outcomes and microbleeds presence. We found no interaction between treatment assignment and microbleed presence for any of the clinical outcomes investigated in either of these studies. Based on the totality of evidence, we concluded that early resumption of antiplatelets in ICH survivors is likely to be safe. Conclusion: Our findings do not support existing concerns surrounding the use of anticoagulants in patients with acute ischemic stroke and microbleeds on MRI, nor for the early resumption of antiplatelets in ICH survivors. / Thesis / Master of Science (MSc) / Diseases of small brain blood vessels can lead to strokes due to blockage or bleeding. Small, asymptomatic brain bleeds on MRIs (microbleeds) are common among affected patients. Patients with clot-induced stroke and microbleeds have a higher risk of both types of strokes. Blood thinners are standard treatments to prevent future clotting events after clot-induced stroke. However, their potential to increase the risk of brain bleeding has raised concerns regarding their use in patients with microbleeds or bleeding-induced stroke. We assessed information from two large, previously completed randomized trials to evaluate the safety of strong blood thinners (anticoagulants) in patients with clot-induced stroke and microbleeds. Additionally, we evaluated the risk vs. benefit of restarting milder blood thinners (antiplatelets) early after bleeding-induced stroke. Bleeding was more prevalent in patients with microbleeds; however, the effect of the anticoagulants tested on bleeding outcomes was not modified by microbleed presence. Overall, our findings suggest that blood thinners are safe in patients with clot-induced stroke and microbleeds, and that early resumption of antiplatelets seems safe in patients with bleeding-induced stroke.

Direct factor Xa inhibitors (FXaI) account for most oral anticoagulant use. FXaI-associated bleeding events are common and are associated with substantial morbidity and mortality. Nonspecific hemostatic therapies such as prothrombin complex concentrates (PCC) are often administered for FXaI-associated bleeding. The mechanism by which these agents improve hemostasis in the setting of direct oral anticoagulation is unclear. Thrombin generation assays may effectively measure the effect of anticoagulation reversal among FXaI-treated patients when bleeding cessation would otherwise be challenging to measure. To build a research program on the utility of thrombin generation assays to measure both the impact of direct oral anticoagulation and anticoagulation reversal, we completed a review of the literature with narrative synthesis and carried out a pilot study to determine the feasibility of a full scale prospective observational study of TGA responses among patients receiving PCC for FXaI-associated major bleeding or needing urgent surgery.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25164号 / 医博第5050号 / 新制||医||1071(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 石見 拓, 教授 大鶴 繁, 教授 江木 盛時 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

This descriptive, correlational, cross-sectional study explored the relationships among the variables self-care action, self-care knowledge, and affiliated individuation and quality of life for persons on chronic warfarin therapy. This study also explored the moderating effects of self-care knowledge and affiliated individuation on quality of life. This research was guided by a theoretical framework based on modeling and role-modeling theory (Erickson, Tomlin, & Swain, 1983). The sample consisted of 83 adults between the ages of 30 to 91 years. The majority of participants were Caucasian, educated, retired and almost evenly distributed between male and female. Each subject completed the following instruments: the Oral Anticoagulation Knowledge (OAK) test, the Duke Anticoagulation Satisfaction Scale (DASS), the Basic Needs Satisfaction Inventory (BNSI), and the generic quality of life survey (SF36v2). Data was analyzed using correlation and hierarchical multiple regression analysis. Results indicated significant correlations among most of the study variables. Self-care action significantly explained variances in all but two quality of life variables. Self-care knowledge and affiliated individuation had statistically significant moderating effects on the DASS negative impact and hassles/burdens subscales. Self-care knowledge also demonstrated a significant moderating effect on the SF36v2 physical function subscale. These findings support the concepts proposed by the study's theoretical framework. This research serves as validation of Acton's (1997) study findings for the concept of affiliated individuation and its value as a self-care resource in a specific clinical population. / text

Introdução. Avaliar o conhecimento, de indivíduos em uso da terapia com anticoagulantes orais (TAO), é uma estratégia que profissionais da saúde podem utilizar para orientar o cuidado dispensado a estas pessoas. O uso de um instrumento psicometricamente válido e confiável é fundamental para garantir uma avaliação adequada. Objetivo. Construir e validar um instrumento para avaliar o conhecimento sobre a TAO. Método. Estudo metodológico e de corte transversal, que seguiu as seguintes etapas: elaboração dos itens, validação de face e conteúdo por um comitê de juízes, estudo piloto e aplicação do instrumento em uma amostra da população estudada. A amostra foi constituída de pacientes adultos, em uso de anticoagulantes orais antagonistas da vitamina K há, pelo menos, seis meses e entrevistados nas unidades de internação ou ambulatórios de três instituições públicas do interior do estado de São Paulo, no período de dezembro de 2013 a agosto de 2014. Participaram 50 indivíduos no estudo piloto e 500 na etapa de validação psicométrica do instrumento. A validação de construto foi verificada pela análise fatorial de informação plena e pela comparação da medida do conhecimento com variáveis associadas ao conhecimento da TAO (escolaridade e tempo de uso do medicamento). A consistência interna foi avaliada pelo teste de Kuder- Richardson (KR 20). O nível de significância adotado para os testes foi de 0,05. Resultados. Inicialmente o instrumento foi composto por 43 itens, entre eles itens de múltipla escolha e questões abertas. Após validação de face e conteúdo foram feitas modificações, dentre elas, a exclusão de questões abertas. A seguir realizado teste piloto, com a nova versão do instrumento denominada Avaliação do conhecimento em anticoagulação oral (IACACO), contendo 32 itens do tipo teste de múltipla escolha, dividido em dois módulos, o primeiro com 28 itens de conhecimentos gerais sobre a TAO (pontuação de 0 a 28) e o segundo, com 4 itens, específico para mulheres em idade fértil (pontuação de 0 a 4). A análise fatorial sugeriu um instrumento unidimensional. Ao avaliarmos o resultado da correlação entre as variáveis anos de estudo e conhecimento da TAO, constatamos correlação positiva e de forte intensidade entre as duas medidas (r = 0,61, p <=0,001). O valor da correlação entre as variáveis conhecimento e tempo de uso do ACO mostrou correlação positiva, mas de fraca intensidade (r = 0,21; p<= 0,001). O Coeficiente KR 20 de Kuder-Richardson foi de 0,86 para o módulo geral (28 itens) e para o instrumento com seus dois módulos (32 itens) foi de 0,85. Conclusão. As análises mostraram resultados favoráveis para o ICACO e trouxeram evidências de que o novo instrumento foi válido e confiável para avaliar o conhecimento dos pacientes em uso da TAO. Análises futuras da Teoria de Resposta ao Item poderão contribuir para a avaliação individual dos itens do IACACO. Não foi determinado ponto de corte para conhecimento suficiente ou não sobre a TAO, cabe ao profissional de saúde ou pesquisador determinar a melhor maneira de interpretar os resultados advindos da aplicação do instrumento. / Introduction. To evaluate the knowledge of individuals using oral anticoagulant therapy (OAT) is a strategy that health professionals can use to guide the care given to these people. The use of a valid and reliable psychometric instrument ensure a proper evaluation. Aim. To construct and validate an instrument to assess the knowledge of the OAT. Method. Methodological and cross-sectional study, which followed the following steps: preparation of items, face and content validation by a committee of judges, pilot study and application of the instrument in a sample of the population studied. The sample consisted of adult patients using oral anticoagulants antagonists vitamin K for at least six months and interviewed in unit cares for pacients and ambulatory clinics of three public institutions in the state of São Paulo, in December 2013 to August 2014. Attended 50 individuals in the pilot study and 500 in the psychometric validation of the instrument step. The construct validity was verified by factor analysis of full information and by comparing the measure of knowledge with variables associated with knowledge of the OAT. Internal consistency was estimated by Kuder- Richardson test (KR 20). The significance level for the tests was 0.05. Results. Initially, the instrument consisted of 43 items, including items of multiple choice and open questions. After validation of face and content changes were made, among them the exclusion of open questions. Following conducted pilot test with the new version of the called knowledge evaluation of oral anticoagulation instrument (KEOAI) containing 32 items of the type test of multiple choice, divided into two modules, the first with 28 items of general knowledge of the OAT ( score 0-28) and the second with 4 items, specific to women of childbearing age (score 0-4). Factor analysis suggested a one-dimensional instrument. When evaluating the results of the correlation between the variables years of study and knowledge of the OAT, we found a positive correlation and strong intensity between the two measurements (r = 0.61, p <=0,001). The value of the correlation between the variables knowledge and OAT usage time showed positive correlation, but low intensity (r = 0.21, p <= 0.001). The coefficient KR 20 Kuder- Richardson was 0.86 for the general module (28 items) and the instrument with its two modules (32 items) was 0.85. Conclusion. Analyses showed favorable results for KEOAI and brought evidence that the new instrument is valid and reliable for assessing the knowledge of patients using the OAT. Future analyzes of Item Response Theory can contribute to the evaluation of individual KEOAI items. It was determined cutoff point for sufficient knowledge or not on the OAT, it is up to the health professional or researcher to determine the best way to interpret the results from the application of the instrument.

Introdução. Avaliar o conhecimento, de indivíduos em uso da terapia com anticoagulantes orais (TAO), é uma estratégia que profissionais da saúde podem utilizar para orientar o cuidado dispensado a estas pessoas. O uso de um instrumento psicometricamente válido e confiável é fundamental para garantir uma avaliação adequada. Objetivo. Construir e validar um instrumento para avaliar o conhecimento sobre a TAO. Método. Estudo metodológico e de corte transversal, que seguiu as seguintes etapas: elaboração dos itens, validação de face e conteúdo por um comitê de juízes, estudo piloto e aplicação do instrumento em uma amostra da população estudada. A amostra foi constituída de pacientes adultos, em uso de anticoagulantes orais antagonistas da vitamina K há, pelo menos, seis meses e entrevistados nas unidades de internação ou ambulatórios de três instituições públicas do interior do estado de São Paulo, no período de dezembro de 2013 a agosto de 2014. Participaram 50 indivíduos no estudo piloto e 500 na etapa de validação psicométrica do instrumento. A validação de construto foi verificada pela análise fatorial de informação plena e pela comparação da medida do conhecimento com variáveis associadas ao conhecimento da TAO (escolaridade e tempo de uso do medicamento). A consistência interna foi avaliada pelo teste de Kuder- Richardson (KR 20). O nível de significância adotado para os testes foi de 0,05. Resultados. Inicialmente o instrumento foi composto por 43 itens, entre eles itens de múltipla escolha e questões abertas. Após validação de face e conteúdo foram feitas modificações, dentre elas, a exclusão de questões abertas. A seguir realizado teste piloto, com a nova versão do instrumento denominada Avaliação do conhecimento em anticoagulação oral (IACACO), contendo 32 itens do tipo teste de múltipla escolha, dividido em dois módulos, o primeiro com 28 itens de conhecimentos gerais sobre a TAO (pontuação de 0 a 28) e o segundo, com 4 itens, específico para mulheres em idade fértil (pontuação de 0 a 4). A análise fatorial sugeriu um instrumento unidimensional. Ao avaliarmos o resultado da correlação entre as variáveis anos de estudo e conhecimento da TAO, constatamos correlação positiva e de forte intensidade entre as duas medidas (r = 0,61, p <=0,001). O valor da correlação entre as variáveis conhecimento e tempo de uso do ACO mostrou correlação positiva, mas de fraca intensidade (r = 0,21; p<= 0,001). O Coeficiente KR 20 de Kuder-Richardson foi de 0,86 para o módulo geral (28 itens) e para o instrumento com seus dois módulos (32 itens) foi de 0,85. Conclusão. As análises mostraram resultados favoráveis para o ICACO e trouxeram evidências de que o novo instrumento foi válido e confiável para avaliar o conhecimento dos pacientes em uso da TAO. Análises futuras da Teoria de Resposta ao Item poderão contribuir para a avaliação individual dos itens do IACACO. Não foi determinado ponto de corte para conhecimento suficiente ou não sobre a TAO, cabe ao profissional de saúde ou pesquisador determinar a melhor maneira de interpretar os resultados advindos da aplicação do instrumento. / Introduction. To evaluate the knowledge of individuals using oral anticoagulant therapy (OAT) is a strategy that health professionals can use to guide the care given to these people. The use of a valid and reliable psychometric instrument ensure a proper evaluation. Aim. To construct and validate an instrument to assess the knowledge of the OAT. Method. Methodological and cross-sectional study, which followed the following steps: preparation of items, face and content validation by a committee of judges, pilot study and application of the instrument in a sample of the population studied. The sample consisted of adult patients using oral anticoagulants antagonists vitamin K for at least six months and interviewed in unit cares for pacients and ambulatory clinics of three public institutions in the state of São Paulo, in December 2013 to August 2014. Attended 50 individuals in the pilot study and 500 in the psychometric validation of the instrument step. The construct validity was verified by factor analysis of full information and by comparing the measure of knowledge with variables associated with knowledge of the OAT. Internal consistency was estimated by Kuder- Richardson test (KR 20). The significance level for the tests was 0.05. Results. Initially, the instrument consisted of 43 items, including items of multiple choice and open questions. After validation of face and content changes were made, among them the exclusion of open questions. Following conducted pilot test with the new version of the called knowledge evaluation of oral anticoagulation instrument (KEOAI) containing 32 items of the type test of multiple choice, divided into two modules, the first with 28 items of general knowledge of the OAT ( score 0-28) and the second with 4 items, specific to women of childbearing age (score 0-4). Factor analysis suggested a one-dimensional instrument. When evaluating the results of the correlation between the variables years of study and knowledge of the OAT, we found a positive correlation and strong intensity between the two measurements (r = 0.61, p <=0,001). The value of the correlation between the variables knowledge and OAT usage time showed positive correlation, but low intensity (r = 0.21, p <= 0.001). The coefficient KR 20 Kuder- Richardson was 0.86 for the general module (28 items) and the instrument with its two modules (32 items) was 0.85. Conclusion. Analyses showed favorable results for KEOAI and brought evidence that the new instrument is valid and reliable for assessing the knowledge of patients using the OAT. Future analyzes of Item Response Theory can contribute to the evaluation of individual KEOAI items. It was determined cutoff point for sufficient knowledge or not on the OAT, it is up to the health professional or researcher to determine the best way to interpret the results from the application of the instrument.

Intraoperative Blutungskomplikationen sind bei der Versorgung von Patienten mit primärer rhegmatogener Netzhautablösung relativ selten. Bei den aufgetretenen Komplikationen handelte es sich fast ausschließlich um leichtere Blutungen, die intraoperativ gut zu beherrschen waren. Die Wahl der Antikoagulation hatte dabei keinen Einfluss auf die Wahrscheinlichkeit des Auftretens intraoperativer Blutungskomplikationen. Dies gilt sowohl für die Thrombozytenaggregationshemmer Acetylsalicylsäure und Clopidogrel als auch für die gerinnungshemmenden Substanzen Heparin und Phenprocoumon. Interessanterweise zeigte sich bei den mit Phenprocoumon behandelten Patienten keine Korrelation zwischen einem erniedrigten Quick-Wert und einer erhöhten intraoperativen Blutungsneigung. Bei den wenigen Patienten, bei denen es unter der Therapie mit Phenprocoumon zu einer Blutung während der Operation kam, lagen die Quick-Werte sogar eher im oberen Bereich. Wenn man nun bedenkt, dass es sich bei der rissbedingten Netzhautablösung um einen Notfall handelt und beim Zuwarten mit einer Progredienz der Ablösung zu rechnen ist, kann eine klare Empfehlung für die sofortige Operation trotz wirksamer Antikoagulation ausgesprochen werden. Untermauert wird dies noch durch die erhöhte Gefahr thromboembolischer Ereignisse, wenn eine indizierte Gerinnungshemmung perioperativ abgesetzt oder auf andere Substanzen umgestellt wird. Schließlich werden nur Patienten antikoaguliert, bei denen dies aufgrund von gravierenden Erkrankungen in der Vorgeschichte indiziert ist. Dazu gehören zum Beispiel abgelaufene tiefe Beinvenenthrombosen oder Embolien, Vorhofflimmern oder auch der Herzklappenersatz. Im Gegensatz zu den Ergebnissen für die Antikoagulation ergab sich eine Abhängigkeit der intraoperativen Blutungswahrscheinlichkeit von der Wahl des operativen Verfahrens. Die wenigsten Blutungen traten bei den rein eindellenden Operationen (Plomben und Cerclagen) auf. Bei den kombinierten Operationen (Plombe oder Cerclage in Kombination mit Pars plana Vitrektomie) lag die Komplikationsrate schon deutlich höher. Die höchste Rate intraoperativer Blutungskomplikationen zeigte sich bei den nicht-eindellenden Operationen (Pars plana Vitrektomien). Dabei war die Komplikationsrate bei den nicht-eindellenden Verfahren gegenüber den rein eindellenden Verfahren signifikant erhöht (p<0,001). Es kann also festgehalten werden, dass intraoperative Blutungen bei der Akutversorgung von Patienten mit rissbedingter Netzhautablösung selten sind und nicht im Zusammenhang mit der Einnahme von Gerinnungshemmern zu stehen scheinen. Die Wahl des Operationsverfahrens hingegen beeinflusst die Rate intraoperativer Blutungskomplikationen.

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