The day that I joined McMaster University and the Department of Health Research Methods, Evidence, and Impact as a Master student, I did not foresee the amazing journey I was embarking on or the impact of my academic achievements. I was continuously challenged to think critically and apply my ideas to real world problems. Seeing the opportunity to make a difference in clinical research and patient care inspired me to begin my PhD studies. Creating knowledge and applying it practically was a difficult task, however, the opportunities to share my research in a dynamic and complex field with the world fuelled my motivation. Completing a PhD has been an incredible privilege for which I will always be grateful. To my family – Mamma, Papa, Mark and Matthew – thank you for your undying and unconditional love, support, and encouragement. A pandemic forced us to come together, and having your support 24/7 (literally) made the journey more enjoyable. To my closest friends, thank you for being a part of my life and supporting my ambitions. We all recognized my ambitiousness would set me on a difficult path and completing a PhD was not my original plan. Thank you for inspiring me to take on the challenge and ensure my work was truly impactful. Thank you for encouraging mental strength, being understanding and willing to lend a hand, reminding me that I can achieve anything I set my mind to, and inspiring me to dare. To my supervisory committee members and independent study supervisor, thank you for your continued interest in my work and for always supporting my ambitions. I am grateful for your patience and belief that I would succeed in completing what I had sought to achieve. Thank you for the chance to work together, and for your constant support and mentorship throughout my PhD journey. To the faculty, staff and fellow students at the Department of Health Research Methods, Evidence, and Impact, and the McMaster Centre for Transfusion Research, thank you for providing the resources, friendship, and guidance I needed to achieve greatness. To the panel members of the ITP Emergency Management Guideline, thank you for believing in this project and making this work possible. I look forward to implementing the results of our efforts into clinical practice. To the ITP patient community, thank you for entrusting me with the task of improving patient care and supporting me along the way. You have enabled me to be a voice for change. To the rare disease community, I know the completion of my PhD journey will not be the end of our work together. To the funding agencies who allowed this project to be possible, the Canadian Institutes of Health Research and Platelet Disorder Support Association, thank you for supporting my PhD journey and the completion of this important work. To my doctoral supervisor, Dr. Donald Arnold, it has been an honour and privilege to have learned from you and received your guidance throughout my PhD journey. Since our initial meeting, when I hobbled into the McMaster Centre for Transfusion Research offices several minutes late, I felt that your kindness and honesty would be the perfect form of mentorship to push me towards success. Thank you for recognizing my ambition and reminding me to keep focused. I will continue to apply this lesson throughout my life and strive for ‘depth’. For many years, you have been my mentor who I reached out to for advice, support, honest feedback, and encouragement. Thank you for imparting your knowledge to me over my PhD journey and teaching me how to be an inspirational mentor who highlights the strengths of their students while simultaneously supporting their growth. Although I may have finally reached the destination in my PhD journey, I know that we will continue to collaborate for many years to come. / Developing clinical practice guidelines (CPGs) for rare diseases is methodologically challenging. As each disease has so few patients, published literature includes low-quality studies or studies that do not directly address the questions of interest. As a result, CPG panelists have limited evidence on which to base their recommendations. Historically, when no evidence was available, CPGs have relied on physician opinion. This does not align with the mandate of CPGs which transparently identifies, appraises, and relies on evidence. The challenges of developing CPGs for rare diseases are exemplified by immune thrombocytopenia (ITP), a rare autoimmune disease that affects approximately 1 in 8,000 people. It predominantly affects females and young adults, and is characterized by low blood platelets that increase the risk of bleeding. Bleeding emergencies in ITP patients are critical, life-threatening events that can cause life-long morbidity and associated health care costs. Treatment of ITP bleeding emergencies requires a rapid, coordinated approach that involves emergency department staff, hematologists, pharmacy, and the laboratory. However, there is no evidence-based CPG for the management of ITP bleeding emergencies. The objectives of my PhD thesis are (1) exploring the heterogeneity of ITP diagnosis using antiplatelet autoantibodies; (2) developing a standardized definition of ITP bleeding emergencies; (3) outlining the synthesis of existing evidence on the treatment of ITP bleeding emergencies through a systematic review; and (4) developing a novel methodology to address the lack of evidence in rare disease CPGs and applying it to develop a CPG for the management of ITP bleeding emergencies. / Thesis / Candidate in Philosophy / Guidelines for rare diseases can be hard to develop because of a lack of information. Doctors and researchers make decisions on rare disease management based on their experiences, which can be limited. Low blood platelets and emergency bleeding can be caused by a rare disease called immune thrombocytopenia (ITP). When emergency bleeds occur, patients need care from the Emergency Department immediately. The problem is that there is no standard way for doctors to treat these ITP bleeding emergencies. My PhD thesis project will fill an important gap for ITP emergency treatment. First, we will assess how ITP patients are diagnosed. Second, we will define an ITP bleeding emergency. Third, we will collect existing information about ITP bleeds. Fourth, we will overcome the challenge of not having enough information by collecting new data from patient records. The method we use to develop ITP guidelines can be used for other rare diseases.

Yang Jie. / "January, 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 204-250). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

No description available.

In oncology, there is a need to optimize drug treatment for efficient eradication of tumors, minimization of adverse effects (AEs), and prolonging patient survival. Pharmacometric models can be developed to streamline information between drug development phases, describe and quantify response to treatment, and determine dose regimens that balance toxicity and efficacy. In this thesis, data from trastuzumab emtansine (T-DM1) and taxane drug treatment were used to develop pharmacometric models of pharmacokinetics (PK), AEs, anti-tumor response, and survival, supporting drug development. T-DM1 is an antibody-drug conjugate (ADC) for treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer. ADCs are a relatively new class of oncologic agents, and contain multiple drug-to-antibody ratio (DAR) moieties in their dose product. The complex distribution of T-DM1 was elucidated through PK models developed using in vitro and in vivo rat and cynomolgus monkey DAR data. Mechanism–based PK/pharmacodynamic (PKPD) models were also developed for T-DM1 that described the AEs thrombocytopenia (TCP) and hepatotoxicity in patients receiving T-DM1. Variable patterns of platelet and transaminase (ALT and AST) response were quantified, including an effect of Asian ethnicity that was related to higher incidences of TCP.  Model simulations, comparing dose intensities (DI) and Grade 3/4 incidences between the approved T-DM1 dose (3.6 mg/kg every three weeks) and weekly regimens, determined that 2.4 mg/kg weekly provided the highest DI. Docetaxel and paclitaxel are taxane treatment options for HER2–negative breast cancer. Tumor response data from these treatments were used to develop a mechanism–based model of tumor quiescence and drug–resistance. Subsequently, a parametric survival analysis found that tumor baseline and the model–predicted time to tumor growth (TTG) were predictors of overall survival (OS). This tumor and OS modeling approach can be applied to other anticancer treatments with similar patterns of drug–resistance. Overall, the pharmacometric models developed within this thesis present new modeling approaches and provide understanding on ADC PK and PKPD (TCP and hepatotoxicity), as well as drug–resistance tumor response. These models can inform simulation strategies and clinical study design, and be applied towards dose finding for anticancer drugs in development, especially ADCs.

<p> </p><p><strong>Conclusion:</strong>Medical treatment may have a role in platelet count after transfusion. Since the TACSI platelets passed the quality requirements, and the vast majority of patients platelet count increased after TACSI platelet transfusion, the TACSI platelets will replace the old method to produce platelets at the Uppsala University hospital.</p><p> </p><p> </p><p><strong>Methods:</strong> A new approach that pools 8 buffy coats (TACSI platelets) that were separated into 2 units instead of 4-6 buffy coats pooled to 1 unit was investigated in this study. After the platelets were extracted from the buffy coats their quality was controlled and subsequently the platelet product was evaluated in 96 patients.</p><p> </p><p><strong>Results:</strong> The results showed that 80 % of the platelet units passed the European quality requirements. Further, the platelet count was increased in most patients that received TACSI platelets.</p><p><strong> Conclusion:</strong> Medical treatment may have a role in platelet count after transfusion. Since the TACSI platelets passed the quality requirements, and the vast majority of patients platelet count increased after TACSI platelet transfusion, the TACSI platelets will replace the old method to produce platelets at the Uppsala University hospital.</p><p> </p><p> </p><p> </p>

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder which results from fetal platelet destruction by maternal antibodies against platelet antigens, including GPIIbIIIa (αIIbβ3 integrin) and GPIbα. β3 integrin is also expressed by angiogenic endothelial cells (ECs) and is required for angiogenesis. Therefore, we investigated whether anti-β3 antibodies in FNIT cross-react with blood vessels of the fetus/neonate and contribute to pathogenesis. Antibodies to GPIbα were used as controls. To mimic human FNIT, β3 integrin- or GPIbα-deficient female mice were immunized with wild-type platelets and bred with wild-type male mice. Pups in both groups had thrombocytopenia but intracranial hemorrhage was only observed in anti-β3-mediated FNIT. Anti-β3-mediated FNIT pups had increased apoptosis in the brain and impaired vascularization of the brain and retina. In addition, anti-β3 sera inhibited proliferation and vascular-like tube formation by ECs in vitro. Therefore, anti-β3 antibodies in FNIT likely impair angiogenesis in the developing fetus/neonate.

Immune thrombocytopenia (ITP) is an autoimmune disorder, mediated mainly by autoantibodies against platelet glycoprotein GPIIbIIIa and GPIbα resulting in enhanced platelet destruction. Decreased platelet production and cellular immunity also contribute to ITP. GPIIbIIIa and GPIbα are distinct platelet receptors. Previous studies suggested that anti-GPIbα (versus anti-GPIIbIIIa)-mediated ITP is less responsive to IVIG therapy. However, little information is available whether antibody specificities also dictate efficacy of Glucocorticosteroids (GC), which are the first-line ITP treatment. Here, I first induced ITP in mice by passive administration of anti-GPIbα or anti-GPIIbIIIa antibodies. Results suggest GCs were more effective at amelioration of anti-GPIIbIIIa-mediated thrombocytopenia. I repeated this observation in an active ITP model, in which splenocytes from wild-type platelet immunized GPIbα-/- or GPIIIa-/- mice were engrafted into wild-type mice, which developed ITP. Thus, I established new murine models of ITP for GC therapy and demonstrated that anti-GPIbα-mediated thrombocytopenia may be less responsive to GC therapy.

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder which results from fetal platelet destruction by maternal antibodies against platelet antigens, including GPIIbIIIa (αIIbβ3 integrin) and GPIbα. β3 integrin is also expressed by angiogenic endothelial cells (ECs) and is required for angiogenesis. Therefore, we investigated whether anti-β3 antibodies in FNIT cross-react with blood vessels of the fetus/neonate and contribute to pathogenesis. Antibodies to GPIbα were used as controls. To mimic human FNIT, β3 integrin- or GPIbα-deficient female mice were immunized with wild-type platelets and bred with wild-type male mice. Pups in both groups had thrombocytopenia but intracranial hemorrhage was only observed in anti-β3-mediated FNIT. Anti-β3-mediated FNIT pups had increased apoptosis in the brain and impaired vascularization of the brain and retina. In addition, anti-β3 sera inhibited proliferation and vascular-like tube formation by ECs in vitro. Therefore, anti-β3 antibodies in FNIT likely impair angiogenesis in the developing fetus/neonate.

Immune thrombocytopenia (ITP) is an autoimmune disorder, mediated mainly by autoantibodies against platelet glycoprotein GPIIbIIIa and GPIbα resulting in enhanced platelet destruction. Decreased platelet production and cellular immunity also contribute to ITP. GPIIbIIIa and GPIbα are distinct platelet receptors. Previous studies suggested that anti-GPIbα (versus anti-GPIIbIIIa)-mediated ITP is less responsive to IVIG therapy. However, little information is available whether antibody specificities also dictate efficacy of Glucocorticosteroids (GC), which are the first-line ITP treatment. Here, I first induced ITP in mice by passive administration of anti-GPIbα or anti-GPIIbIIIa antibodies. Results suggest GCs were more effective at amelioration of anti-GPIIbIIIa-mediated thrombocytopenia. I repeated this observation in an active ITP model, in which splenocytes from wild-type platelet immunized GPIbα-/- or GPIIIa-/- mice were engrafted into wild-type mice, which developed ITP. Thus, I established new murine models of ITP for GC therapy and demonstrated that anti-GPIbα-mediated thrombocytopenia may be less responsive to GC therapy.

Thematic paper (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2006. / LICL has E-Thesis 0012 ; please contact computer services. LIRV has E-Thesis 0012 ; please contact circulation services.