Joost C M Meijers

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (374)2100.02 Total impact

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    ABSTRACT: Background: Epidemiologic studies have shown that patients with severe asthma have increased risk of pulmonary embolism, in particular patients with frequent asthma exacerbations. Therefore, we hypothesized that asthma exacerbations are associated with increased hemostatic activity. Objective: To investigate if induced loss of asthma control is associated with changes in coagulation and fibrinolytic parameters in peripheral blood. Methods: We performed a prospective, inhaled steroid-withdrawal study in 23 patients with moderate to moderately severe asthma, consisting of a baseline visit and a visit after loss of asthma control. During the visits we measured asthma control questionnaire (ACQ), atopy, lung function, inflammatory markers (eosinophils and neutrophils), and hemostatic parameters in plasma. Results: Complete cessation of inhaled corticosteroids led to a loss of asthma control in 22 out of 23 patients. We found increased asthma symptoms (ACQ 0.9 vs. 2.9, p<0.01), significantly reduced lung function (forced expiratory volume in 1 second (FEV1 ) 3.51L vs. 3.13L, p<0.01) and increased levels of eosinophils in plasma (0.26x10(E9) /L vs. 0.16x10(E9) /L, p=0.03) in patients after loss of asthma control. However, we observed no significant changes in the coagulation and fibrinolysis parameters. Conclusion: Loss of asthma control after cessation of inhaled corticosteroids does not lead to increased hemostatic activation in patients with moderate to moderately severe asthma. This suggests that more severe inflammation or additional risk factors are required for activation of coagulation or reduction of fibrinolysis in asthma. This article is protected by copyright. All rights reserved.
    Clinical & Experimental Allergy 10/2015; DOI:10.1111/cea.12667 · 4.77 Impact Factor
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    M L R Cunha · J C M Meijers · S Middeldorp ·
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    ABSTRACT: Despite knowledge of various inherited risk factors associated with venous thromboembolism (VTE), no definite cause can be found in about 50% of patients. The application of data-driven searches such as GWAS has not been able to identify genetic variants with implications for clinical care, and unexplained heritability remains. In the past years, the development of several so-called next generation sequencing (NGS) platforms is offering the possibility of generating fast, inexpensive and accurate genomic information. However, so far their application to VTE has been very limited. Here we review basic concepts of NGS data analysis and explore the application of NGS technology to VTE. We provide both computational and biological viewpoints to discuss potentials and challenges of NGS-based studies.
    Thrombosis and Haemostasis 10/2015; 114(5). DOI:10.1160/TH15-05-0411 · 4.98 Impact Factor

  • Journal of the American College of Cardiology 10/2015; 66(15):B91-B92. DOI:10.1016/j.jacc.2015.08.919 · 16.50 Impact Factor
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    ABSTRACT: Asthma patients show evidence of a procoagulant state in their airways, accompanied by an impaired function of the anticoagulant protein C system. We aimed to study the effect of recombinant human activated protein C (rhAPC) in allergic asthma patients.We conducted a randomised, double-blind, placebo-controlled, proof-of-concept study in house dust mite (HDM) allergic asthma patients. Patients were randomised to receive intravenous rhAPC (24; n=12) or placebo (n=12) for 11 h. 4 h after the start of infusion, a first bronchoscopy was performed to challenge one lung segment with saline (control) and a contralateral segment with a combination of HDM extract and lipopolysaccharide (HDM+LPS), thereby mimicking environmental house dust exposure. A second bronchoscopy was conducted 8 h after intrabronchial challenge to obtain bronchoalveolar lavage fluid (BALF).rhAPC did not influence HDM+LPS induced procoagulant changes in the lung. In contrast, rhAPC reduced BALF leukocyte counts by 43% relative to placebo, caused by an inhibitory effect on neutrophil influx (64% reduction), while leaving eosinophil influx unaltered. rhAPC also reduced neutrophil degranulation products in the airways.Intravenous rhAPC attenuates HDM+LPS-induced neutrophil migration and protein release in allergic asthma patients by an effect that does not rely on coagulation inhibition.
    European Respiratory Journal 09/2015; DOI:10.1183/13993003.00459-2015 · 7.64 Impact Factor
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    ABSTRACT: Mortality and morbidity in bacterial meningitis results from the pro-inflammatory response and dysregulation of coagulation and fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is activated (TAFIa) by free thrombin or in complex with thrombomodulin, plays an anti-fibrinolytic role during fibrin clot degradation, but also has an anti-inflammatory role by inactivating proinflammatory mediators, such as complement activation products. To assess the role of TAFI in pneumococcal meningitis. We performed a prospective nationwide genetic association study in patients with bacterial meningitis, determined TAFI and complement levels in CSF, and assessed the function of TAFI in a pneumococcal meningitis mouse model using Cpb2 (TAFI) knockout mice. polymorphisms (reference sequence: rs1926447 and rs3742264) in the CPB2 gene, coding for TAFI, were related with development of systemic complications in patients with pneumococcal meningitis. Higher protein levels of TAFI in CSF were significantly associated with CSF complement levels (C3a, iC3b and C5b-9) and with more systemic complications in patients with bacterial meningitis. The risk allele of rs1926447 (TT) was associated with higher levels of TAFI in CSF. In the murine model, consistent with the human data, Cpb2-deficient mice had decreased disease severity reflected by lower mortality, attenuated cytokine levels and bacterial outgrowth in the systemic compartment during disease, without differences in the brain compartment, as compared with wild-type mice. These findings suggest that TAFI plays an important role during pneumococcal meningitis, which is likely to be mediated through inhibition of the complement system, and influences the occurrence of systemic complications and inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 09/2015; DOI:10.1111/jth.13132 · 5.72 Impact Factor
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    Tom Plug · J. Arnoud Marquart · Pauline F. Marx · Joost C.M. Meijers ·
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    ABSTRACT: Background Thrombin-activatable fibrinolysis inhibitor (TAFI) is a risk factor for coronary heart disease. TAFI is proteolytically activated by thrombin, the thrombin-thrombomodulin complex and plasmin. Once active, it dampens fibrinolysis and inflammation. The aim of this study was to generate TAFI-derived peptides that specifically modulate TAFI activation and activity.Methods34 overlapping TAFI peptides, and modifications thereof, were synthesized. The effects of these peptides on TAFI activation and TAFIa activity were determined. In addition, the binding of the peptides to thrombin were determined.ResultsFour peptides (peptides 2, 18, 19 and 34) inhibited TAFI activation and two peptides (peptides 14 and 24) inhibited TAFIa activity directly. Peptide 2 (Arg12-Glu28) and peptide 34 (Cys383-Val401) inhibited TAFI activation by the thrombin-thrombomodulin complex with IC50 values of 41.9±9.1 and 6.1±0.9 μM, respectively. However, no inhibition was observed in the absence of thrombomodulin. This suggests that the regions Arg12-Glu28 and Cys383-Val401 in TAFI are involved in thrombomodulin-mediated TAFI activation. Peptide 18 (Gly205-Ser221) and peptide 19 (Arg214-Asp232) inhibited TAFI activation by thrombin and the thrombin-thrombomodulin complex. Furthermore, these peptides bound to thrombin (KD: 1.5±0.4 and 0.52±0.07 μM for peptides 18 and 19 respectively), suggesting that Gly205-Asp232 of TAFI is involved in binding to thrombin. Peptide 14 (His159-His175) inhibited TAFIa activity. The inhibition was TAFIa specific, since no effect on the homologous enzyme carboxypeptidase B was observed.ConclusionsTAFI-derived peptides show promise as new tools to modulate TAFI activation and TAFIa activity. Furthermore, these peptides revealed potential binding sites on TAFI for thrombin and the thrombin-thrombomodulin complex.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 09/2015; DOI:10.1111/jth.13133 · 5.72 Impact Factor
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    ABSTRACT: Introduction: Protein Z (PZ)-dependent protease inhibitor (ZPI) is a serine protease inhibitor that efficiently inhibits activated factor X when ZPI is in complex with PZ. We previously reported significantly higher concentrations of plasma ZPI (and PZ) in women during normal pregnancy than in non-pregnant women. Methods: We explored the possible contribution of estrogen to the ZPI levels in patients with or without bilateral oophorectomy (OVX), which induces artificial menopause where blood estrogen levels drastically decrease. One hundred ninety-one pre-menopausal Japanese women who underwent open hysterectomy owing to neoplasms participated in this study and were divided into two groups: 98 OVX and 93 Non-OVX cases. Plasma ZPI was measured by ELISA. Results and conclusion: Contrary to our working hypothesis, plasma ZPI levels increased significantly in the OVX group after surgery when compared with the pre-operation levels. When these patients were individually analyzed, their ZPI value also rose significantly from pre-operation to post-operation levels. In contrast, plasma PZ levels remained unchanged. The significantly increased ZPI and unchanged PZ levels were also observed in the Non-OVX group. The increased ZPI levels were not significantly related to 17β-estradiol, luteinizing hormone or follicular stimulating hormone levels, clearly indicating that estrogen did not contribute to the plasma ZPI concentrations. Typical acute phase reactants fibrinogen and C-reactive protein (CRP) were also significantly elevated after surgery in both OVX and Non-OVX groups. However, only weakly significant linear relationships were observed between ZPI and fibrinogen or CRP, indicating the presence of alternative regulatory mechanisms underlying their plasma concentrations.
    Thrombosis Research 09/2015; DOI:10.1016/j.thromres.2015.09.020 · 2.45 Impact Factor
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    ABSTRACT: Factor XIII(a) [FXIII(a)] stabilizes clots and increases resistance to fibrinolysis and mechanical disruption. FXIIIa also mediates red blood cell (RBC) retention in contracting clots and determines venous thrombus size, suggesting FXIII(a) is a potential target for reducing venous thrombosis. However, the mechanism by which FXIIIa retains RBCs in clots is unknown. We determined the effect of FXIII(a) on human and murine clot weight and composition. Real-time microscopy revealed extensive RBC loss from clots formed in the absence of FXIIIa activity, and RBCs exhibited transient deformation as they exited the clots. Fibrin band-shift assays and flow cytometry did not reveal crosslinking of fibrin or FXIIIa substrates to RBCs, suggesting FXIIIa does not crosslink RBCs directly to the clot. RBCs were retained in clots from mice deficient in α2-antiplasmin, thrombin-activatable fibrinolysis inhibitor, or fibronectin, indicating RBC retention does not depend on these FXIIIa substrates. RBC retention in clots was positively-correlated with fibrin network density; however, FXIIIa inhibition reduced RBC retention at all network densities. FXIIIa inhibition reduced RBC retention in clots formed with fibrinogen that lacks γ-chain crosslinking sites, but not in clots that lack α-chain crosslinking sites. Moreover, FXIIIa inhibitor concentrations that primarily block α-, but not γ-, chain crosslinking decreased RBC retention in clots. These data indicate FXIIIa-dependent retention of RBCs in clots is mediated by fibrin α-chain crosslinking. These findings expose a newly-recognized, essential role for fibrin crosslinking during whole blood clot formation and consolidation, and establish FXIIIa activity as a key determinant of venous thrombus composition and size. Copyright © 2015 American Society of Hematology.
    Blood 08/2015; 126(16). DOI:10.1182/blood-2015-06-652263 · 10.45 Impact Factor
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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; 309(8):ajplung.00102.2015. DOI:10.1152/ajplung.00102.2015 · 4.08 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 · 5.72 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; 71(4). DOI:10.1016/j.jinf.2015.05.016 · 4.44 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; 29(9). DOI:10.1096/fj.15-271312 · 5.04 Impact Factor
  • C Naudin · S M Hurley · E Malmström · T Plug · O Shannon · J C M Meijers · M Mörgelin · L Björck · H Herwald ·
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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 · 4.98 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 · 3.99 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 · 5.68 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 · 4.98 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 · 5.72 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 · 5.72 Impact Factor
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    ABSTRACT: Background: 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. Methods: A total of 37 obese subjects who underwent hip surgery were randomized to subcutaneous liraglutide or placebo for 4 consecutive days, starting one day prior to surgery. Glucose levels and coagulation indices at three fixed time-points (pre-operative, 2. h post-operative and 3. days post-operative) were measured. Results: Liraglutide reduced glucose at day three post-surgery (median glucose (IQR) liraglutide 5.5 (5.2-5.7) vs. placebo 5.8 (5.5-6.2); difference 0.3. mmol/L, P=. 0.04). Changes in 6 out of 8 coagulation indices studied did not differ between the two groups. Only D-dimer levels were significantly lower in the liraglutide group at day three post-surgery and FVIII levels were significantly higher in the liraglutide group 2. h post-surgery. Conclusion: Although the human GLP-1 analogue liraglutide moderately reduced post-operative blood glucose levels in non-diabetic and prediabetic obese patients undergoing elective hip surgery, no changes were observed with respect to 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 · 5.72 Impact Factor

Publication Stats

10k Citations
2,100.02 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
  • 2007-2009
    • Leiden University Medical Centre
      • Department of Clinical Epidemiology
      Leiden, South Holland, Netherlands
  • 2006-2007
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      لا هویا, California, United States
  • 2000-2005
    • 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, Washington, United States
  • 1988
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands