Over the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk... Show moreOver the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk factors like female hormones, thyroid hormone and obesity result in a hypercoagulable state and increased risk for venous thrombosis, since these are currently poorly understood. As these risk factors are all, to a certain extent, able to interfere with liver metabolism we hypothesized that they modulate hepatic transcription of coagulation genes, either directly via nuclear hormone receptors and hormone response elements in target genes (female hormones and thyroid hormone), or indirectly as a result of altered liver homeostasis (obesity). To study these hypotheses, we used an in vivo approach, which not only gives the opportunity to study the risk factor-mediated transcriptional modulation of coagulation genes, but also allowed us to study the relation between transcriptional changes on the one hand and plasma protein levels and a thrombotic tendency on the other. The data presented in this thesis clearly demonstrate that modulation of hepatic coagulation gene transcription is a key mechanism by which acquired risk factors for venous thrombosis impact the hemostatic balance. Show less
In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), a large population-based case-control study, we investigated lifestyle factors as risk... Show moreIn the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), a large population-based case-control study, we investigated lifestyle factors as risk factors for venous thrombosis. Overweight, smoking and alcohol consumption were addressed and pregnancy and the postpartum period were evaluated in women. Due to the large sample size of the study it was possible to investigate the joint effect of these risk factors with important genetic risk factors for venous thrombosis such as the factor V Leiden and the prothrombin 20210A mutation. In addition to these lifestyle related risk factors, two polymorphisms within the promoter region of the protein C gene were studied as risk factors for venous thrombosis and the influence of genotypic variation on plasma protein C levels was assessed. Finally, we described our experience with the inclusion of two different control groups in the MEGA study. Show less
