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Rare bleeding disorders are a group of inherited conditions caused by a deficiency of blood coagulation factors. Due to the low prevalence of these conditions in the general population, there is a scarcity of data to make informed, evidence-based clinical decisions. In this population who are highly susceptible to excessive bleeding, surgeries and invasive procedures pose an additional level of risk for bleeding-related and non-bleeding-related complications, especially in the perioperative period. The data scarcity in patients with rare bleeding disorders is further compounded by an infrequent rate of invasive procedures, sometimes attributed to the hemostatic challenges faced by such interventions among other factors. To address the problem of insufficient data for healthcare decision-making, as well as the assessment of perioperative outcomes in this population, this thesis explores the use of routinely collected data for the creation of a novel surgical database used for the assessment of perioperative hemostasis, complications, and initial surgical plan deviations in patients with rare bleeding disorders. Across five chapters, this thesis provides the methodology for the creation of the Indiana Hemostasis and Thrombosis Center (IHTC) Surgical Database, a descriptive analysis of the population and procedures, and assessment of perioperative outcomes. Approaches to ensure the validity of study results including confounder adjustment by variable selection methods, data quality improvement, missing data description, and imputation methods, were explored. Evidence from randomized controlled was also reviewed using Cochrane methodology to summarize the efficacy of clotting factor concentrates for the prevention of bleeds and bleeding-related complications in patients with hemophilia. Based on findings from the different approaches (observational study designs, randomized controlled trials, and systematic review methodology), recommendations were made regarding methodological and analytical considerations required to ensure valid and reliable perioperative outcome assessment in patients with rare bleeding disorders. The following provides a brief outline of each chapter. Chapter 1 is an introduction that outlines each of the studies in this thesis. Chapter 2 is a descriptive overview of the design, structure, and exploratory analysis of data captured in the IHTC-Surgical Database over a 21-year period. Chapter 3 is a retrospective cohort study that assessed the association between inhibitor status and perioperative hemostasis, complications, and initial surgical plan deviations in patients with hemophilia A and B. Chapter 4 is a systematic review that examined the efficacy of clotting factor concentrates for the prevention of bleeds and bleeding-related complications in patients with hemophilia. Chapter 5 outlines key findings, limitations, implications of the research in this thesis, and methodological considerations for the assessment of perioperative outcomes in patients with bleeding disorders. / Thesis / Doctor of Philosophy (PhD)

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Submitted by Maria Creuza Silva (mariakreuza@yahoo.com.br) on 2016-04-14T19:51:38Z No. of bitstreams: 1 Disse MP. Silvia Helena L. Rodrigues. 2015.pdf: 548263 bytes, checksum: 6d3ed80388e26635a912e50c92938c23 (MD5) / Approved for entry into archive by Maria Creuza Silva (mariakreuza@yahoo.com.br) on 2016-04-18T12:22:40Z (GMT) No. of bitstreams: 1 Disse MP. Silvia Helena L. Rodrigues. 2015.pdf: 548263 bytes, checksum: 6d3ed80388e26635a912e50c92938c23 (MD5) / Made available in DSpace on 2016-04-18T12:22:40Z (GMT). No. of bitstreams: 1 Disse MP. Silvia Helena L. Rodrigues. 2015.pdf: 548263 bytes, checksum: 6d3ed80388e26635a912e50c92938c23 (MD5) / As coagulopatias hereditárias são doenças hemorrágicas decorrentes da deficiência quantitativa/qualitativa de um ou mais fatores de coagulação sanguínea, sendo as hemofilias as mais importantes e frequentes. Os pacientes com hemofilia podem desenvolver anticorpos (inibidores) contra o fator deficiente, o que constitui em um desafio terapêutico. O tratamento das crises hemorrágicas em pacientes com inibidor é realizado com agentes bypassing. Este estudo é importante para se ampliar o conhecimento em base epidemiológica dos pacientes que utilizaram agentes bypassing possibilitando o aprimoramento da assistência prestada. Objetivo: Analisar o perfil de utilização dos agentes bypassing distribuídos pelo Ministério da Saúde durante os anos de 2012 e 2013. Metodologia: Trata-se de um estudo descritivo, transversal, de abordagem quantitativa, com base nos dados dos pacientes cadastrados no sistema Hemovida Web Coagulopatias, que utilizaram agentes bypassing nestes anos. Resultados: o perfil de utilização dos agentes bypassing é representado pelos pacientes na faixa etária até 29 anos (69,5%), ensino fundamental incompleto (23,8%), sexo masculino (83,8%), raça branca (43,6%), residentes na região sudeste (48,9%), com Hemofilia A (63%), forma grave da hemofilia (71%), presença de inibidor positiva (56,9%) e inibidor de altos títulos (60,5%). Embora tenha sido evidenciada a utilização off-label (2,8%) para o tratamento de coagulopatias não descritas na bula destes medicamentos. Considerações: Embora tenha sido evidenciado a utilização off-label, o perfil delineado está de acordo com os achados da literatura sobre os fatores associados ao desenvolvimento de inibidores, principal indicação de uso de agentes bypassing, e com as recomendações do Ministério da Saúde.

<p> Inherited bleeding disorders can be caused by mutations affecting platelet, coagulation, or fibrinolytic proteins. Quebec platelet disorder (QPD) is a rare, autosomal dominant disorder associated with increased expression of the fibrinolytic enzyme urokinase plasminogen activator (uPA) in platelets. Individuals with QPD experience delayed-onset bleeding after hemostatic challenges that is attenuated with fibrinolytic inhibitor therapy. The aims of this thesis were to: 1) determine if increased platelet uPA contributes to QPD clot lysis in vitro; 2) investigate whether QPD individuals have increased urinary uPA, as some individuals experience hematuria; and 3) map the genetic locus of QPD, and look for the putative mutation. Studies of clot lysis indicated that QPD platelets induce a gain-of-function defect in fibrinolysis when platelets are incorporated into clots. This suggests that accelerated fibrinolysis may contribute to QPD bleeding. Studies of urinary uPA in QPD showed that uPA is not increased, indicating that hematuria in QPD is likely a consequence of increased platelet uPA. This finding also suggests that uPA overexpression in QPD may be megakaryocyte-specific. Linkage studies showed that QPD is strongly linked to a 2 megabase region on chromosome 10 that harbors the uPA gene, PLA U. No mutations in PLA U or its regulatory regions were identified; however, a common haplotype for a 32.5 kilobase region around PLA U, including inheritance of a rare, linked polymorphism, suggests this is the most likely locus for QPD. mRNA studies in QPD platelets showed that QPD selectively increases expression of the linked PLAU allele, without similar increases in megakaryocyte progenitors or in saliva. These findings implicate a cis-mutation near PLA U as the cause of QPD. This thesis provides novel insights on the fibrinolytic abnormality in QPD blood, and on the QPD genetic locus. which will be important for identifying the precise mutation that converts normally prohemostatic platelets to profibrinolytic cells. </p> / Thesis / Doctor of Philosophy (PhD)

<p>  </p> <p>With the discovery and treatment of any disease comes the important question of its genetic prevalence. This is especially important for animals under strict breeding control, such as dogs, because this can provide essential information regarding breeding pair decisions. Thus, the focus of this thesis is to investigate the genetic prevalence of three different diseases: 1) Factor VII Deficiency (FVIID), 2) Collie Eye Anomaly (CEA), and 3) Progressive Rod-Cone Degeneration-Progressive Retinal Atrophy (prcd-PRA). Factor VII Deficiency (FVIID) is a clotting disorder observed in both humans and dogs, characterized by impeded function of the Factor VII protein. In dogs, FVIID is caused by a single nucleotide substitution (c.407G>A) in the <em>F7 </em>gene. This mutation, identified in a colony of research Beagles, is also present in dogs with a wide variety of distantly-related breed backgrounds and in mixed-breed dogs, suggesting an ancient, ancestral origin. Given the relatively common presence of this variant, it was hypothesized that this genetic mutation could be contributing to excessive bleeding in canine autopsy cases that could not be attributed to typical causes. DNA from formalin-fixed paraffin-embedded tissues (n = 67 cases) were Sanger sequenced for the FVIID c.407G>A mutation, and all were determined to be homozygous wild-type. Therefore, the tested variant is not associated with the unexplained bleeding in these cases, and it is not a logical diagnostic test to apply to similar cases in the future.</p> <p><br></p> <p>CEA and prcd-PRA are ophthalmic genetic diseases of concern often included in commercial genetic testing panels. A large dataset spanning 15+ years provided by a commercial partner company (OptiGen/Wisdom Panel, Kinship) encompassed dogs tested for the CEA-associated <em>NHEJ1</em> deletion (n = 33,834 dogs) and the prcd-PRA causal mutation in <em>PRCD</em> (n = 86,667 dogs). Disease trends were observed graphically and analyzed with Chi-square goodness-of-fit testing and regression modeling for disease status and genotype classification. Both diseases had a statistically significant change in genotype frequencies from the first year of data to the last; both diseases also had a negative association between progression of time and overall probability of a dog being disease-positive or a carrier/heterozygous. This suggests that genetic testing results are being incorporated into breeding decisions, although affected dogs were still being identified by the end of this study. Different breeds, AKC groups, FCI groups, genetic clades, and geography were also investigated to determine impact on overall disease trend. </p>