Joost C M Meijers

Academisch Medisch Centrum Universiteit van Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (365)2069.97 Total impact

  • 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 · 6.08 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 · 6.08 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 · 11.04 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; 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 · 4.94 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; DOI:10.1016/j.jinf.2014.10.006 · 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.
  • 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 · 6.08 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
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    ABSTRACT: Objective-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. Approach and Results-Atherosclerotic plaques in the carotid arteries of Apoe(-/-) mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (P<0.05) in factor XI antisense oligonucleotide-treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense-treated animals. No neutrophils were present. Conclusions-Factor XI antisense oligonucleotides safely prevent thrombus formation on acutely ruptured atherosclerotic plaques in mice. Furthermore, perturbed carotid arteries from factor XI antisense-treated animals show a less severe inflammatory response.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2014; 34(8). DOI:10.1161/ATVBAHA.114.303209 · 6.34 Impact Factor
  • Niraj Mishra, Joost C. M. Meijers, Paul J. Declerck, Ann Gils
    Thrombosis Research 06/2014; 133(6). DOI:10.1016/j.thromres.2014.03.051 · 2.43 Impact Factor
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    ABSTRACT: Objective-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. Approach and Results-Plaque rupture after ultrasound treatment evoked immediate formation of subocclusive thrombi in the carotid arteries of Apoe(-/-) mice, which became unstable in the presence of structurally different FXIIa inhibitors. In contrast, inhibition of FVIIa reduced thrombus size at a more initial stage without affecting embolization. Genetic deficiency in FXII (human and mouse) or FXI (mouse) reduced ex vivo whole-blood thrombus and fibrin formation on immobilized plaque homogenates. Localization studies by confocal microscopy indicated that FXIIa bound to thrombi and fibrin particularly in luminal-exposed thrombus areas. Conclusions-The FVIIa- and FXIIa-triggered coagulation pathways have distinct but complementary roles in atherothrombus formation. The tissue factor-FVIIa pathway contributes to initial thrombus buildup, whereas FXIIa bound to thrombi ensures thrombus stability.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2014; 34(8). DOI:10.1161/ATVBAHA.114.303315 · 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). DOI:10.1160/TH13-09-0798 · 5.76 Impact Factor

Publication Stats

9k Citations
2,069.97 Total Impact Points


  • 2000–2015
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Internal Medicine
      • • Department of Vascular Medicine
      Amsterdamo, North Holland, Netherlands
    • Maastricht University
      • Department of Biochemistry
      Maestricht, Limburg, Netherlands
  • 2004–2014
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Laboratory of Experimental Internal Medicine
      Amsterdamo, North Holland, 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
  • 2007
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1987–2003
    • Utrecht University
      • • Institute of Biomembranes
      • • Department of Hematology
      Utrecht, Utrecht, Netherlands
  • 1990–1992
    • University of Washington Seattle
      • Department of Biochemistry
      Seattle, WA, United States