Joost C M Meijers

Academic Medical Center (AMC), Amsterdamo, North Holland, Netherlands

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Publications (360)2022.33 Total impact

  • American Journal of Respiratory and Critical Care Medicine 01/2015; 191(2):230-3. · 11.04 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; · 2.43 Impact Factor
  • British Journal of Haematology 12/2014; · 4.96 Impact Factor
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    ABSTRACT: Background During pneumonia, inflammation and coagulation are activated as part of anti-bacterial host defense. Activated protein C (APC) has anticoagulant and anti-inflammatory properties and until recently was a registered drug for the treatment of severe sepsis. Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia.Methods We aimed to investigate the effect of high APC levels during experimental pneumococcal pneumonia. Wild type (WT) and APC overexpressing (APChigh)-mice were intranasally infected with S. pneumoniae and sacrificed after 6, 24 or 48 hours, or followed in a survival study.ResultsIn comparison to WT mice, APChigh-mice showed decreased bacterial dissemination to liver and spleen, while no differences in bacterial loads were detected at the primary site of infection. Although no differences in the extent of lung histopathology were seen, APChigh-mice showed a significantly decreased recruitment of neutrophils into lung tissue and bronchoalveolar lavage fluid. Activation of coagulation was not altered in APChigh-mice. No differences in survival were observed between WT and APChigh-mice (P =0.06).ConclusionAPC overexpression improves host defense during experimental pneumococcal pneumonia. This knowledge may add to a better understanding of the regulation of the inflammatory and procoagulant responses during severe Gram-positive pneumonia.
    BMC Infectious Diseases 11/2014; 14(1):559. · 2.56 Impact Factor
  • British Journal of Haematology 11/2014; · 4.94 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; · 4.02 Impact Factor
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    ABSTRACT: 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.
    PLoS neglected tropical diseases. 10/2014; 8(10):e3214.
  • Atherosclerosis 08/2014; 235(2):e17-e18. · 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; · 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). · 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; · 6.08 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 06/2014; 9(6):e99890. · 3.53 Impact Factor
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    ABSTRACT: Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2014; · 6.34 Impact Factor
  • Niraj Mishra, Joost C.M. Meijers, Paul J. Declerck, Ann Gils
    Thrombosis Research 06/2014; · 2.43 Impact Factor
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    ABSTRACT: Atherothrombosis is the main cause of myocardial infarction and ischemic stroke. Although the extrinsic (tissue factor-factor VIIa [FVIIa]) pathway is considered as a major trigger of coagulation in atherothrombosis, the role of the intrinsic coagulation pathway via coagulation FXII herein is unknown. Here, we studied the roles of the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques both in vivo and ex vivo.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2014; · 5.53 Impact Factor
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    ABSTRACT: Recombinant factor VIIa (rFVIIa) is registered for treatment of inhibitor-complicated haemophilia, and a once-daily prophylactic administration of rFVIIa is successful in reducing the number of bleeding events. This suggests that a single rFVIIa dose has a pro-haemostatic effect up to 24 hours (h), which is difficult to explain given its half-life of 2 h. In this study, six pigs received a 90 µg/kg rFVIIa bolus. Plasma was collected and platelets were isolated at various time points up to 48 h, and analysed for FVIIa levels and associated haemostatic activity. Elevated plasma FVIIa levels were detected up to 24 h post-administration (36 (32-56) mU/ml [median (interquartile range [IQR]), 24 h] vs 2 (2-14) mU/ml [baseline]). Corresponding prothrombin time (PT) values remained shortened compared to baseline until 24 h post-administration (9.4 (9.3-9.9) seconds (s) [24 h] vs 10.5 (10.2-11.0) s [baseline], p ≤0.01). The lag time in thrombin generation testing as well as clotting times in plasma-based assays were shortened up to 12 or 24 h post-administration, respectively (lag times 1.8 (1.7-2.1) minutes (min) [12 h] vs 2.3 (2.3-2.6) min [baseline], p ≤0.01 and clotting times 3.8 (3.2-3.9) min [24 h] vs 5.2 (4.6-5.5) min [baseline], p ≤0.001). Platelet FVIIa levels were elevated up to 48 h (7.7 (3.4-9.0) ng VIIa/mg actin [48 h] vs 2.5 (0.7-4.8) ng VIIa/mg actin [baseline]). In conclusion, elevated and haemostatically active plasma and platelet FVIIa levels are detectable up to 24-48 h following rFVIIa administration in pigs. This prolonged pro-haemostatic effect of FVIIa may explain the prophylactic efficacy of a once-daily rFVIIa treatment.
    Thrombosis and Haemostasis 04/2014; 112(2). · 5.76 Impact Factor
  • Joost C M Meijers
    Blood 03/2014; 123(11):1629. · 9.78 Impact Factor
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    ABSTRACT: BackgroundA common complication after aneurysmal subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI), which is associated with vasospasm and other mechanisms such as microthrombosis. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity plays a role in the prevention of thrombus formation in the cerebral microvasculature. Previously, we observed that patients with DCI have lower levels of ADAMTS13.Objectives To examine if recombinant human ADAMTS13 (rADAMTS13) reduces cerebral microthrombi formation and brain injury in an experimental mouse model of SAH including wildtype and ADAMTS13 -/- mice.Methods Experimental SAH was induced using the prechiasmatic blood injection model. The following experimental groups were investigated: 1) C57BL/6J mice (n=10); 2) C57BL/6J mice (n=10) treated with rADAMTS13 20 minutes after SAH; 3) ADAMTS13 -/- mice (n=10); and 4) ADAMTS13 -/- mice (n=10) treated with rADAMTS13 20 minutes after SAH. Mice were sacrificed at 48 hours. Results are presented as the mean with standard errors of the mean.ResultsInfusion with rADAMTS13 reduced the extent of microthrombosis with approximately 50% both in wildtype mice (mean fibrinogen area: 0.28±0.09% versus 0.15±0.04%; p=0.20) and ADAMTS13 -/- mice (mean fibrinogen area: 0.32±0.05% versus 0.16±0.03%; p=0.016). In addition, rADAMTS13 reduced brain injury with more than 60% both in wildtype mice (mean microglia area: 0.65±0.18% versus 0.18±0.04%; p=0.013) and ADAMTS13 -/- mice (mean microglia area: 1.24±0.36% versus 0.42±0.13%; p=0.077).Conclusions Our results support the further study of rADAMTS13 as a treatment option for the prevention of microthrombosis and brain injury after SAH.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 03/2014; · 6.08 Impact Factor
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    ABSTRACT: Treatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known. We evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis. Thirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs. Addition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001). The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma. The anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis.
    PLoS ONE 02/2014; 9(2):e88390. · 3.53 Impact Factor
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    ABSTRACT: Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2-EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR-overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response.
    Thrombosis and Haemostasis 01/2014; 111(5). · 5.76 Impact Factor

Publication Stats

8k Citations
2,022.33 Total Impact Points


  • 2006–2014
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 2002–2014
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2000–2014
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Center for Infection and Immunity Amsterdam
      • • Department of Vascular Medicine
      • • Academic Medical Center
      • • Department of Cardiology and Cardio-thoracic Surgery
      Amsterdamo, North Holland, Netherlands
  • 2013
    • Universitair Medisch Centrum Groningen
      • Department of Surgery
      Groningen, Province of Groningen, Netherlands
    • University of Groningen
      • Department of Surgery
      Groningen, Province of Groningen, Netherlands
  • 1987–2011
    • University Medical Center Utrecht
      • • Department of Clinical Chemistry and Haematology
      • • Department of Hematology
      Utrecht, Utrecht, Netherlands
  • 2007–2009
    • Lund University
      • Department of Clinical Sciences
      Lund, Skane, Sweden
  • 2005–2009
    • Leiden University Medical Centre
      • • Department of Clinical Epidemiology
      • • Department of Hematology
      Leiden, South Holland, Netherlands
  • 2008
    • KU Leuven
      • Faculty of Pharmaceutical Sciences
      Leuven, VLG, Belgium
  • 1990–2006
    • University of Washington Seattle
      • • Department of Epidemiology
      • • Department of Biochemistry
      Seattle, WA, United States
  • 2004
    • Slotervaartziekenhuis
      Amsterdamo, North Holland, Netherlands
  • 1987–2002
    • Utrecht University
      • • Institute of Biomembranes
      • • Department of Hematology
      Utrecht, Utrecht, Netherlands
  • 2001
    • Slotervaart Ziekenhuis Amsterdam
      Amsterdamo, North Holland, Netherlands