During my research project we mainly focussed on studying the pathophysiology of venous and arterial thrombosis in mice. When we transiently lowered plasma protein levels of natural anticoagulants... Show moreDuring my research project we mainly focussed on studying the pathophysiology of venous and arterial thrombosis in mice. When we transiently lowered plasma protein levels of natural anticoagulants antithrombin and protein C using RNA interference, mice developed venous thrombosis in the head. In contrast to other mouse models for venous thrombosis where surgery is required for provoking the disease, mice injected with RNA interference against the mRNA of Serpinc1 and Proc (antithrombin and protein C, respectively) developed venous thrombosis without additional handlings. In this unique form of venous thrombosis, we studied the roles of platelets, neutrophils, and coagulation factor XII. These factors have been shown to be indispensable in experimental venous thrombosis in other mouse models, and they have been introduced as novel therapeutic targets. For the second part of my thesis we again used the RNA interference approach, to lower natural anticoagulation in atherosclerotic mice. When we lowered protein C in these mice, they developed atherothrombosis in the aortic root without any additional intervention. This unique form of atherothrombosis has been showed in multiple independent experiments, and we aimed to further characterize the process to learn more about prevention atherothrombosis in atherosclerotic mice and the role of protein C. Show less
The main objectives of this thesis were to investigate the association between kidney disease and venous and arterial thrombosis and to provide insight in the mechanism of the association between... Show moreThe main objectives of this thesis were to investigate the association between kidney disease and venous and arterial thrombosis and to provide insight in the mechanism of the association between kidney disease and thrombosis. Furthermore, the mortality risks for hemodialysis patients with catheter, fistula and graft vascular accesses were investigated. Our studies showed that kidney disease was associated with an increased risk of venous thrombosis. We showed that patients with chronic kidney disease stages 1__3 (early stages) had an almost 2-fold increased risk of venous thrombosis as compared with subjects without chronic kidney disease. We also showed that patients with a severely decreased kidney function (estimated glomerular filtration rate <30 ml/min) had a 6-fold increased risk of venous thrombosis as compared with persons with a normal kidney function. Furthermore, it was shown that dialysis patients have increased risks of myocardial infarction and ischemic stroke. Dialysis patients with a catheter had increased mortality risks as compared with dialysis patients with an arteriovenous access (fistula or graft). An important mechanism for the increased thrombosis risk in patients with a kidney disease could be hypercoagulability (increased factor VIII and von Willebrand factor levels). Show less
Veneuze en arteri_le trombose zijn twee van de belangrijkste oorzaken van ziekte en sterfte in Westerse landen. Hoewel de laatste jaren is er veel bekend geworden over de oorzaken die de kans op... Show moreVeneuze en arteri_le trombose zijn twee van de belangrijkste oorzaken van ziekte en sterfte in Westerse landen. Hoewel de laatste jaren is er veel bekend geworden over de oorzaken die de kans op het krijgen van trombose verhogen, zijn er nog veel onduidelijkheden. In dit proefschrift hebben we getracht om naar aanleiding van eerder uitgevoerde genetische en observationele studies nieuwe risicofactoren voor deze twee soorten trombose op te zoeken. Tevens is de samenhang tussen arteri_le en veneuze trombose en de preventie voor trombose tijdens zwangerschap besproken. Show less
The research described throughout this thesis aims to gain better understanding of determinants of plasma levels of VWF and FVIII. Because high plasma levels of both proteins are well established... Show moreThe research described throughout this thesis aims to gain better understanding of determinants of plasma levels of VWF and FVIII. Because high plasma levels of both proteins are well established risk factors for venous and arterial thrombosis, we also studied effects of these determinants on the risk of thrombosis where the study designs allowed it. Whether high FVIII levels are causative to an increase in the risk of venous thrombosis remains to be determined. The research described here was successful in identifying several determinants of plasma levels of VWF and FVIII, however many new questions were raised. It can safely be assumed that fluid homeostasis and RAS play a role in the regulation of VWF and FVIII levels. The exact routes and mechanisms through which effects on levels are accomplished are not understood yet. Furthermore, fluid homeostasis and RAS probably play a more complex role in coagulation than merely inducing VWF secretion from WPb and thus raising VWF and FVIII levels. Show less
