Myocardial infarction and ischaemic stroke are both forms of arterial thrombosis. It is unclear to what extent hypercoagulability is a causal factor of these diseases and whether this effect might... Show moreMyocardial infarction and ischaemic stroke are both forms of arterial thrombosis. It is unclear to what extent hypercoagulability is a causal factor of these diseases and whether this effect might be different for myocardial infarction and ischaemic stroke. Several measures of hypercoagulability were investigated in the RATIO study, a nationwide population based case-control study which includes 248 women with myocardial infarction, 203 women with ischaemic stroke and 925 control women, all under 50 years of age. Chapter 2 describes the relationship of a positive family history of arterial thrombosis and the risk of either myocardial infarction or ischaemic stroke. Chapters 3-6 focus on the intrinsic coagulation proteins. Chapters 7-9 describe a genetic approach that focuses on the role of fibrinogen and coagulation factor XIII. Chapter 10 discusses the role of the fibrinolytic capacity, chapter 11 discusses VWF and ADAMTS13, and chapter 12 discusses the risk of myocardial infarction and ischaemic stroke associated with the presence of markers of the antiphospholipid syndrome. Chapter 13 provides a summary and discussion of these results. These results suggest that hypercoagulability is a cause of ischaemic stroke, whereas it does not have a major effect on the risk of myocardial infarction in young women. Show less
The studies presented in this thesis explored several pathogenic mechanisms underlying von Willebrand disease that is characterized by a quantitative or functional deficiency of von Willebrand... Show moreThe studies presented in this thesis explored several pathogenic mechanisms underlying von Willebrand disease that is characterized by a quantitative or functional deficiency of von Willebrand factor, in particular with respect to intracellular storage in Weibel-Palade body and regulated secretion of von Willebrand factor. By using molecular biology, confocal and electron microscopic techniques, storage and secretion of von Willebrand factor were analyzed for von Willebrand disease variants identified in the patients. These studies advanced our understanding of von Willebrand disease at the molecular and cellular levels. HEK293 cells and endothelial cells derived from patients__ peripheral blood were established as two useful model-systems for examining von Willebrand factor structure-function relationships in the context of von Willebrand disease. Using these model-systems we have demonstrated that von Willebrand factor mutations may impair its storage and secretion and thus lead to a quantitative deficiency of this factor in the patients. Furthermore, we demonstrated that alteration in the structure of von Willebrand factor, by natural mutations that occur in von Willebrand disease patients, modulates von Willebrand factor string formation and function. We propose that alteration in von Willebrand factor string formation and function may be another new mechanism that contributes to the bleeding tendency in von Willebrand disease. Show less
