The work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related... Show moreThe work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related risk factors described in young and middle-aged populations and the risk of venous thrombosis (VT) in the elderly; second, we aimed to provide insight into several long-term consequences (i.e., health-related quality of life (HRQoL) and long-term risk of mortality) after a first VT at old age. Show less
Lower-leg cast immobilization and (elective) knee arthroscopy are associated with increased risk of symptomatic venous thrombosis, i.e., 2% and 0.6%, respectively. Currently applied... Show moreLower-leg cast immobilization and (elective) knee arthroscopy are associated with increased risk of symptomatic venous thrombosis, i.e., 2% and 0.6%, respectively. Currently applied thromboprophylaxis strategy, with low-molecular weight heparin, were found to be not optimal in both patient groups. In order to improve this, knowledge about underlying mechanisms for hypercoagulability following lower-leg cast application and knee arthroscopy is indispensable. However, as yet, this is not well understood. In this thesis, we established the effect of lower-leg trauma and knee arthroscopy on the coagulation system. We found that lower-leg trauma induces endothelial activation, hyperinflammation and a shift of the haemostatic balance towards a hypercoagulable state. Endothelial activation and hypercoagulability after lower-leg trauma are associated with the risk of venous thrombosis in the first three months. For knee arthroscopy, on the other hand, we did not detect any changes in plasma which point in the direction of thrombus formation. It becomes clear that in both situations, different mechanistic pathways of the development of venous thrombosis are involved. The knowledge provided by this thesis can be considered as the first step in the exploration of novel prevention targets for venous thrombosis and potential biomarkers for prediction of venous thrombosis in both patient populations. Show less
Patients with lower leg cast immobilization or who had knee arthroscopy have an increased risk of venous thrombosis. Because of this increased risk, thromboprophylaxis was given to the majority of... Show morePatients with lower leg cast immobilization or who had knee arthroscopy have an increased risk of venous thrombosis. Because of this increased risk, thromboprophylaxis was given to the majority of these patients in the Netherlands, despite insufficient evidence for its effect. In this thesis, two large randomized controlled trials (including 1500 patients each, in which half of patients were randomized to prophylaxis with Low Molecular Weight Heparin (LMWH) and half of patients to no treatment) are described. Despite having an increased VTE risk, routine thromboprophylaxis with low dose LMWH did not decrease VTE risk in these patients. Therefore, we recommend no routine thromboprophylaxis with anticoagulants to these patients. Identification of high-risk patients and selective treatment of patients can be beneficial. Therefore, prediction models for the development of VTE in these patients were developed. The prediction models had good predictive value and were validated in two other studies. Hence, identification of high-risk patient can help to optimize prophylactic treatment: providing a higher dose or longer duration of anticoagulant treatment to patients with an additionally increased risk, whilst patients with a low risk will not be needlessly exposed to the burden and risk of anticoagulants. Show less
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
Several studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The... Show moreSeveral studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The aim of this thesis was to investigate the associations of traditional cardiometabolic risk factors with risk of a first and recurrent venous thrombosis. We showed that levels of major lipids, i.e. total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, were not associated with a first venous thrombosis. In contrast, low levels of apolipoproteins B and A1 were associated with an increased risk of a first event. Regarding recurrence, tests for lipid levels, glucose levels and hematologic variables did not identify patients at an increased risk of recurrent venous thrombosis, and these tests should not be done for this indication nor influence decisions on duration of anticoagulant treatment. In this thesis, we further searched for associations between lipids and hemostatic factors, and found that levels of vitamin K-dependent factors (VKDFs), including factor IX, were associated with triglyceride levels. We hypothesized that this association could be explained by common mechanisms, regulating levels of both VKDFs and triglycerides. Show less
Patients with deep vein thrombosis or pulmonary embolism remain at risk for recurrent venous thrombosis. This risk is pronounced in the first months after the acute episode and declines in... Show morePatients with deep vein thrombosis or pulmonary embolism remain at risk for recurrent venous thrombosis. This risk is pronounced in the first months after the acute episode and declines in subsequent years. Although the existence of an extensive list of risk factors may seem reassuring, it does not come close to give us all the answers: many people have several of these risk factors but never develop thrombosis; others suffer from thrombosis but have none. Therefore, the challenge that we are facing today is not to just add more risk factors to this list but rather to integrate them all in a causal model that allows us to understand how and when thrombotic disease develops. The idea behind “the thrombosis potential model” is that an individual is at risk for venous thrombosis throughout life, which is reflected in the ‘thrombosis potential’ and that each risk factor contributes to increase the potential. Only when the combination of thrombosis risk factors reach a certain potential, venous thrombosis will occur. In this thesis, the thrombosis potential model will be applied to several known risk factors for venous thrombosis to better understand why first and recurrent venous thrombosis can develop in an individual patient. Show less
Secondary prevention of recurrent venous can be achieved in two ways, either by elimination of modifiable risk factors or by extending the anticoagulant treatment period in patients at high risk... Show moreSecondary prevention of recurrent venous can be achieved in two ways, either by elimination of modifiable risk factors or by extending the anticoagulant treatment period in patients at high risk of recurrence. The aim of this thesis was to identify modifiable risk factors for as well as factors that might be able to predict recurrent venous thrombotic events. This thesis reports on an increased risk of recurrences in women who continue or start using hormonal contraceptives after a first venous thrombotic event, suggesting that refraining from this modifiable risk factor decreases the risk of recurrence. Furthermore, this thesis describes several factors, male sex, unprovoked first event, levels of coagulation factor VIII and antibiotic use to be associated with recurrent venous thrombosis. These factors should eventually be taken together and used to build a prognostic model, which will be able to predict recurrences at a refined and individual level. Show less
In this thesis we show the results of the AT-AGE study, a two-center, population based case-control study in Leiden, the Netherlands and Burlington, Vermont, US, in which consecutive patients aged... Show moreIn this thesis we show the results of the AT-AGE study, a two-center, population based case-control study in Leiden, the Netherlands and Burlington, Vermont, US, in which consecutive patients aged 70 years and older with deep venous thrombosis (DVT) in the leg or a pulmonary embolism (PE), were identified. The AT-AGE study was specifically designed to optimise the participation-rate in the older population. Therefore, we performed home visits to all participants. We showed that conventional risk factors such as immobilisation due to hospital admission, and also immobility at home, due to for instance infection and minor injury, increase the risk of venous thrombosis. Also genetic risk factors, such as Factor V Leiden (FVL, rs6025) and the prothrombin 20210A mutation (PT20210, rs1799963) increase the risk of venous thrombosis. We report the presence of age-specific risk factors: functional impairment, low hand grip strength and venous insufficiency, such as varicose veins and leg oedema. Also we identified new high risk groups in older people, e.g., recent hospital discharge in which preventive measures could be of special interest. Show less
This thesis aimed to identify possible risks associated with erythropoiesis-simulating agent (ESA) use. First, trends in anemia management are described, showing less ESA use in Swedish patients... Show moreThis thesis aimed to identify possible risks associated with erythropoiesis-simulating agent (ESA) use. First, trends in anemia management are described, showing less ESA use in Swedish patients with chronic kidney disease (CKD) and less ESA-treated patients had a hemoglobin above 12 g/dL. Furthermore it is shown that ESA- treated pre-dialysis patients in the Netherlands received more antihypertensive agents than patients without ESA, confirming the hypertensive effect of ESA. However, no relevant difference in routinely measured blood pressure was observed between patients with and without ESA treatment, thus the hypertensive effect of ESAs could be controlled in clinical practice. In addition, no excess of thrombotic events was shown in ESA-treated dialysis patients compared to patients without ESA treatment. In contrast, a higher risk of cardiovascular events with ESA use was indicated in Danish patients with multiple myeloma and myelodyslastic syndrome. Also, with two analytical approaches, a harmful effect of high ESA doses on mortality was indicated in Dutch dialysis patients. Last, it was shown that ESA resistance was associated with mortality in both hemodialysis and peritoneal dialysis patients. To conclude, treatment with high ESA doses was associated with a higher risk of mortality, but the mechanism is largely unknown. Show less
Venous thromboembolism is a common disease that can lead to potential fatal complications. The diagnosis and treatment of a first venous thromboembolism has been well studied, however the... Show moreVenous thromboembolism is a common disease that can lead to potential fatal complications. The diagnosis and treatment of a first venous thromboembolism has been well studied, however the diagnostic management and therapy of recurrent venous thromboembolism still have limitations. This thesis discusses a new imaging technique for recurrent deep venous thrombosis and the duration of treatment after a recurrent venous thromboembolism. It shows that Magnetic Resonance Direct Thrombus Imaging might be a potential diagnostic tool for the diagnostic management of recurrent venous thromboembolism. Furthermore the prognosis after a first deep vein thrombosis is discussed by means of recurrence and bleeding risks. Show less
In this thesis the relation between thyroid hormones and the coagulation system will be examined. As an introduction, the hypothalamic-pituitary-thyroid axis, the coagulation system and their... Show moreIn this thesis the relation between thyroid hormones and the coagulation system will be examined. As an introduction, the hypothalamic-pituitary-thyroid axis, the coagulation system and their interactions will be discussed. A short overview of the literature preceding the research reported in this thesis is about the relation between thyroid hormones, the coagulation system, and risk of bleeding and venous thrombosis. In conclusion, in the studies in this thesis we found strong evidence that higher than average levels of FT4 increase the risk of venous thrombosis. Weak evidence is provided that lower than average levels of FT4 give an increased risk of bleeding in patients using vitamin K antagonists. A hypothyroid state possesses probably both pro- and anti-coagulant properties. The effect of FT4 on venous thrombosis is mediated at least by coagulation factors factor VIII and von Willebrand factor. Show less
Venous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral... Show moreVenous thrombosis is a disease that occurs in 1-2 per 1000 people per year. At the time of their first venous thrombosis, approximately 50% of women are exposed to reproductive risk factors (oral contraception, postmenopausal hormone therapy, pregnancy and the puerperium). In this thesis, we showed that these women are at particularly high risk of venous thrombosis if they have previously experienced an episode of superficial vein thrombosis, or are over the age of 50 years (Chapters 2 and 3). There is no known male counterpart to female reproductive risk factors. Nevertheless, the incidence of venous thrombosis is approximately similar in men and women. In this thesis we established that, once female reproductive risk factors are taken into account, men have an approximately twofold higher risk of both first and recurrent venous thrombosis than women (Chapters 4 and 5). Further to these findings, in Chapter 6, we reviewed the literature on sex-specific risk factors for venous thrombosis. We hypothesized that sex-specific genetic risk factors, an excess in overweight and smoking, or hypercoagulable changes such as microalbuminuria may explain the higher risk of venous thrombosis in men than in women. Show less
The aim of this thesis was to identify new risk factors for first and recurrent venous thrombosis of both the upper and lower extremity, and assess the incidence of recurrence and mortality after a... Show moreThe aim of this thesis was to identify new risk factors for first and recurrent venous thrombosis of both the upper and lower extremity, and assess the incidence of recurrence and mortality after a first venous thrombosis. An overview was provided of the current literature on risk factors and treatment for a first venous thrombosis of the upper extremity (chapter 2). We investigated the association between levels of coagulation factors, blood group and a first venous thrombosis of the upper extremity (chapter 3), and studied risk factors for a recurrent event in patients with a first venous thrombosis of the upper extremity (chapter 4). Furthermore, we studied the association between venous thrombosis and long-term mortality (chapter 5). In this study we found that patients with thrombosis died more of chronic obstructive pulmonary disease (COPD) than expected from population figures. COPD was found to be a risk factor for a first venous thrombosis in chapter 6. We studied the incidence of recurrent venous thrombosis, as well as sex, age and an idiopathic first venous thrombosis as risk factors for recurrence (chapter 7). Body height was studied as a risk factor for both first and recurrent venous thrombosis in combination with mobility (chapter 8). Show less
Oral contraceptive use is associated with venous thrombosis. However, the mechanism behind this remains unclear. The aim of this thesis was to evaluate genetic variation in the first-pass... Show moreOral contraceptive use is associated with venous thrombosis. However, the mechanism behind this remains unclear. The aim of this thesis was to evaluate genetic variation in the first-pass metabolism of contraceptives, to identify the clinical implications of hormonal contraceptive use after a thrombotic event and to provide an overview of the risk of venous thrombosis per combined oral contraceptive. We found that the UGT2B7 gene in the first-pass metabolism may at least in part explain the risk of venous thrombosis in oral contraceptive users. Furthermore, 20% of women continued or switched to a different contraceptive after a thrombotic event. Contraceptive use after an event was associated with a threefold increased risk of recurrent venous thrombosis, which depended on the ethinylestradiol dose, type of progestagen and whether the contraceptive was triphasic or not. All ten combined oral contraceptives commonly used and included in the analysis increased the risk of a first venous thrombosis. The highest risk of venous thrombosis was found among users of drospirenone with 30 _g ethinylestradiol, cyproterone acetate with 35 _g ethinylestradiol and levonorgestrel with 50 _g ethinylestradiol. Users of levonorgestrel with 20 _g ethinylestradiol had the lowest risk of venous thrombosis among combined oral contraceptive users. Show less
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
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
Since the introduction of the first contraceptive pill in 1959, the development of new hormonal contraceptives has focused on maintaining the benefits of oral contraceptives while reducing their... Show moreSince the introduction of the first contraceptive pill in 1959, the development of new hormonal contraceptives has focused on maintaining the benefits of oral contraceptives while reducing their adverse effects. Four approaches have been used to optimize the risk-benefit profile: (i) lowering of the steroid dose; (ii) development of new formulas and schedules of administration; (iii) development of new steroids and (iv) development of new routes of administration. The first objective of this thesis was to compare the multiphasic schedule of administration of oral contraceptives with the classic monophasic schedule of administration in terms of contraceptive effectiveness, bleeding pattern and discontinuation. The second objective was to predict the thrombotic risk of oral contraceptives containing the new steroid drospirenone by comparing the thrombin generation-based APC-resistance in users of pills containing drospirenone with the APC-resistance in users of pills containing other progestogens. We also focused on the biological basis of acquired APC-resistance in oral contraceptive users by studying the two main determinants of the thrombin generation-based APC-resistance test, free protein S and tissue factor pathway inhibitor free antigen. In addition, we tested the usefulness of sex hormone binding globulin as a new marker for the thrombotic risk of a hormonal contraceptive. The third objective was to estimate the thrombotic risk of contraceptives which administer steroids vaginally, transdermally or intrauterine by assessing the effect of these contraceptives on thrombin generation-based APC-resistance. At last we evaluated whether varying levels of estradiol and progesterone during a natural menstrual cycle are associated with differences in APC-resistance. Show less
Venous thrombosis results from blood coagulation in veins, most frequently in the deep veins of the leg. Risk factors for venous thrombosis may be environmental or genetic; in most cases venous... Show moreVenous thrombosis results from blood coagulation in veins, most frequently in the deep veins of the leg. Risk factors for venous thrombosis may be environmental or genetic; in most cases venous thrombosis occurs after an environmental trigger on a background of increased susceptibility. This thesis describes research into the genetic variability that determines why some are more prone to develop venous thrombosis than others. Known genetic variants and the family history of venous thrombosis were evaluated as risk factors, and new variants were identified in a large association study of thousands of single nucleotide polymorphisms. Finally, the possibility of genetic profiling was explored, making use of known and newly identified genetic variants. 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
This thesis elaborates the occurrence of venous thrombosis in cancer patients. Cancer is known to be associated with venous thrombosis with a spectrum of clinical manifestations varying from deep... Show moreThis thesis elaborates the occurrence of venous thrombosis in cancer patients. Cancer is known to be associated with venous thrombosis with a spectrum of clinical manifestations varying from deep vein thrombosis of the leg and pulmonary embolism, recurrent thrombophlebitits saltans et migrans (also called Trousseau__s syndrome) to disseminated intravascular coagulation and arterial embolism. The causes of venous thrombosis can be divided in environmental risk factors such as bed rest, surgery, plaster cast, trauma, long-distance travel, oral contraceptives or pregnancy and puerperium and genetic risk factors such as factor V Leiden and prothrombin 20210A mutation. Various factors may contribute to the development of venous thrombosis in cancer patients, and circulating mucins as well as circulating microparticles which express active TF on their surface may provide a missing link between cancer and thrombosis in (adeno) carcinoma patients. Treatment options include vitamin K antagonists and low-molecular-weight heparins, and the long-term use of these heparins in prevention of venous thrombosis may improve the outcome in comparison with oral anticoagulants. Further research is needed to better understand the morbidity and mortality associated with thrombosis in cancer patients and to optimize strategies of prevention and treatment Show less
