Joost C M Meijers

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (301)1643.09 Total impact

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    ABSTRACT: Puumala virus (PUUV) infection causes over 5000 cases of hemorrhagic fever in Europe annually and can influence the hemostatic balance extensively. Infection might lead to hemorrhage, while a recent study showed an increased risk of myocardial infarction during or shortly after PUUV infection. The mechanism by which this hantavirus influences the coagulation system remains unknown. Therefore we aimed to elucidate mechanisms explaining alterations seen in primary and secondary hemostasis during PUUV infection. By using low passage PUUV isolates to infect primary human umbilical vein endothelial cells (HUVECs) we were able to show alterations in the regulation of primary- and secondary hemostasis and in the release of fibrinolysis regulators. Our main finding was an activation of secondary hemostasis due to increased tissue factor (TF) expression leading to increased thrombin generation in a functional assay. Furthermore, we showed that during infection platelets adhered to HUVEC and subsequently specifically to PUUV virus particles. Infection of HUVEC with PUUV did not result in increased von Willebrand factor while they produced more plasminogen activator inhibitor type-1 (PAI-1) compared to controls. The PAI-1 produced in this model formed complexes with vitronectin. This is the first report that reveals a potential mechanism behind the pro-coagulant changes in PUUV patients, which could be the result of increased thrombin generation due to an increased TF expression on endothelial cells during infection. Furthermore, we provide insight into the contribution of endothelial cell responses regarding hemostasis in PUUV pathogenesis.
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    ABSTRACT: An unbalance between the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 is a risk factor for thrombosis. Here, we assessed levels and functionality of VWF and ADAMTS13 in patients undergoing off-pump lung transplantation. We analyzed plasma of 10 patients and distinguished lung transplantation-specific effects from those generally accompanying open-chest surgeries by comparing results with 11 patients undergoing off-pump coronary bypass graft (CABG) surgery. Forty healthy volunteers were included for reference values. VWF antigen levels as well as the VWF ristocetin cofactor activity/VWF antigen ratio increased during lung transplantation and after CABG surgery. An increase in VWF propeptide levels was paralleled by a decrease in ADAMTS13 activity. This was more pronounced during lung transplantation. Similarly, the capacity of plasma to support platelet aggregation under shear flow conditions in vitro was more increased during lung transplantation. The proportion of high molecular weight VWF multimers was elevated in both groups without evidence for ultra-large VWF. VWF's collagen binding activity remained unchanged. In conclusion, a hyperactive primary hemostatic system develops during lung transplantation resulting both from a pronounced (functional) increase of the VWF molecule and decrease of ADAMTS13. This may increase the risk of platelet thrombosis within the allograft. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    American Journal of Transplantation 04/2015; DOI:10.1111/ajt.13225 · 6.19 Impact Factor
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    ABSTRACT: Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1(-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ~50 %. Homozygous lowTFPI mice and heterozygous controls had ~10 % and ~50 % of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ~10 % (but not with ~50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia.
    Thrombosis and Haemostasis 04/2015; 113(6). DOI:10.1160/TH14-12-1053 · 5.76 Impact Factor
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    ABSTRACT: Background The initiating trigger in the development of deep vein thrombosis (DVT) is as yet unidentified. It has been suggested that tissue factor-bearing microparticles play a key-role, which indicate a role for the tissue factor (TF)-pathway in the initiation of DVT.Objective To assess the role of the TF-pathway in the initiation of venous thrombosis, we measured plasma levels of factor VII and VIIa in patients with acute DVT and in controls.Methods148 patients diagnosed with acute DVT and 179 controls were included in this study. Antigen levels of FVII and FVIIa were measured using assays recently developed in our laboratory.ResultsMedian FVII levels in patients were 109.8 % (IQR 86.0-153.2) compared to 102.2 % (IQR 76.1-141.7) in controls. Individuals with FVII levels in the upper quartile had a 1.6-fold increased risk for the presence of a DVT (OR 1.6, 95% CI 0.8 – 3.1). Median FVIIa levels in patients were 50.2 ng/ml (IQR 25.2-86.1) compared to 96.6 ng/ml (IQR 69.9-168.9) in controls. Individuals with FVIIa levels in the lowest quartile had a more than 5-fold increased risk for the presence of a DVT (OR 5.5, 95% CI 2.8 – 10.6). Both risks did not change substantially after adjustment for potential confounders.Conclusion Decreased plasma levels of FVIIa in patients with deep vein thrombosis may indicate ongoing consumption of FVIIa and suggest a contributory role for TF in venous thrombus formation.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2015; DOI:10.1111/jth.12980 · 5.55 Impact Factor
  • T Plug, J C M Meijers
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    ABSTRACT: A new TAFI deletion mutant, constructed by Zhou et al. [1], provides us with new clues on the mysterious mechanism of spontaneous TAFIa self-destruction. Thrombin-Activatable Fibrinolysis Inhibitor (TAFI), also known as procarboxypeptidase U, procarboxypeptidase R and procarboxypeptidase B2, is encoded by the CPB2 gene [2]. TAFI is synthesized in the liver and circulates in plasma as a proenzyme. During coagulation, TAFI is activated by a single proteolytic cleavage at Arg92 that releases the activation peptide from the catalytic domain [3]. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 03/2015; DOI:10.1111/jth.12900 · 5.55 Impact Factor
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    ABSTRACT: Hyperglycaemia during and after hip surgery is associated with coagulation activation and an increased risk of venous thromboembolism. Whether lowering of glucose levels during hip surgery diminishes coagulation activation is unknown. We investigated the efficacy of the human GLP-1 analogue liraglutide to lower glucose during and after hip surgery and studied its influence on coagulation activation.
    03/2015; 133. DOI:10.1016/j.bbacli.2015.03.001
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    ABSTRACT: Background Coagulopathy has a high prevalence in critically ill patients. An increased INR is a common trigger to transfuse fresh frozen plasma (FFP), even in the absence of bleeding. Thereby, FFP is frequently administered in these patients. However, efficacy of FFP to correct hemostatic disorders in non-bleeding recipients is questioned.Objectives To assess whether INR prolongation parallels changes in other tests investigating hemostasis and evaluate the coagulant effects of a fixed dose of FFP in non-bleeding critically ill patients with a coagulopathy.Methods Markers of coagulation, individual factor levels and levels of natural anticoagulants were measured. Also thrombin generation and thromboelastometry (ROTEM) assays were performed before and after FFP transfusion (12 ml/kg) to 38 non-bleeding critically ill patients with an increased INR (1.5-3.0).ResultsAt baseline, levels of factor II, V and VII as well as levels of protein C, S and antithrombin were reduced and thrombin generation was impaired. ROTEM variables were within reference ranges, except for prolonged INTEM CFT. FFP transfusion increased levels of coagulation factors (factor II (34% [26-46] before vs. 44% [38-52] after), factor V (48% [28-76] before vs. 58% [44-90] after) and factor VII (25% [16-38] before vs. 37% [28-55] after)) as well as levels of anticoagulant proteins. Thrombin generation was unaffected by FFP transfusion (endogenous thrombin potential (72% [51-88] before vs. 71% [42-89] after), while ROTEM EXTEM CT and MCF slightly improved in response to FFP.Conclusion In non-bleeding critically ill patients with a coagulopathy, FFP transfusion failed to induce a more procoagulant state.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 03/2015; DOI:10.1111/jth.12908 · 5.55 Impact Factor
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    ABSTRACT: We investigated a small Dutch family with a bleeding diathesis, prolonged prothrombin and activated partial thromboplastin times, in whom no classifying diagnosis was made. The two affected relatives had severely decreased in vitro thrombin generation, and levels of tissue factor pathway inhibitor (TFPI) were strongly increased. To identify the genetic cause of the bleeding diathesis, we performed whole exome sequencing analysis of all living relatives. We found a novel gain-of-function mutation in F5 gene (c.C2588G), which leads to an aberrant splicing of F5 and ultimately to a short factor V protein (missing 623 amino acids from the B domain) which we called Factor V Amsterdam. Factor V Amsterdam binds to TFPI, prolonging its half-life and concentration. This is the second report of an association between a shorter form of factor V and increased TFPI levels, resulting in severely reduced thrombin generation and a bleeding tendency. Copyright © 2015 American Society of Hematology.
    Blood 01/2015; 125(11). DOI:10.1182/blood-2014-08-592733 · 9.78 Impact Factor
  • American Journal of Respiratory and Critical Care Medicine 01/2015; 191(2):230-3. DOI:10.1164/rccm.201407-1228LE · 11.99 Impact Factor
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    ABSTRACT: Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and sepsis. Activated protein C (APC) has been implicated as an important anticoagulant and anti-inflammatory mediator. We here sought to determine the role of the anticoagulant and cytoprotective functions of endogenous APC during pneumonia and sepsis caused by S. pneumoniae. Mice were treated intraperitoneally with monoclonal antibody (mAb) 1609 (which inhibits both anticoagulant and cytoprotective effects of APC), mAb 1591 (which inhibits only the anticoagulant effects of APC) or a control antibody mAb prior to infection with viable S. pneumoniae via the airways (to induce pneumonia) or via the tail vein (to induce primary sepsis). Mice were analyzed at 24 or 48hours after infection. mAb 1609, but not mAb 1591, enhanced the procoagulant response to pneumococcal pneumonia and sepsis, as indicated by elevated levels of thrombin-antithrombin complexes and D-dimer in plasma and lungs. mAb 1609 only modestly affected the fibrinolytic response (elevated plasma and lung levels of the fibrinolysis inhibitor plasminogen activator inhibitor type I during sepsis) and cytokine release (elevated plasma interleukin-6 concentrations during pneumonia). The cytoprotective effects of endogenous APC reduce activation of coagulation during murine pneumococcal pneumonia and sepsis. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Thrombosis Research 01/2015; DOI:10.1016/j.thromres.2014.12.020 · 2.43 Impact Factor
  • British Journal of Haematology 12/2014; DOI:10.1111/bjh.13257 · 4.96 Impact Factor
  • Maurits L van Montfoort, Joost C M Meijers
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    ABSTRACT: The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. © 2014 by The American Society of Hematology. All rights reserved.
  • British Journal of Haematology 11/2014; DOI:10.1111/bjh.13210 · 4.96 Impact Factor
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    ABSTRACT: Human tuberculosis (TB) remains an important cause of death globally. Bangladesh is one of the most affected countries. We aimed to investigate the impact of pulmonary TB on pro- and anticoagulant mechanisms. This prospective study was conducted in Chittagong, Bangladesh. We performed an in-depth analysis of coagulation activation and inhibition in plasma obtained from 64 patients with primary lung TB and 11 patients with recurrent lung TB and compared these with 37 healthy controls. Additionally, in nine patients coagulation activation was studied in bronchoalveolar lavage fluid (BALF) harvested from the site of infection and compared with BALF from a contralateral unaffected lung subsegment. Relative to uninfected controls, primary and recurrent TB were associated with a systemic net procoagulant state, as indicated by enhanced activation of coagulation (elevated plasma levels of thrombin-antithrombin complexes, D-dimer and fibrinogen) together with impaired anticoagulant mechanisms (reduced plasma levels of antithrombin, protein C activity, free protein S, and protein C inhibitor). Activation of coagulation did not correlate with plasma concentrations of established TB biomarkers. Coagulation activation could not be detected at the primary site of infection in a subset of TB patients. Pulmonary TB is associated with a systemic hypercoagulable state. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
    Journal of Infection 10/2014; DOI:10.1016/j.jinf.2014.10.006 · 4.02 Impact Factor
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    ABSTRACT: Background During a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of this study was to investigate whether hyperferritinaemia in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances. Methodology/Principal Findings Levels of ferritin, standard laboratory markers, sIL-2R, IL-18 and coagulation and fibrinolytic markers were determined in samples from patients with uncomplicated dengue in Aruba. Levels of ferritin were significantly increased in dengue patients compared to patients with other febrile illnesses. Moreover, levels of ferritin associated significantly with the occurrence of viraemia. Hyperferritinaemia was also significantly associated with thrombocytopenia, elevated liver enzymes and coagulation disturbances. The results were validated in a cohort of dengue virus infected patients in Brazil. In this cohort levels of ferritin and cytokine profiles were determined. Increased levels of ferritin in dengue virus infected patients in Brazil were associated with disease severity and a pro-inflammatory cytokine profile. Conclusions/Significance Altogether, we provide evidence that ferritin can be used as a clinical marker to discriminate between dengue and other febrile illnesses. The occurrence of hyperferritinaemia in dengue virus infected patients is indicative for highly active disease resulting in immune activation and coagulation disturbances. Therefore, we recommend that patients with hyperferritinaemia are monitored carefully.
    PLoS neglected tropical diseases 10/2014; 8(10):e3214. DOI:10.1371/journal.pntd.0003214 · 4.72 Impact Factor
  • Atherosclerosis 08/2014; 235(2):e17-e18. DOI:10.1016/j.atherosclerosis.2014.05.019 · 3.97 Impact Factor
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    ABSTRACT: Rationale: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels and increased risk for coronary artery disease (CAD). ADH is caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin 9 (PCSK9). However, in a proportion of ADH cases mutations in these genes are not found. Objective: To identify a fourth locus associated with ADH. Methods and Results: Parametric linkage analysis combined with exome sequencing in a FH4 family resulted in the identification of the variant p.Glu97Asp in STAP1, encoding signal transducing adaptor family member 1. Sanger sequencing of STAP1 in 400 additional unrelated FH4 probands, in which mutations in the established LDL-associated genes were ruled out, identified a second p.Glu97Asp carrier and three additional missense variants, p.Leu69Ser, p.Ile71Thr, and p.Asp207Asn. STAP1 carriers (N=40) showed significantly higher plasma total cholesterol and LDL-c levels compared to non-affected relatives (N=91). Conclusions: We mapped a novel ADH locus at 4p13, and identified four variants in STAP1 that associate with ADH.
    Circulation Research 07/2014; 115(6). DOI:10.1161/CIRCRESAHA.115.304660 · 11.09 Impact Factor
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    ABSTRACT: Coagulation factor deficiencies are thought to interfere with the detection of the phospholipid-dependent coagulation inhibitor known as lupus anticoagulant (LA). Treatment with vitamin K antagonists (VKA) in particular, is thought to preclude accurate LA assessment. For this reason, the procedure to detect LA includes a mixing test, in which coagulation factor deficiencies are corrected by mixing samples with an equal volume of normal plasma. Despite these mixing tests, interpretation of LA test results is considered difficult in patients receiving high intensity VKA treatment. As a result, VKA treatment is often temporarily discontinued to allow LA assessment. However, whether coagulation factor deficiencies influence LA test results is unclear. We found that neither deficiency of a single coagulation factor, nor a functional coagulation factor deficiency due to high intensity VKA treatment, resulted in false positive dRVVT- or APTT-based (silica clotting time; SCT) LA test results. LA was readily detected in unmixed samples from VKA-treated LA-positive patients with both dRVVT and SCT reagents. VKA treatment caused an underestimation of the strength of the LA with SCT reagents, but did not lead to misclassification of LA status. Although mixing with normal plasma during both screen and confirm tests allowed more accurate assessment of the strength of the LA with SCT reagents in samples with an international normalised >2.5, the mixing procedure itself lead to misclassification of LA in weakly positive samples from patients not treated with VKA. Based on these findings, we conclude that mixing studies are not necessary during LA-assessment.
    Thrombosis and Haemostasis 07/2014; 112(4). DOI:10.1160/TH14-02-0122 · 5.76 Impact Factor
  • T. Plug, G. Kramer, J. C.M. Meijers
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    ABSTRACT: BackgroundTAFI is a proenzyme that links coagulation and fibrinolysis. TAFI can be activated by thrombin, the thrombin/thrombomodulin (IIa/TM) complex and plasmin by cleaving off the first 92 amino acids from the enzyme. In silico analysis of the TAFI sequence revealed a potential thrombin cleavage site at Arg12. The aim of this study was to determine whether TAFI can be cleaved at Arg12 and if this cleavage plays a role in TAFI activation.MethodsA peptide based on the first 18 amino acids of TAFI was used to determine whether thrombin was able to cleave at Arg12. Mass spectrometry was performed to determine if the Arg12 cleaved peptide was released from full-length TAFI. Furthermore, a TAFI mutant in which Arg12 was replaced by a glutamine (TAFI-R12Q) was constructed and characterized with respect to its activation kinetics.ResultsThe peptide and mass spectrometry data showed that thrombin was able to cleave TAFI at Arg12, but with low efficiency in full-length TAFI. Characterisation of the TAFI-R12Q mutant showed no difference in thrombin-mediated activation compared to wild-type TAFI. However, there was a ~60-fold impairment in TAFI activation of TAFI-R12Q by the IIa/TM complex.Conclusions Arg12 of TAFI plays an important role in thrombomodulin-mediated TAFI activation by thrombin. Thrombin is able to cleave TAFI at Arg12, but it remains to be determined if Arg12 is part of an exosite for thrombomodulin or that cleavage at Arg12 accelerates thrombomodulin-mediated TAFI activation.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 07/2014; 12(10). DOI:10.1111/jth.12674 · 5.55 Impact Factor
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    ABSTRACT: Background: To study the regenerative capacity of the endothelium in patients with coronary artery disease (CAD), we cultured blood outgrowth endothelial cells (BOECs) of patients with premature CAD and their first degree relatives (FDR). Additionally we evaluated the influence of statin treatment on circulating BOEC precursors in subjects with subclinical atherosclerosis. Methods and Results: Patients with premature CAD (men <51 yr, women <56 yr) and their FDRs were included. Based on coronary calcification (CAC) scores FDRs were divided in a group of healthy subjects (CAC = 0) and subjects with subclinical atherosclerosis (CAC>0). We did not observe differences in the number of BOEC colonies and proliferation between premature CAD patients and FDRs. FDRs with subclinical atherosclerosis had lower colony numbers compared with healthy FDRs, however this was not statistically significant, and BOEC proliferation was significantly impaired (OR = 0.45, 95% CI 0.21-0.96). Unexpectedly, the number of BOEC colonies and BOEC proliferation were similar for premature CAD patients and healthy FDRs. Since a considerable number of premature CAD patients used statins, we studied the number of BOEC precursors as well as their proliferative capacity in ten individuals with subclinical atherosclerosis, before and after statin therapy. Interestingly, FDRs with subclinical atherosclerosis showed a significant increase in the number of BOEC colonies after statin therapy. Conclusion: BOEC proliferation of subjects with subclinical atherosclerosis is impaired compared with healthy controls. In these subjects, statin therapy significantly increased the number of circulating BOEC precursors as well as their proliferative capacity, revealing a beneficial effect of statins on endothelial regeneration.
    PLoS ONE 06/2014; 9(6):e99890. DOI:10.1371/journal.pone.0099890 · 3.53 Impact Factor

Publication Stats

7k Citations
1,643.09 Total Impact Points

Institutions

  • 2004–2015
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Laboratory of Experimental Internal Medicine
      Amsterdamo, North Holland, Netherlands
  • 2001–2015
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Internal Medicine
      • • Department of Vascular Medicine
      Amsterdamo, North Holland, Netherlands
  • 2013
    • Universitair Medisch Centrum Groningen
      • Department of Surgery
      Groningen, Province of Groningen, Netherlands
  • 2006–2011
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 1987–2010
    • University Medical Center Utrecht
      • • Department of Clinical Chemistry and Haematology
      • • Department of Hematology
      Utrecht, Utrecht, Netherlands
  • 2009
    • Leiden University Medical Centre
      • Department of Clinical Epidemiology
      Leiden, South Holland, Netherlands
  • 2000–2007
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1987–2003
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 1990–1992
    • University of Washington Seattle
      • Department of Biochemistry
      Seattle, WA, United States