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
Kooiman, J.; Rein, N. van; Hagen, N. van; Cannegieter, S.C.; Meer, F.M. van der; Huisman, M.V. 2013
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
The aims of this thesis were to investigate the efficacy and safety of outpatient treatment of patients with pulmonary embolism (PE) and to identify the best method for selection of PE patients for... Show moreThe aims of this thesis were to investigate the efficacy and safety of outpatient treatment of patients with pulmonary embolism (PE) and to identify the best method for selection of PE patients for outpatient treatment. Therefore, we performed the Hestia study and compared the selection of patients with the Hestia criteria to other methods for risk stratification, for example the simplified Pulmonary Embolism Severity Index and the method described in the European Society of Cardiology guidelines. Show less
Pasha, S.M.; Klok, F.A.; Bijl, N. van der; Roos, A. de; Kroft, L.J.M.; Huisman, M.V. 2012
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
Reitsma, P.H.; Versteeg, H.H.; Middeldorp, S. 2012
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
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
In venous thrombosis, a blood clot develops in a vein, usually a deep vein of the leg, causing obstruction of the blood flow. Venous thrombosis is a multicausal disease, in which genes and... Show moreIn venous thrombosis, a blood clot develops in a vein, usually a deep vein of the leg, causing obstruction of the blood flow. Venous thrombosis is a multicausal disease, in which genes and environment interact. One of the environmental factors that increases the risk of venous thrombosis is long distance travel. This thesis describes the results of several studies on epidemiological aspects of the association between long distance travel and venous thrombosis. In a study among frequently traveling employees of international organizations, the absolute risk of venous thrombosis after long distance flights, the effect of duration of travel, time after travel and exposure to several flights at the same time and the effect of interaction with other risk factors for venous thrombosis was assessed. In a population-based case-control study, the effect of elevated levels of coagulation factors in long distance travelers was evaluated. Finally, the occurrence of venous thrombosis among commercial airline pilots was studied. The main conclusion is that the risk of venous thrombosis in healthy travellers is not high enough to promote widespread use of aggressive prophylaxis, such as anticoagulant therapy. However, in some travellers at increased risk, the risk-benefit ratio may favour the use of prophylactic measures. 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
