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
Air travel has become a well-known risk factor for venous thrombosis with an absolute risk of 1 in 4600 long-haul flights and a dose-response relationship with duration and number of flights. In... Show moreAir travel has become a well-known risk factor for venous thrombosis with an absolute risk of 1 in 4600 long-haul flights and a dose-response relationship with duration and number of flights. In this thesis we studied the pathophysiology that underlies the risk as well as the effect of behaviour of passengers on the risk of thrombosis after air travel. To study the pathophysiology, we conducted a case-crossover study in which we investigated the effect on the coagulation system of 8 hours of air travel, 8 hours of immobilisation in a cinema and 8 hours of daily activities in 71 volunteers. Behaviour of passengers was studied in the MEGA study, a large case-control study on risk factors of venous thrombosis. The main conclusion of this thesis is that immobilisation alone does not explain coagulation activation after air travel. A factor that seems to contribute is hypoxia. The results of this thesis do not support the theories that fluid loss, air pollution, infection or stress play a role in coagulation activation after air travel. Certain kinds of behaviour during air travel affect the risk of venous thrombosis. Lastly, harmless prevention methods possibly counter the effect of immobilisation. Show less
Deep venous thrombosis is a common disease. Already in 1856 it was suggested that immobilization could cause venous thrombosis. However, so far little research has shown whether exercise or... Show moreDeep venous thrombosis is a common disease. Already in 1856 it was suggested that immobilization could cause venous thrombosis. However, so far little research has shown whether exercise or ambulation could decrease the risk of venous thrombosis. We performed a historical review regarding the role of venous thrombosis risk in the change of the practices regarding ambulation after delivery. We could not find well-performed studies showing that early ambulation reduced venous thrombosis risk. Furthermore we performed two studies on the relation between participating in physical activity and venous thrombosis risk. In one case-control study in the Netherlands we showed that exercise decreases the risk of venous thrombosis. However, in a cohort study in elderly people from the USA, we showed that exercise seemed to increase this risk. A possible explanation for this difference might be due to an increased risk of injuries among elderly people as we showed that injuries increase the risk of venous thrombosis 5 fold. Furthermore we showed that for the very rare thrombosis of the arm, sports activities which highly involve the arm result in an increased risk. In summary, although immobilization seems to increase venous thrombosis risk, it is unclear whether mobilization or exercise decrease this risk. Show less
Genetic factors play an important role in the regulation of human life span but the exact pathways remain to be elucidated, however they may be interrelated with the regulation of human... Show moreGenetic factors play an important role in the regulation of human life span but the exact pathways remain to be elucidated, however they may be interrelated with the regulation of human reproduction. It is argued that an innate cytokine profile supportive of Th1-type T cells favors survival of infectious diseases (with longevity as the ultimate), but women with this profile are found less likely to have successful pregnancies (progeny). The probability of a normal fertility was found to increase more than 10-fold when the innate cytokine profile was characterized by high IL-10 (Th-2 cytokine) and low TNF- (Th-1 cytokine) responsiveness. The IL10 –2849 AA genotype was found to be associated with a decreased fertility and fecundity (time to pregnancy) in females, possibly due to the lower expected IL10 responsiveness. Rheumatoid arthritis (RA) is an example of a Th-1 mediated disease. It was found that the phenotype of joint destruction in RA was associated with the phenotype of reported miscarriages, suggesting common genetic risk factors for each of these two traits, possibly through the innate Th-1/Th-2 phenotype. Factor V Leiden (FVL) is a point mutation in the factor V gene generating a 7-fold increase in incidence of deep vein thrombosis. Specific advantages of the FVL mutation in early pregnancy (implantation) might balance its potentially harmful effects later in life and explain the remarkably high prevalence of this mutation in the general population. Show less
