von Willebrand factor (VWF) is a multimeric glycoprotein involved in primary hemostasis, recruiting platelets to the site of damaged vessels and acting as a carrier for factor VIII. Quantitative or... Show morevon Willebrand factor (VWF) is a multimeric glycoprotein involved in primary hemostasis, recruiting platelets to the site of damaged vessels and acting as a carrier for factor VIII. Quantitative or qualitative alterations of VWF cause von Willebrand disease (VWD), an inherited bleeding disorder. Conversely, increased VWF levels have been associated with various thrombotic conditions. In this thesis, we investigated the dual role of VWF in bleeding and thrombosis, focusing on VWD and deep vein thrombosis (DVT). In the first part of the thesis, we demonstrated the utility of in silico tools and heterologous cell systems in proving the disease-causing role of VWF variants thus contributing to the confirmation of patient diagnoses. In the second part, we focused on type 3 VWD, the most severe form of this disorder caused by a lack of VWF. We showed that patients with missense variants had a higher VWF propeptide/VWF antigen ratio than carriers of VWF null alleles. This suggested that secreted VWF is rapidly removed from circulation in these patients. Subsequently, we estimated the prevalence of VWF neutralizing and non-neutralizing antibodies, confirming that they are rare side effects of replacement therapy. We also demonstrated that the detection of epitope-specific VWF inhibitors is affected by the test used. In the last part of the thesis, we evaluated the role of ADAMTS13-VWF equilibrium in the pathogenesis of DVT, showing that a slight decrease in ADAMTS13 activity, particularly when combined with increased VWF levels, increases DVT risk. We then sequenced ADAMTS13, VWF, and F8 genes and confirmed that DVT patients carrying a rare ADAMTS13 variant exhibited lower ADAMTS13 activity than non-carriers. Show less
Hemophilia is a rare X-linked hereditary bleeding disorder, caused by a mutation in the F8 or F9 gene. In the last 50 years, hemophilia treatment has changed tremendously and the impact of these... Show moreHemophilia is a rare X-linked hereditary bleeding disorder, caused by a mutation in the F8 or F9 gene. In the last 50 years, hemophilia treatment has changed tremendously and the impact of these changes on current clinical outcomes is unknown.Therefore, we comprehensively assessed the changes in health status over time of patients with hemophilia using observational study data. Our results show that clinical outcomes of these patients have improved tremendously over the past decades. The annual bleeding rate and the proportion of patients with joint impairment have decreased strongly. In addition, HCV has almost been eradicated among patients with hemophilia in the Netherlands. As a result, life expectancy has increased to where it is almost equal to that of the general population.Although clinical outcomes have improved in many ways, inhibitor development continues to be a significant problem in patients treated with clotting factor products. Therefore, using three different study approaches, we also evaluated several methods to better predict the risk of inhibitor development (which is still a significant complication of treatment with FVIII). The results of these studies are promising and could be used to improve current inhibitor prediction strategies and inform future research on this topic. Show less
Bleeding events are frequently encountered in hemato-oncology patients. To prevent this, in periods of thrombocytopenia patients receive prophylactic platelet transfusions, based on the platelet... Show moreBleeding events are frequently encountered in hemato-oncology patients. To prevent this, in periods of thrombocytopenia patients receive prophylactic platelet transfusions, based on the platelet counts. However, beside platelet counts many other patients factors likely contribute to the bleeding risk.In this thesis we focus on describing current clinical practice to prevent bleedings in a subpopulation of patients with persistent deep thrombocytopenia, risk factors for bleeding, and prediction of bleeding. We also describe a ongoing study which aims to identify and quantify risk factors in future.With this knowledge, in the ultimate goal is to predict bleeding more accurate based on patient characteristics and/or biomarkers. This could be a first step towards more personalized bleeding prevention strategies. Show less
The scope of the thesis is: “bleeding in patients with hypoproliferative thrombocytopenia”. Despite platelet transfusions bleeding occurs frequently in these patients and besides highlighting the... Show moreThe scope of the thesis is: “bleeding in patients with hypoproliferative thrombocytopenia”. Despite platelet transfusions bleeding occurs frequently in these patients and besides highlighting the variance in methodology of assessing bleeding symptoms and reporting in different bleeding scales, various risk factors for bleeding are illustrated in the introduction of the thesis. In the three following chapters the scoring of bleeding symptoms, the adjudication of symptoms in bleeding scales and the methodology concerning these aspects and more of a large platelet transfusion trial comparing pathogen reduced platelets (by using the Mirasol technique) to control platelet products is described. Chapter five describes the results of this randomized controlled trial and in the following chapter the association between endothelial damage (as measured by microalbuminuria in patients) and bleeding is described. Alternative bleeding scales besides the WHO bleeding scale are described in chapter seven and the last chapter summarizes the findings. Show less
Blood coagulation is a complex system in which the proteins of the coagulation cascade play an important role. Aberrations in pro- or anticoagulant protein levels may be at the basis of coagulation... Show moreBlood coagulation is a complex system in which the proteins of the coagulation cascade play an important role. Aberrations in pro- or anticoagulant protein levels may be at the basis of coagulation-related pathological events, such as bleeding or thrombosis. Here the relations of altered coagulation factor levels and venous thromboembolism, the tissue factor threshold which needs to be overcome to initiate coagulation and the in vitro validation of APC-resistant FV as a possible alternative treatment of factor XI deficiency are explored. Show less
The overall goal of this thesis was to identify patients who are at high risk for major bleedings during anticoagulant treatment and to reduce the number of major bleeds. The first part looks... Show moreThe overall goal of this thesis was to identify patients who are at high risk for major bleedings during anticoagulant treatment and to reduce the number of major bleeds. The first part looks into methodology of observational studies. It shows that biases in observational studies may be an explanation why statins seem to have many unintended effects. The second part looks into bleeding complications and shows that patient with three concomitant anticoagulants experience high major bleeding rates. Also, a study was performed in which plasma and DNA of participants was collected, to identify risk factors for major bleeds in the future. The first results show that damage to vessel walls increases the risk of major bleeding. Interventions to reduce the number of bleeding events were to dose nadroparin od instead of bid. In addition, multi-dose drug dispensing may increase adherence of medication. Also, vitamin K1 tablets are easier to ingest and this thesis shows that the tablets are as effective in reducing the INR as the oral solution. Show less
This thesis describes new knowledge of FNAIT in preparation of a national wide screening program. It illustrates the prevalence of FNAIT among pregnant women and the risk of adverse outcome,... Show moreThis thesis describes new knowledge of FNAIT in preparation of a national wide screening program. It illustrates the prevalence of FNAIT among pregnant women and the risk of adverse outcome, outlines current management, evaluates risks of missing a diagnosis of FNAIT, studies the efficacy of a lower dose of immunoglobulins in preventing bleedingcomplications,shows the time of bleeding onset of fetal ICH during pregnancy and illustrates the longterm outcome of children with ICH. Show less
Aim of this thesis was to evaluate contemporary care and prognosis for patients with acute coronary syndrome and identify pitfalls in its treatment. Complications after coronary stent implantation... Show moreAim of this thesis was to evaluate contemporary care and prognosis for patients with acute coronary syndrome and identify pitfalls in its treatment. Complications after coronary stent implantation were explored and demonstrated that in sirolimus-eluting stents, the benefit of reduced repeat revascularization during one year after primary PCI was not sustained during long-term follow-up. Additionally, an increased risk of very late stent thrombosis was suggested. Late stent malapposition, more commonly observed after this stent type and suspected to be involved in the multifactorial etiology of stent thrombosis, is shown to persist in the greater portion of STEMI patients during long-term follow-up, depending on the degree of vessel wall remodelling and change in plaque burden. Women were identified as a sub-population with poorer prognosis early after STEMI. Identification of high-risk patients, and estimation of infarct size and prognosis, which a single measurement of troponin already may indicate, facilitates individualized treatment and likely results in better outcomes. Although numerous novel treatment modalities emerged in recent years, certain pitfalls become increasingly important. Major bleeding is one of them, responsible for an excess mortality amongst STEMI patients after primary PCI, and should be incorporated in risk stratification models for the choice of treatment strategy. Show less
According to current guidelines, patients with thrombocytopenia due to myelosuppression are supported with platelet concentrates in order to prevent and treat bleeding complications using... Show moreAccording to current guidelines, patients with thrombocytopenia due to myelosuppression are supported with platelet concentrates in order to prevent and treat bleeding complications using algorithms which include the level of thrombocytopenia as well as varying clinical parameters, e.g. concomitant infection, the use of anticoagulant drugs, specific interventions. In the last three decades, mainly driven by safety issues, several platelet product changes were made with leukoreduction in the eighties of the previous century, plasma reduction and the use of additive solution in the nineties and the use of pathogen reduction in the first decade of this century.This thesis is mainly based on two randomised controlled trials testing the clinical efficacy of the use of additive solutions and pathogen reduction, essentially showing a decreased clinical efficacy as well as a decrease in adverse transfusion events. A bette r understanding of the pathophysiology of bleeding, thrombocytopenia and platelet transfusion refractoriness will lead to improvements in supportive care as well as patient survival, the common goal of all physicians. Show less
