Thromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it... Show moreThromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it at the same time increases risk of bleeding. With nationwide data from Statistics Netherlands, antithrombotic therapy and relevant clinical outcomes were comprehensively examined in the patient population of atrial fibrillation, overall or among those with comorbid cancer. The results suggest the patient population was increasingly receiving anticoagulants, driven by the newly introduced medication- direct oral anticoagulant and guided by the CHA2DS2-VASc score, and meanwhile the patient population experienced fewer ischemic stroke and major bleeding. In spite of these promising changes, suboptimal medication adherence and potential underuse of anticoagulants remain directions for further improvement. Antithrombotic agent use during pregnancy was also examined in the general Dutch pregnant population, which featured a surge in antiplatelet prescriptions, and risk of preeclampsia/eclampsia decreased and several newborn outcomes improved simultaneously. Together, the studies presented in this thesis provide an overview of antithrombotic therapy in the Netherlands in recent years, providing insights for further improving this treatment and relevant patient outcomes. Show less
Pulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades,... Show morePulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades, diagnosing PE is still a difficult process due to the non-specific symptoms, which can frequently overlap with symptoms of other cardiopulmonary diseases. Currently recommended diagnostic strategies for suspected acute PE consist of standardized assessment of the clinical pre-test probability (CPTP) using validated clinical decision rules (CDRs) and D-dimer testing. PE is considered safely ruled out in patients with a non-high CPTP and a normal D-dimer test. Imaging tests as computed tomography pulmonary angiography (CTPA) are required in the case of a high CPTP and/or abnormal D-dimer test to confirm the diagnosis. The first part of this thesis describes the challenges of diagnosing PE in general and in specific clinically relevant patient subgroups. Moreover, this part evaluates the diagnostic performance of non-invasive diagnostic strategies for suspected PE in specific relevant patient subgroups. The second part of this thesis focuses on venous thrombotic complications in hospitalized patients with COVID-19. Show less
Recurrent pregnancy loss (RPL) is a poorly understood condition that comes with many uncertainties, both for affected couples and healthcare providers. Important goals are to provide answers to... Show moreRecurrent pregnancy loss (RPL) is a poorly understood condition that comes with many uncertainties, both for affected couples and healthcare providers. Important goals are to provide answers to these couples and to improve their pregnancy outcomes. To achieve this, we need a better understanding of contributing and predictive factors. Until now, the male role in RPL has been underexposed. In this thesis, we aimed to expand our knowledge regarding the ‘forgotten father’ in RPL. We have found strong clues that in RPL, male contribution really matters.The main conclusions are that advanced paternal age and paternal smoking are associated with an increased risk of pregnancy loss, that inclusion of paternal factors into a prediction model improves the accuracy of predicting ongoing pregnancy after RPL, and that impaired immunomodulatory effects of seminal plasma may play a role in RPL. At the same time, our studies have led to new questions and uncovered new challenges, which are excellent opportunities for further research. Show less
Pregnancy can be seen as an immunologic paradox. Even though the fetus expresses paternally inherited alloantigens it is protected from rejection by a proper regulation of the maternal immune... Show morePregnancy can be seen as an immunologic paradox. Even though the fetus expresses paternally inherited alloantigens it is protected from rejection by a proper regulation of the maternal immune system. With the studies described in this thesis, we want to get more insight in the immunologic mechanisms that play a role in pregnancy. The results of this research can help to identify underlying etiologies in patients with unexplained pregnancy complications, such as recurrent miscarriage. Identifying these causes is important for providing answers and taking away anxiety in these couples, and eventually for the development of effective therapies. Furthermore, elucidating the mechanism leading to survival or rejection of the fetal allograft is not only essential for our understanding of processes leading to normal and abnormal pregnancies, but may also result in important concepts in the field of transplantation and autoimmunity. Show less
During pregnancy a unique situation arises in which the mother's immune system accepts the fetus, which carries both maternal and paternal genes, and does not reject it as can occur in solid organ... Show moreDuring pregnancy a unique situation arises in which the mother's immune system accepts the fetus, which carries both maternal and paternal genes, and does not reject it as can occur in solid organ transplantation. The aim of this dissertation was to unravel the immunological mechanisms that ensure tolerance during a healthy pregnancy and uncover how alterations could contribute to the development of pregnancy complications, such as pre-eclampsia and preterm birth.We applied the new technique mass cytometry and the associated computational analyzes to map all immune cells of the mother during a healthy pregnancy. Furthermore, we demonstrated the presence of three types of functional regulatory CD4+ T cells, identified a phenotype of CD8+ T cells that can offer both tolerance and immunity against infections, and demonstrated potential cross-reactivity of T cells against fetal allo-antigens. The results described in this thesis have contributed to a better understanding of healthy pregnancies and form a basis on which further research can be built. Show less
Pulmonary embolism (PE) refers to a blood clot in the pulmonary artery or one of its branches, which is most commonly originating from deep venous thrombosis (DVT) of the legs or pelvis. Venous... Show morePulmonary embolism (PE) refers to a blood clot in the pulmonary artery or one of its branches, which is most commonly originating from deep venous thrombosis (DVT) of the legs or pelvis. Venous thrombo-embolism (VTE) encompasses both pulmonary embolism (PE) and deep venous thrombosis (DVT). VTE is the third most frequent cardiovascular disease and it is a major cause of mortality, morbidity and chronic disease and disability. In Europe, it affects 430,000 patients each year and worldwide the overall annual incidence is 100-200 per 100,000 inhabitants. The diagnostic process of patients with suspected PE is challenging due to the non-specific symptoms and clinical presentation. Integrated diagnostic algorithms including validated clinical decision rules, high sensitive D-dimer tests and imaging tests such as computed tomography pulmonary angiography (CTPA) may guide the clinician, and close adherence to the diagnostic algorithm is of crucial importance for the clinical outcome of patients with suspected PE. The focus of this thesis is the diagnostic management of patients with suspected PE. Show less
In normal pregnancy the fetus, although a semi-allograft, is tolerated by the maternal immune system. It has been suggested that an inadequate maternal allo-immune response to the paternal... Show moreIn normal pregnancy the fetus, although a semi-allograft, is tolerated by the maternal immune system. It has been suggested that an inadequate maternal allo-immune response to the paternal antigens of the fetus is responsible for a proportion of the unexplained recurrent miscarriage. In chapter 2 we provide an overview on the possible role of the HLA system in recurrent miscarriage. No consistent conclusions can be drawn since the observed odd ratios found were relatively small and the risk of bias in the selected studies was high. In chapter 3 we compared the genetic polymorphisms of HLA-G in women with recurrent miscarriage with women with uneventful pregnancy. The HLA-G UTR-4 haplotype was less frequently observed in women with recurrent miscarriage, suggesting an immunoregulatory role of this haplotype. The combined results from chapter 4, chapter 6 and chapter 7 suggest that in a portion of women with unexplained recurrent miscarriage antibody-mediated rejection of the fetal allograft may play a role. We showed in chapter 8 that human seminal plasma contains all kinds of immunoregulatory factors and has an immunomodulatory effect on T cells. In chapter 9 a matched case-control study practicing oral sex was negatively associated with the occurrence of recurrent miscarriage. Show less
Cardiovascular disease (CVD) is the leading cause of death in women in the Western world. In this thesis, several studies are presented examining the association between recurrent miscarriage and... Show moreCardiovascular disease (CVD) is the leading cause of death in women in the Western world. In this thesis, several studies are presented examining the association between recurrent miscarriage and cardiovascular disease. Main aim of this thesis was to assess whether miscarriages are independently associated with an increased risk of cardiovascular disease later in life. And, if this was true, to identify cardiovascular risk factors and predict long term cardiovascular disease risk in women with a history of recurrent miscarriage. We found an increased risk of ischemic heart disease in women with a history of two (multivariate analysis HR 1.82) and three or more miscarriages (HR 3.18), irrespective whether consecutive or not (chapter 2). Women with a history of recurrent miscarriage have significantly higher 10- and 30-year cardiovascular risk scores compared to women with a history of no miscarriage. These results indicate an opportunity for the early identification of women prone to cardiovascular disease later in life. Women with a history of two or more miscarriages must be made aware of their increased cardiovascular risk and appropriate risk factor modifications will have to be offered, for example life style advises; weight management and smoking control. Show less
Glycosylation is an important way in which proteins, the functional agents of our body, can be modified to alter and expand their functional repertoire. Glycans consist of monosaccharides that... Show moreGlycosylation is an important way in which proteins, the functional agents of our body, can be modified to alter and expand their functional repertoire. Glycans consist of monosaccharides that are linked in a chained and branching fashion, often to form specific epitopes that are of clinical and biopharmaceutical interest. In order to study glycosylation, there is a need for high-throughput analysis methodology. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is a prominent example of this, as it can rapidly provide information on the monosaccharide compositions of glycans. However, it is challenging for the method to yield information on the structural aspects of glycosylation, as well as on glycans carrying sialic acids. These sialylated glycans are prone to in-source and metastable decay, and tend to require chemical derivatization to allow their analysis. The aim of this thesis is the development and application of new methodology for MALDI-MS N-glycomics, and, with a focus on metabolic syndrome and rheumatoid arthritis, to increase our understanding of the role of N-glycosylation in health and disease. A principal outcome of the work is a sialic acid derivatization protocol that allows the mass-based discrimination of alpha-2,3- and alpha-2,6-linked sialic acids, facilitating their study in a high-throughput setting. Show less
The clinical manifestations and outcomes of systemic lupus erythematosus (SLE) are remarkably heterogeneous. In this thesis, issues relating to the diagnosis and prognosis of SLE were studied,... Show moreThe clinical manifestations and outcomes of systemic lupus erythematosus (SLE) are remarkably heterogeneous. In this thesis, issues relating to the diagnosis and prognosis of SLE were studied, focussing on the application of histopathologic evaluation in conjunction with clinical features in the setting of lupus nephritis (LN) and neuropsychiatric SLE (NP-SLE). In the first part, we demonstrated that classification criteria for SLE cannot be unequivocally applied to patients from nephrology clinics who present with full house glomerular deposits suggestive of LN/SLE. The patients with full house glomerular deposits without clinical SLE represented a distinct entity with a remarkably poor renal outcome. In the second part, clinical and histopathologic determinants of renal outcome were investigated to improve prognostication in LN. First, we identified a subgroup of patients with class III/IV LN with favourable renal outcome indicating that the current classification warrants refinement. Next, we identified prognosticators that may add to the current histopathologic classification of LN. The last part of this thesis was focused on the aetiopathogenesis of SLE, in which the complement system was identified as an important player and thereby therapeutic target in neuropsychiatric lupus and in which pregnancy-acquired microchimerism in relation to the occurrence of SLE was further investigated. Show less
This dissertation describes the development of glyco-bioinformatics tools that facilitate the high-throughput data processing of glycomics and glycoproteomics experiments, specifically for both... Show moreThis dissertation describes the development of glyco-bioinformatics tools that facilitate the high-throughput data processing of glycomics and glycoproteomics experiments, specifically for both MALDI-TOF-MS (Chapter 2) and LC-ESI-MS (Chapter 3). The developed methods also provide various quality control parameters that assist the researcher in curating both the measured spectra and quantified analytes, thereby providing high-quality data in a high-throughput manner.The tools that were developed within this thesis have been used to identify the influence of glycosylation on trypsin efficacy of Immunoglobulin G (Chapter 3) and two biological cohorts. Specifically, to investigate the serum N-glycosylation during and after pregnancy (Chapter 5) and to identify the differences in the N-glycosylation between maternal and fetal serum and IgG (Chapter 6). Show less
In this thesis several aspects of SLE were investigated. First, we studied interobserver agreement concerning class III/IV lupus nephritis lesions in a renal biopsy and found that agreement was... Show moreIn this thesis several aspects of SLE were investigated. First, we studied interobserver agreement concerning class III/IV lupus nephritis lesions in a renal biopsy and found that agreement was poor. This seemed, in part, due to inconsistent or ambiguous definitions as provided in the 2004 ISN/RPS classification. This led us to re-evaluate the current classification with an international group of highly experienced nephrologists. Second, we compared and summarized the lupus nephritis management guidelines that were published in 2012. Third, we studied microchimerism in peripheral blood of women with SLE and control subjects. We found that women with SLE have more microchimerism in their peripheral blood than control subjects. Then, we studied microchimerism in the peripheral blood of women with SLE and control subjects during and after pregnancy. We found that only just after delivery did the SLE patients have more chimeric cells in the granulocyte fraction than control subjects. These results suggest that after pregnancy chimeric cells become undetectable in peripheral blood, but possibly remain at other sites, only to re-emerge after un unknown trigger. Finally, we compared sporadic and familial lupus nephritis to find that, although there were clinical differences, no differences in histology or genetic background were apparent. Show less
Using the results from a two-year nationwide prospective study, this thesis shows numerous (risk) factors associated with severe acute maternal morbidity (SAMM) in the Netherlands and validates... Show moreUsing the results from a two-year nationwide prospective study, this thesis shows numerous (risk) factors associated with severe acute maternal morbidity (SAMM) in the Netherlands and validates the WHO Maternal Near Miss (MNM) tool to detect and monitor SAMM worldwide. The ratio behind the different subjects selected in this thesis is explained by differences in economic disparity throughout the globe. Where the effect of poverty is undeniably present in maternal health care, we hypothesize that wealth might also have a negative impact on pregnancy outcome. Show less
Low birth weight including preterm birth and intrauterine growth retardation, remains important in sub-Saharan Africa and particularly highly prevalent in Gabon. Among the risk factors of... Show more Low birth weight including preterm birth and intrauterine growth retardation, remains important in sub-Saharan Africa and particularly highly prevalent in Gabon. Among the risk factors of low birth weight in sub-Saharan Africa are very young maternal age, first pregnancy, poor gestational nutrition and small stature of the mother. In Gabon, besides malaria, the other two major parasitic infections namely urogenital schistosomiasis and the filarial infection Loa loa, are common in pregnant women. Maternal schistosomiasis like malaria showed to be associated with higher proportions of low birth weight babies. Mefloquine as an alternative preventive treatment, despite showing no difference with sulphadoxine – pyrimethamine in preventing low birth weight, was however more effective in preventing malaria infection and anaemia. Mefloquine administered for the prevention of malaria was effective against concomitant urogenital schistosomiasis, suggesting that mefloquine could seriously be considered as a combined intervention for both malaria and schistosomiasis during pregnancy, and an alternative to praziquantel. Maternal infection with L. loa was associated with expansion in the neonatal cord blood of functionally activate Tregs that kept Th1 and Th17 immune responses in check, providing some insights on the impact of in utero exposure on the offspring’s development and health. Show less
Preeclampsia is a complication of pregnancy which can suddenly change from a relatively mild phenotype into a life-threatening situation. One of the organs that is always involved during... Show morePreeclampsia is a complication of pregnancy which can suddenly change from a relatively mild phenotype into a life-threatening situation. One of the organs that is always involved during preeclampsia is the kidney. The placenta plays an important role in the renal pathophysiology of preeclampsia. The placenta produces excessive amounts of anti-angiogenic factors which are associated with systemic endothelial dysfunction. Although the underlying mechanisms of renal injury during preeclampsia remain unclear, women with preeclampsia have an increased risk of developing renal disease later in life. This observation suggests that preeclampsia __marks__ the mother__putatively in combination with pre-existent conditions__which might contribute to serious sequel throughout her life. 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
Preeclampsia is a pregnancy-specific condition that originates in the placenta. Despite decades of research, its pathogenesis remains largely unknown. However, several risk factors for preeclampsia... Show morePreeclampsia is a pregnancy-specific condition that originates in the placenta. Despite decades of research, its pathogenesis remains largely unknown. However, several risk factors for preeclampsia have been identified, including a (family) history of preeclampsia, autoimmune disease and conditions associated with endothelial damage, including hypertension, diabetes mellitus and preexistent renal disease. This thesis aims to further investigate through which mechanisms these risk factors increase the risk for preeclampsia. It deals with both the genetic background of preeclampsia, as well as the role of complement activation in its pathogenesis. Finally, it touches upon the role of angiogenic factors in the development of preeclampsia. Show less
Over the last two decades, there has been substantial progress in the area of blood safety in Uganda. In contrast, little attention has been paid to transfusion safety in Uganda and there are gaps... Show moreOver the last two decades, there has been substantial progress in the area of blood safety in Uganda. In contrast, little attention has been paid to transfusion safety in Uganda and there are gaps in laboratory and clinical transfusion practices within hospitals. Assessment of the current practice at Mulago and Mbarara Referral Hospitals showed inadequate documentation of the transfusion process, and poor monitoring of blood recipients. Our findings also indicated that one in every 16 transfused Ugandans and a similar number of RhD negative pregnant women possessed clinically significant red blood cell (RBC) alloantibodies in their plasma. However, RBC alloantibody screening is not performed during pre-transfusion and antenatal testing in the country. Thus, alloimmunized recipients and babies of RhD negative mothers are at high risk of morbidity and mortality due to haemolytic transfusion reactions (HTRs) and haemolytic disease of the fetus and the newborn (HDFN). Furthermore, data on the occurrence of acute and delayed HTRs and HDFN in Uganda are lacking. A cost-effectiveness analysis showed that introduction of RBC alloantibody screening would be cost-effective and improve blood transfusion safety. Therefore, there is need to improve immunohaematological testing in Uganda so that RBC alloimmunization and the consequences thereof may be prevented. Show less
Group B Streptococcus (GBS, Streptococcus agalactiae) has been recognized as an important cause of perinatal morbidity and mortality. The frequency of GBS colonization ranges from 10% to 35% in... Show moreGroup B Streptococcus (GBS, Streptococcus agalactiae) has been recognized as an important cause of perinatal morbidity and mortality. The frequency of GBS colonization ranges from 10% to 35% in women of reproductive age. GBS colonization can be transient, intermittent or persistent. Vertical transmission of GBS from mother to child occurs during labor. Studies on vertical GBS transmission in colonized mothers during labor report incidences of colonization of the infant between 16 and 69%. Early-onset group B streptococcal disease (GBS-EOD) occurs in approximately 1% of newborns who are colonized with GBS. Established risk factors for acquiring GBS-EOD are prolonged rupture of membranes, preterm labor, intrapartum fever, GBS bacteriuria during pregnancy or a previous child with GBS-EOD. Intrapartum antibiotic prophylaxis (IAP) given to women at risk of transmitting GBS to their baby may prevent GBS-EOD. Identification of mothers at risk may be performed by screening (taking a culture during pregnancy to detect maternal colonization) and/ or by identifying pregnancies with one or more of the established risk factors for GBS-EOD. Since the overall effect of the Dutch guideline on the incidence of GBS-EOD is disappointing, adaptation of the Dutch guidelines should be reconsidered. The aim of this thesis is to contribute to the information needed for the establishment of an optimal prevention strategy for GBS-EOD. In this thesis, studies on prevalence of GBS carriage, risk factors for GBS-sepsis in relation to GBS carriage, timing of GBS cultures, association of GBS carriage and preterm labor and resistance of GBS for antibiotics are combined. 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
