Joost C M Meijers

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (344)1963.79 Total impact

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    ABSTRACT: Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation and data suggests that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor Dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed Dabigatran (10mg/g) or placebo chow during a three-week HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with Dabigatran levels reported in human trials. Surprisingly, Dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P<0.05) and decreased IL-4 levels (P<0.01), without influencing other HDM-induced responses. Considering the limited effects of Dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of Dabigatran in patients with asthma. Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    AJP Lung Cellular and Molecular Physiology 08/2015; DOI:10.1152/ajplung.00102.2015 · 4.04 Impact Factor
  • Cheung YW · Barco S · Hutten BA · J.C.M. Meijers · Middeldorp S · Coppens M.
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    ABSTRACT: BACKGROUND: Four-factor prothrombin complex concentrate (PCC, Cofact, Sanquin Blood Supply) 50 IU/kg increased thrombin generation beyond baseline values in healthy, rivaroxaban-treated subjects. OBJECTIVE: Assess whether infusion with doses of 37.5 and 25 IU/kg of PCC reverses the anticoagulant effect of high dose apixaban, another oral direct factor Xa inhibitor. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 6 healthy subjects received twice-daily apixaban 10 mg for 3.5 days followed by a single bolus of PCC 37.5 IU/kg, PCC 25 IU/kg, or placebo. The primary outcome was the effect of PCC 15 minutes after infusion on thrombin generation (endogenous thrombin potential [ETP]); secondary outcomes were the immediate effect of PCC on prothrombin time (PT) and the effect of PCC compared with placebo over 24 hours on ETP and PT. RESULTS: Fifteen minutes after infusion of 37.5 IU/kg and 25 IU/kg PCC, ETP increased from 41±11% to 56±23% (p=0.06) and from 44±12% to 51±15% (p=0.03), respectively. ETP significantly differed over time between PCC 37.5 IU/kg and placebo during 24 hours after infusion (p<0.01). Both PCC dosages restored apixaban-induced PT prolongation after 15 minutes (p<0.01) which was sustained over 24 hours. CONCLUSION: Both PCC 37.5 IU/kg and 25 IU/kg improved coagulation parameters in healthy subjects, suggestive of partial reversal of the anticoagulant effect of apixaban. This implies that PCC might be considered in patients with apixaban-associated bleeding. However, ETP was not immediately restored to pre-apixaban levels suggesting that these dosages are too low to instantly and fully restore haemostasis at peak apixaban levels.
    Journal of Thrombosis and Haemostasis 08/2015; DOI:10.1111/jth.13115 · 5.55 Impact Factor
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    ABSTRACT: Previous studies concluded that haemorrhage is one of the most accurate prognostic factors of mortality in leptospirosis. Therefore, endothelial cell activation was investigated in relation to disease severity in severe leptospirosis. Prospective cohort study of severe leptospirosis patients. Plasma levels of sE-selectin and Von Willebrand factor (VWF) were determined. Consequently, an in vitro endothelial cell model was used to assess endothelial activation after exposure to virulent Leptospira. Finally, immune activation, as a potential contributing factor to endothelial cell activation, was determined by soluble IL2-receptor (sIL-2r) and soluble Fas-ligand (sFasL) levels. Plasma levels of sE-selectin and VWF strongly increased in patients compared to healthy controls. Furthermore, sE-selectin was significantly elevated (203 ng/ml vs. 157 ng/ml, p < 0.05) in survivors compared to non-survivors. Endothelial cells exposed to virulent Leptospira showed increased VWF expression. E-selectin and ICAM-1 expression did not change. Immunohistochemistry revealed the presence of intracellular Leptospira and qPCR suggested replication. In vivo analysis showed that increased levels of sFasL and sIL-2r were both strongly associated with mortality. Furthermore sIL-2r levels were increased in patients that developed bleeding and significantly correlated to duration of hospital stay. Markers of endothelial activation and immune activation were associated with disease severity in leptospirosis patients. Copyright © 2015. Published by Elsevier Ltd.
    The Journal of infection 06/2015; DOI:10.1016/j.jinf.2015.05.016 · 4.02 Impact Factor
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    ABSTRACT: Circulating microRNAs (miRNAs) have been reported as biomarkers for disease diagnosis. RT-qPCR is most commonly used to detect miRNAs; however, no consensus on the most appropriate method for data normalization exists. Via a standardized selection method, we aimed to determine separate miRNA normalization panels for RT-qPCR measurements on whole blood, platelets, and serum. Candidate miRNAs were selected from studies describing circulating miRNA microarray data in the Gene Expression Omnibus or ArrayExpress. miRNA expression data of healthy controls were retrieved from each study. For each sample type, we selected those miRNAs that were least variable and sufficiently highly expressed in multiple microarray experiments, performed on at least 2 different platforms. Stability of the candidate miRNAs was assessed using NormFinder and geNorm algorithms in a RT-qPCR cohort of 10 patients with coronary artery disease and 10 healthy controls. We selected miRNA normalization panels for RT-qPCR measurements on whole blood, platelets, and serum. As a validation, we assessed the precision of all 3 panels in 3 independent RT-qPCR cohorts and compared this with normalization for miR-16 or RNU6B. The proposed normalization panels for whole blood, platelets, and serum show better precision than normalization for miR-16 or RNU6B.-Kok, M. G. M., Halliani, A., Moerland, P. D., Meijers, J. C. M., Creemers, E. E., Pinto-Sietsma, S.-J. Normalization panels for the reliable quantification of circulating microRNAs by RT-qPCR. © FASEB.
    The FASEB Journal 05/2015; DOI:10.1096/fj.15-271312 · 5.48 Impact Factor
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    ABSTRACT: Activation of thrombin is a critical determinant in many physiological and pathological processes including haemostasis and inflammation. Under physiological conditions many of these functions are involved in wound healing or eradication of an invading pathogen. However, when activated systemically, thrombin can contribute to severe and life-threatening conditions by causing complications such as multiple multi-organ failure and disseminated intravascular coagulation. In the present study we investigated how the activity of thrombin is modulated when it is bound to the surface of Streptococcus pyogenes. Our data show that S. pyogenes bacteria become covered with a proteinaceous layer when incubated with human plasma, and that thrombin is a constituent of this layer. Though the coagulation factor is found attached to the bacteria with a functional active site, thrombin has lost its capacity to interact with its natural substrates and inhibitors. Thus, the interaction of bacteria with human plasma renders thrombin completely inoperable at the streptococcal surface. This could represent a host defense mechanism to avoid systemic activation of coagulation which could be otherwise induced when bacteria enter the circulation and cause systemic infection.
    Thrombosis and Haemostasis 05/2015; 114(3). DOI:10.1160/TH15-02-0127 · 5.76 Impact Factor
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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.
    Frontiers in Microbiology 04/2015; 6. DOI:10.3389/fmicb.2015.00220 · 3.94 Impact Factor
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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; 15(7). 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; 13(7). 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; 13(6). 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.
    Biochimica et Biophysica Acta - Clinical 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; 13(6). 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 · 10.43 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; 135(3). DOI:10.1016/j.thromres.2014.12.020 · 2.43 Impact Factor
  • British Journal of Haematology 12/2014; 169(6). 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.
    Hematology 12/2014; 2014(1):60-5. DOI:10.1182/asheducation-2014.1.60 · 2.86 Impact Factor
  • British Journal of Haematology 11/2014; 169(2). 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; 70(4). 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

Publication Stats

9k Citations
1,963.79 Total Impact Points


  • 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
      • • Academic Medical Center
      • • Department of Vascular Medicine
      Amsterdamo, North Holland, Netherlands
  • 2013
    • University of Groningen
      • Department of Surgery
      Groningen, Province of Groningen, 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
  • 2006–2007
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 2000–2007
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1987–2003
    • Utrecht University
      • Department of Hematology
      Utrecht, Utrecht, Netherlands
  • 1990–1992
    • University of Washington Seattle
      • Department of Biochemistry
      Seattle, WA, United States
  • 1988
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands