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
This thesis aimed to evaluate and improve the risk stratification of outpatient management in acute pulmonary embolism (PE) patients. In addition, this thesis aimed to establish current patterns of... Show moreThis thesis aimed to evaluate and improve the risk stratification of outpatient management in acute pulmonary embolism (PE) patients. In addition, this thesis aimed to establish current patterns of home treatment and to assess the safety of anticoagulant treatment in PE patients. Finally, this thesis aimed to provide an overview of outpatient treatment of venous thromboembolism (VTE) in cancer patients at high risk of adverse events. Show less
Pulmonary embolism is a serious and potentially life-threatening disease in the acute phase, and may also have a major impact on a patient’s daily life in the long run. The overall aim of this... Show morePulmonary embolism is a serious and potentially life-threatening disease in the acute phase, and may also have a major impact on a patient’s daily life in the long run. The overall aim of this thesis was evaluating important aspects of the post-pulmonary embolism syndrome with an emphasis on early diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) and the associated consequence for patients’ prognosis. Show less
Venous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of... Show moreVenous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of upper extremity, abdomen and cerebrum. As symptoms of VTE are nonspecific, the diagnosis of VTE is based on diagnostic tests, including clinical decision rules (CDR), D-dimer tests and imaging. Although the diagnostic management of VTE has greatly advanced in recent years with the introduction of novel CDRs and high-sensitive D-dimer tests, the diagnosis may still be challenging in certain settings. The latter is mainly caused by the indirect way of thrombus visualisation by current imaging tests, such as by showing incompressibility with compression ultrasonography (CUS) or a filling defect on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI).This thesis focuses on challenging settings for diagnosing VTE, including suspected recurrent ipsilateral DVT, upper extremity DVT, cerebral vein thrombosis and portal vein thrombosis. We studied a novel imaging technique called Magnetic Resonance Non-Contrast Thrombus Imaging (MR-NCTI) and its application in these different VTE settings. Show less
The post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE)... Show moreThe post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE) respectively. We have reviewed the literature on arguments for and against routine screening of CTEPH in patients after an episode of an acute PE. The incidence of CTEPH is relevant in this evaluation. In a systematic review and meta-analysis we showed a CTEPH incidence of 0.56% in all comers and of ~3% in the survivors. We showed that a very recent developed screening algorithm, the InShape II algorithm, is sensitive and reproducible for detecting early CTEPH in the course of an acute PE. Beside this, most patient who were diagnosed with CTEPH in the course of an acute PE already showed signs of CTEPH on the initial CT scan made for PE diagnosis.In the last chapter we focus on PTS in the course of a DVT. In patients included in the MEGA database the 0-1 year incidence was 21.8%, after 8 years of follow-up an additional 7% developed PTS. During follow-up PTS symptoms improves in almost 70% of patients. 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 this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of... Show moreIn this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of thrombosis in the elderly population, in order to advance our basic understanding of physiological age-related changes that increase the risk of venous thrombosis and which may ultimately lead to improved personalized interventions. In this chapter firstly background information will be provided on risk factors for venous thrombosis, focussing specifically on age as a risk factor. Secondly, the role of veins and venous valves in the development of venous thrombosis will be discussed and thirdly, global assays as a potential tool to identify patients at high risk for venous thrombosis will be considered. The study populations used in this thesis will discussed, and an outline of this thesis will be provided. Show less
The studies described in this thesis aim to improve both the diagnostic strategy in patients with suspected pulmonary embolism as well as the therapeutic management in patients with proven acute... Show moreThe studies described in this thesis aim to improve both the diagnostic strategy in patients with suspected pulmonary embolism as well as the therapeutic management in patients with proven acute pulmonary embolism. Show less
This thesis describes studies that aimed to evaluate and improve the diagnostic work-up and management of pulmonary embolism. Age-adjusted D-dimer testing was found to be an effective and... Show more This thesis describes studies that aimed to evaluate and improve the diagnostic work-up and management of pulmonary embolism. Age-adjusted D-dimer testing was found to be an effective and safe strategy to reduce the need for CT-imaging in elderly patients with clinically suspected pulmonary embolism. Furthermore, this thesis demonstrates that patients with proven pulmonary embolism who fulfil the Hestia criteria can be safely treated at home, without the need for further prognostic assessment. In the vast majority of patients treated for pulmonary embolism, complete thromboembolic resolution had occurred after six months as assessed by CT pulmonary angiography. The last part of this thesis describes that the outcome of cancer patients incidentally diagnosed with pulmonary embolism mimics the outcome of cancer patients with symptomatic pulmonary embolism. Show less
The aim of this thesis is to provide more insight into the relationship between pulmonary embolic burden, right and left ventricular function and dysfunction, using ECG-synchronized multidetector... Show moreThe aim of this thesis is to provide more insight into the relationship between pulmonary embolic burden, right and left ventricular function and dysfunction, using ECG-synchronized multidetector-row computed tomography (MDCT). We demonstrated that RV and LV function can be accurately measured by using ECG-synchronized MDCT. Contrary to non-ECG synchronized MDCT-measured RV function, ECG-synchronized technique is a more accurate reflection of the hemodynamic consequences of different embolic locations on RV function. ECG-synchronized MDCT is able to distinguish patients with central PE from those with peripheral PE, while non-ECG-synchronized MDCT is not. RV dysfunction (RV-EF below 35%) is independently predicted by an obstruction index above 50% or a LV-EF below 45%. 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
Pulmonary embolism is traditionally, since autopsy studies by Virchow in the mid 1800s, thought to originate from embolization of a deep-vein thrombosis, resulting in two clinical manifestations of... Show morePulmonary embolism is traditionally, since autopsy studies by Virchow in the mid 1800s, thought to originate from embolization of a deep-vein thrombosis, resulting in two clinical manifestations of one disease: venous thrombosis. The incidence of deep-vein thrombosis in the population is twice as high as the incidence of pulmonary embolism, i.e. 1 per 1000 and 0.5 per 1000 person-years respectively. The aim of this thesis was to assess whether pulmonary embolism and deep-vein thrombosis are always the same disease or not, and to answer this question with regard to etiology (genetic and acquired risk factors) and anatomical distribution of thrombi in the veins. We studied this question in two populations: the PEDLAR study and the MEGA case-control study. In the PEDLAR study we assessed the origin of pulmonary embolism using a total body Magnetic Resonance Direct Thrombus Imaging technique. We proposed several mecha nisms for the absence of deep-vein thrombi in more than half of the patients with pulmonary embolism. In addition, we investigated the effect of aging on venous valve thickness. This was performed in an ultrasonography study, with participants from 20 to 80 years old (the aging venous valves study). We hypothesized that part of the increasing incidence in venous thrombosis with age can be explained by increasing valve thickness. Show less
Chapter 1 reviews technical developments of cardiac CT and current status, recommendations and future perspective of various clinical cardiac CT applications. In chapter 2, the eff ect of dose... Show moreChapter 1 reviews technical developments of cardiac CT and current status, recommendations and future perspective of various clinical cardiac CT applications. In chapter 2, the eff ect of dose reduction on diagnostic performance in CT coronary angiography is assessed. Chapter 3 evaluates the eff ect of thin-slice image reconstructions on coronary artery calcium measurements. In chapter 4, the assessment of Agatston scores using coronary CT angiography is studied. Chapter 5 evaluates the predictive value of CT-derived RV/LV ratios and cardiac biomarkers for short term clinical outcome in patients with suspected acute PE. In chapter 6, the incremental value of ventricular function with ECG-synchronized cardiac CT over standard pulmonary CTA-derived RV/LV ratios for predicting clinical outcome in patients with suspected acute PE is discussed. Chapter 7 studies the influence of timing of NT-pro-BNP sampling for predicting adverse clinical outcome. Show less
This thesis describes the diagnostic management, short term prognosis and long term complications of pulmonary embolism. We have validated a newly derived clinical decision rule, the revised Geneva... Show moreThis thesis describes the diagnostic management, short term prognosis and long term complications of pulmonary embolism. We have validated a newly derived clinical decision rule, the revised Geneva score, for predicting the pre-test probability of having acute pulmonary embolism. This rule can be used in clinical practice to managge patients with suspected pulmonary embolism. We further found that NT-pro-BNp levels are the best predictors of benign clinical course, when compared to troponin and D-dimer levels, and CT derived maesurements of the right ventricular volume and function. Finally, we demonstrate that although the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism is very low, the long term clinical course after pulmonary embolism is complicated frequently by mortalitity, recurrent venous thombosis, newly diagnosed maligancies and arterial cardiovascular events. 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
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
Pulmonary embolism is a potentially fatal disease in which early recognition and institution of anticoagulant treatment can prevent mortality. The diagnostic tools available to establish whether a... Show morePulmonary embolism is a potentially fatal disease in which early recognition and institution of anticoagulant treatment can prevent mortality. The diagnostic tools available to establish whether a patient has a pulmonary embolism were limited to pulmonary angiography and ventilation-perfusion scintigraphy. Both tests have considerable limitations. Helical CT evolved as a new technique in diagnosing PE and gained widespread interest but has been implemented rapidly, without appropriate assessment in clinical practice. The Christopher-study was performed to investigate whether a dichotomization of the Wells clinical decision rule, classifying patients into __PE unlikely__ and __PE likely__ in combination with a D-dimer test is safe to rule out pulmonary embolism in patients with a clinical suspicion. Furthermore, the study was designed to investigate whether helical CT is safe to rule out PE without performing any additional diagnostic tests. In patients in whom PE was excluded by a clinical decision rule indicating __PE unlikely__ combined with a negative D-dimer, during three months of follow-up venous thrombo-embolism was diagnosed in 5 out of 1028 untreated patients (0.5%, 95%CI: 0.2-1.1). In patients in whom CT had ruled out PE, during three months follow-up 18 of 1446 untreated patients experienced a venous thrombo-embolic event (1.3%, 95%CI: 0.7-2.0). In conclusion, the Christopher-study demonstrates that a simple diagnostic algorithm consisting of a dichotomised clinical decision rule, D-dimer and helical CT can guide treatment decisions with a low risk of subsequent venous thrombo-embolism. Show less
In the Antelope study availability, use and diagnostic accuracy of spiral CT in patients clinically suspected of PE was investigated. This study was divided in two separate phases, starting with a... Show moreIn the Antelope study availability, use and diagnostic accuracy of spiral CT in patients clinically suspected of PE was investigated. This study was divided in two separate phases, starting with a prospective evaluation of available diagnostic techniques part of the diagnostic consensus strategy in The Netherlands in a specifically designed algorithm. Phase I showed that in a direct comparison with the gold standard sensitivity and specificity of spiral CT is too low to endorse its role as a single test to exclude pulmonary embolism. Also spiral CT had a limited added value as a second procedure following ventilation-perfusion scintigraphy. The accuracy of CT was significantly better in cases with interobserver agreement and good image quality. The available data of phase I was used for a cost-effectiveness analysis. Combined with recent literature data two new strategies were proposed and studied independently. Phase II showed in a prospective clinical management study that spiral CT can be used safely as a first line test to rule out pulmonary embolism in clinically suspected patients. It is also possible to reliably determine an alternative diagnosis in 25% of all patients. A new questionnaire showed that since 1997 the use of spiral CT has increased considerably. Show less
