M de Haas

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (205)858 Total impact

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    ABSTRACT: Objective: To evaluate the effect of red blood cell (RBC) antibody screening in the 27th week of pregnancy in Rhc-negative women, on detection of alloimmunisation, undetected at first trimester screening ('late' alloimmunisation), and subsequent haemolytic disease of the fetus and newborn (HDFN), to assess risk factors for late alloimmunisation. Design: Prospective cohort and nested case-control study. Setting: The Netherlands. Population: Two-year nationwide cohort. Methods: Prospective inclusion of Rhc-negative women with negative first trimester screening and of screen-negative controls. Assessment of incidence and numbers needed to screen (NNS) of late alloimmunisation and HDFN; logistic regression analysis to establish risk factors for late alloimmunisation. Main outcome measures: Late alloimmunisation, HDFN. Results: Late alloimmunisation occurred in 99 of 62 096 (0.159%) Rhc-negative women; 90% had c/E antibodies and 10% non-Rhesus antibodies. Severe HDFN (fetal/neonatal transfusion) occurred in two of 62 096 (0.003%) of Rhc-negative women and 2% of late alloimmunisations; moderate HDFN (phototherapy) occurred in 20 children [22.5%; 95% confidence interval (CI), 13.8-31.1%]. Perinatal survival was 100%. The NNS to detect one HDFN case was 2823 (31 048 for severe, 3105 for moderate HDFN). Significant risk factors were former blood transfusion [odds ratio (OR), 10.4; 95% CI, 1.14-94.9], parity (P-1: OR, 11.8; 95% CI, 3.00-46.5; P > 1: OR, 7.77; 95% CI, 1.70-35.4) and amniocentesis/chorionic villus sampling during current pregnancy (OR, 9.20; 95% CI, 1.16-72.9). Conclusions: Additional screening of Rhc-negative women improved the detection of late alloimmunisation and HDFN, facilitating timely treatment, with a NNS of 2823. Independent risk factors for late alloimmunisation were blood transfusion, parity and chorionic villus sampling/amniocentesis in the current pregnancy. The occurrence of most factors before the current pregnancy suggests a secondary immune response explaining most late alloimmunisations. Tweetable abstract: Third trimester screening for alloimmunisation in Rhc-neg women improves detection and treatment of severe HDFN.
    Full-text · Article · Dec 2015 · BJOG An International Journal of Obstetrics & Gynaecology

  • No preview · Article · Oct 2015 · Immunohematology / American Red Cross
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    ABSTRACT: In Autoimmune Hemolytic Anemia autoantibodies against erythrocytes lead to increased clearance of the erythrocytes, which in turn results in a potentially fatal hemolytic anemia. Depending on whether IgG or IgM antibodies are involved, response to therapy is different. Proper identification of the isotype of the anti-erythrocytes autoantibodies is therefore crucial. However, detection of IgM autoantibodies can be challenging. We therefore set out to improve anti-erythrocyte IgM detection. Direct detection using a FACS-based approach did not yield satisfactory improvements. Next, we analyzed whether presence of complement C3 on patient erythrocytes can be used for indirect detection of anti-erythrocyte IgM. To this end, we fractionated patient sera by size exclusion chromatography and tested which fractions yielded complement deposition on erythrocytes. Strikingly, we found that all patients with C3 on their erythrocytes according to standard diagnostic tests, had an IgM anti-erythrocyte component that could activate complement, even if no such autoantibody had been detected with any other test. This also included all tested patients with only IgG and C3 on their erythrocytes that would previously have been classified as a IgG-only mediated auto-immune hemolytic anemia. Depleting patient sera for either IgG or IgM and testing the remaining complement activation confirmed this result. In conclusion, complement activation in auto-immune hemolytic anemia is mostly IgM-mediated and the presence of covalent C3 on patients erythrocytes can be taken as footprint for the presence of anti-erythrocyte IgM. Based on this finding, we propose a diagnostic workflow that will aid in choosing the optimal treatment strategy.
    Preview · Article · Sep 2015 · Haematologica
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    ABSTRACT: Objective: Investigation of the accuracy and national implementation of foetal Rhesus-D typing (fRhD), introduced in 2011 for RhD-negative pregnant women. Design: Descriptive, national study. Method: Results of fRhD in pregnant women in the first year after implementation were compared to results from cord blood RhD typing of the child. Results: 0.05% of the fRhD results was false negative (9/18.383; 95% CI: 0.02-0.09), and 0.85% was false positive (157/18.383; 95% CI: 0.73-1.00). fRhD was incorrectly omitted in fewer than 1% of pregnant women. In 96.1% of the pregnant women, antenatal administration of anti-D prophylaxis was recorded. Recording of postnatal anti-D administration turned out to be lower (92%), but locally recorded data showed that postnatal anti-D was omitted in fewer than 2% of cases. Conclusion: The percentage of false negative fRhD was statistically significantly lower (p < 0.05) than the critical limit of 0.25% determined beforehand by the Programme Committee of the Dutch Antenatal Screening Programme for Infectious Diseases and Erythrocyte Immunisation. The percentage of false positive fRhD was considered acceptable, and implementation of fRhD was more or less complete. Routine RhD-typing on cord blood was therefore omitted from January 2013. Antenatal and postnatal anti-D administration is now specifically indicated for RhD-negative pregnant women when fRhD is positive, thus saving about 10,000 unnecessary antenatal anti-D administrations per year. RhD-typing on cord blood is now performed only if the RhD blood type of the child of a RhD-negative mother is unknown at delivery, if a positive fRhD was found for multiple births, and in exceptional situations, e.g. if fRhD typing is not possible due to a rare genetic variation.
    No preview · Article · Apr 2015 · Nederlands tijdschrift voor geneeskunde
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    ABSTRACT: To elucidate causes of false-positive fetal RHD screening results obtained with cell-free DNA. Fetal RHD screening was performed in 32,222 samples from RhD negative women by multiplex real-time-PCR in triplicate for RHD-exons 5 and 7 using cell-free DNA isolated from maternal plasma obtained in the 27(th) gestational week. PCR results were compared to cord blood serology in 25,789 pregnancies (80.04%). False-positive cases were analyzed. Known biological causes (RHD variant genes), technical causes of discordance and errors around blood sampling were investigated with leukocyte DNA from maternal and cord blood, and cell-free DNA from stored maternal plasma. Not only RHD but also Y-chromosome (DYS14) sequences were present in four plasma samples from RHD negative women bearing an RHD negative girl. Sample mix-up and other sampling errors could be excluded in three samples. These results indicate that false-positive fetal RHD screening results can be caused by cell-free DNA fragments in maternal plasma derived from a third cell line that is not representative for either the maternal genome or the genome of the vital fetus. We propose that remaining (cyto)trophoblasts of a vanishing twin are the underlying mechanism and we estimate a frequency of this phenomenon of 0.6%. © 2015 John Wiley & Sons, Ltd. This article is protected by copyright. All rights reserved.
    No preview · Article · Apr 2015 · Prenatal Diagnosis
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    ABSTRACT: Non-invasive fetal blood group typing.
    No preview · Article · Apr 2015 · ISBT Science Series
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    ABSTRACT: Haemolytic Disease of the Fetus and Newborn (HDFN) is caused by maternal alloimmunization against red blood cell antigens. In severe cases, HDFN may lead to fetal anaemia with a risk for fetal death and to severe forms of neonatal hyperbilirubinaemia with a risk for kernicterus. Most severe cases are caused by anti-D, despite the introduction of antental and postnatal anti-D immunoglobulin prophylaxis. In general, red blood cell antibody screening programmes are aimed to detect maternal alloimmunization early in pregnancy to facilitate the identification of high-risk cases to timely start antenatal and postnatal treatment. In this review, an overview of the clinical relevance of red cell alloantibodies in relation to occurrence of HDFN and recent views on prevention, screening and treatment options of HDFN are provided. © 2015 International Society of Blood Transfusion.
    Full-text · Article · Apr 2015 · Vox Sanguinis
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    ABSTRACT: Serologic determination of the Vel- phenotype is challenging due to variable Vel expression levels. In this study we investigated the genetic basis for weak Vel expression levels and developed a high-throughput genotyping assay to detect Vel- donors. In 548 random Caucasian and 107 Vel+(w) donors genetic variation in the SMIM1 gene was studied and correlated to Vel expression levels. A total of 3366 Caucasian, 621 black, and 333 Chinese donors were screened with a high-throughput genotyping assay targeting the SMIM1*64_80del allele. The Vel+(w) phenotype is in most cases caused by the presence of one SMIM1 allele carrying the major allele of the rs1175550 SNP in combination with a SMIM1*64_80del allele or in few cases caused by the presence of the SMIM1*152T>A or SMIM1*152T>G allele. In approximately 6% of Vel+(w) donors genetic factors in SMIM1 could not explain the weak expression. We excluded the possibility that lack of expression of another blood group system was correlated with weak Vel expression levels. Furthermore, using a high-throughput Vel genotyping assay we detected two Caucasian Vel- donors. Weak Vel expression levels are caused by multiple genetic factors in SMIM1 and probably also by other genetic or environmental factors. Due to the variation in Vel expression levels, serologic determination of the Vel- phenotype is difficult and a genotyping assay targeting the c.64_80del deletion in SMIM1 should be used to screen donors for the Vel- phenotype. © 2015 AABB.
    Full-text · Article · Feb 2015 · Transfusion
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    ABSTRACT: Immune-mediated platelet destruction is most frequently caused by allo- or autoantibodies via Fcγ-receptor (FcγR)-dependent phagocytosis. Disease severity can be predicted neither by antibody isotype nor by titer, indicating other factors to play a role. Here we show that the acute-phase protein C-Reactive Protein (CRP), a ligand for Fc-receptors on phagocytes, enhances antibody-mediated platelet destruction by human phagocytes in vitro, and in vivo in mice. Without anti-platelet antibodies, CRP was found to be inert towards platelets, but it bound to phosphorylcholine exposed after oxidation triggered by anti-platelet antibodies, thereby enhancing platelet phagocytosis. CRP levels were significantly elevated in patients with allo- and autoantibody-mediated thrombocytopenias compared to healthy controls. Within a week, IVIg-treatment in children with newly diagnosed immune thrombocytopenia led to significant decrease of CRP levels, increased platelet numbers and clinically decreased bleeding severity. Furthermore, the higher the level of CRP at diagnosis, the longer it took before stable platelet counts were reached. These data suggest CRP to amplify antibody-mediated platelet destruction and may in part explain the aggravation of thrombocytopenia upon infections. Hence, targeting CRP could offer new therapeutic opportunities for these patients. Copyright © 2014 American Society of Hematology.
    Full-text · Article · Dec 2014 · Blood
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    ABSTRACT: Childhood immune thrombocytopenia (ITP) is a rare autoimmune bleeding disorder. Most children recover within 6-12 months, but individual course is difficult to predict. We performed a systematic review and meta-analysis to identify predictors of chronic ITP. We found 1399 articles; after critical appraisal 54 studies were included. The following predictors of chronic ITP in children, assessed in at least three studies, have been identified: female gender (OR 1.17, 95% CI 1.04-1.31), older age at presentation (age ≥11 years OR 2.47, 95% CI 1.94-3.15), no preceding infection or vaccination (OR 3.08, 95 CI 2.19-4.32), insidious onset (OR 11.27, 95% CI 6.27-20.27), higher platelet counts at presentation (≥20 x10(9)/L: OR 2.15, 95% CI 1.63-2.83) presence of anti-nuclear antibodies (OR 2.87, 95% 1.57-5.24) and treatment with a combination of methylprednisolone and intravenous immunoglobulin (OR 2.67, 95% CI 1.44-4.96). Children with mucosal bleeding at diagnosis or treatment with intravenous immunoglobulin alone developed less often chronic ITP (OR 0.39; 95% CI 0.28-0.54 and OR 0.71; 95% CI 0.52-0.97, respectively). The protective effect of intravenous immunoglobulin is remarkable and needs confirmation in prospective randomized trials as well as future laboratory studies to elucidate the mechanism of this effect.
    No preview · Article · Oct 2014 · Blood

  • No preview · Conference Paper · Oct 2014
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    ABSTRACT: Background RhIG is obtained from hyperimmunized healthy anti-D donors (HIDs) boosted with D+ red blood cells (RBCs). One hypothesis for its mechanism of action is fast clearance of opsonized D+ RBCs through Fcγ receptor (FcγR)III. Levels of immunoglobulin (Ig)G Fc-fucosylation influence interactions with FcγRIII, with less Fc-fucosylation strengthening the interaction.Study Design and Methods Anti-D IgG1 Fc-glycosylation patterns in 93 plasma samples from 28 male and 28 female Dutch HIDs and RhIG were analyzed with mass spectrometry. The Fc-glycosylation profiles of HIDs were evaluated with regard to their immunization history.ResultsHID sera demonstrated clearly lowered anti-D Fc-fucosylation compared to normal IgG fucosylation (93%); this was more pronounced for female than for male HIDs (47% vs. 65%, p = 0.001). RhIG preparations from seven manufacturers varied greatly in the level of Fc-fucosylation (56%-91%). The level of fucosylation slightly increased upon repeated immunization, although it remained fairly constant over time. The RhIG from the different manufacturers all demonstrated increased Fc-galactosylation (64%-82%) compared to total IgG (38%-51%).Conclusion RhIG preparations vary in Fc-fucosylation and all demonstrate increased galactosylation. Despite not knowing the exact working mechanism, immunoprophylaxis could perhaps be optimized by selection of donors whose anti-D have low amounts of Fc-fucose, to increase the clearance activity of anti-D preparations, as well as high amounts of galactosylation, for anti-inflammatory effects. Implementing a biologic assay in the standardization of RhIG preparations might be considered.
    Full-text · Article · Oct 2014 · Transfusion
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    ABSTRACT: Background Alloantibodies directed against antigens of the Kell blood group system are clinically significant. In the Netherlands, the KEL1 antigen is determined in all blood donors. In this study, after phenotyping of KEL:1-positive donors, genotyping analysis was conducted in KEL:1,-2 donors to identify possible KEL*02 variant alleles.Study Design and MethodsA total of 407 donors with the KEL:1,-2 phenotype were genotyped for the KEL*01/02 polymorphism, followed by direct sequencing of the KEL gene if the KEL*02 allele was detected. Two K0 patients were also included. Transcript analysis was conducted in two probands with the KEL*02. M05 allele defined by a synonymous mutation (G573G). Flow cytometry analysis to determine the expression of Kell antigen was performed.ResultsThirty KEL:1,-2 individuals (30/407, 7.4%) with discrepant KEL*01/02 genotype were identified. Seven novel alleles were identified: KEL*02(R86Q, R281W)mod, KEL*02(L133P)null, KEL*02(436delG)null, KEL*02(F418S)null, KEL*02(R492X)null, KEL*02(L611R)null, and KEL*02(R700X)null. Nine variant alleles described before were detected: KEL*02N.06, KEL*02N.15, KEL*02N.17, KEL*02N.19, KEL*02N.21, KEL*02M.02, KEL*02M.04, KEL*02M.05, and KEL*02(Q362K)mod. A transcript lacking Exon 16 was identified in two probands with the KEL*02M.05 allele as described before. Finally, flow cytometry analysis showed a decreased total Kell expression and a relatively increased KEL1 expression in individuals with the KEL:1,2null or KEL:1,2mod phenotype, compared to KEL:1,2 controls.Conclusion In 7.4% of a group of tested KEL:1,-2 Dutch donors, a KEL*02null or KEL*02mod allele was found. A relatively increased KEL1 antigen expression in KEL:1,2null and KEL:1,2mod individuals suggest that the expression of Kell-XK complexes depends on the availability of the XK protein.
    No preview · Article · Aug 2014 · Transfusion
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    Full-text · Dataset · Jul 2014
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    ABSTRACT: AimThe aim of this study was to provide an overview of fetal/neonatal alloimmune neutropenia (FNAIN), together with advice on the clinical management.Methods Neutrophil serology in The Netherlands is centralised at Sanquin Diagnostic Services. We examined FNAIN cases between 1 January 1991 and 1 July 1 2013 to determine the number of cases diagnosed, the relationship with human neutrophil antigen (HNA) antibody, the clinical presentation and therapeutic interventions.ResultsWe identified 35 FNAIN cases. The detected HNA antibodies were: anti- HNA-1a (n=7), anti-HNA-1b (n=12), anti-HNA-1c (n=2), anti-HNA-2 (n=8), anti-HNA-3a (n=1), anti-HNA-5a (n=1) and anti-FcγRIIIb (n=4). No infections were diagnosed in 14 neonates and the other 21 neonates suffered from omphalitis (n=6), urinary tract infection (n=1), candida mucositis (n=1), fever of unknown origin (n=6) and sepsis (n=7, 20%). Parity, gestational age, birth weight, neutrophil counts and antibody specificity were not significantly different for cases with, and without, infections. All the infected children were treated with antibiotics. No children died.Conclusion More than half (21) of the 35 cases of FNAIN presented with infections and most implicated were HNA-1a, HNA-1b and HNA-2. Treatment with antibiotics seemed adequate. A neonatal neutropenia workflow model for use in neonatal intensive care units is presented.This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2014 · Acta Paediatrica
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    ABSTRACT: Despite its generally transient and benign course, childhood immune thrombocytopenia has a large impact on health related quality of life. Recently published guidelines state that quality of life should be taken into account while making decisions on management in childhood immune thrombocytopenia. Therefore, we assessed health related quality of life in children with newly diagnosed immune thrombocytopenia in a prospective multicenter study. One hundred seven children aged 6 months-16 years (mean age 5.57 years) were included. We used Pediatric Quality of Life InventoryTM; (PedsQLTM) and Kids ITP Tools (KIT) questionnaires at diagnosis and during standardized follow-up. Scores on the PedsQL™ Core Scales were compared with those of healthy children. Relationships between health related quality of life scores and treatment modality, bleeding tendency and course of the disease were examined. KIT proxy reports and KIT parent self-reports showed significant higher health related quality of life scores in children who recovered versus children with persisting immune thrombocytopenia (at 3 months: KIT parent self-report score 80.85 for recovered patients (n=69) versus 58.98 for patients with persistent disease (n=21), p<0.001). No significant differences in health related quality of life were found between children with mild versus moderate bleeding and between children who received intravenous immunoglobulin versus children who were carefully observed. In conclusion, health related quality of life of children with newly diagnosed immune thrombocytopenia is not influenced by treatment modality or bleeding severity, but only by clinical course of the disease. (Dutch Trial Register identifier: NTR TC1563).
    Preview · Article · Jun 2014 · Haematologica
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    ABSTRACT: Haemolytic disease of the fetus and newborn (HDFN) may occur when maternal IgG antibodies against red blood cells (RBCs), often anti-RhD (anti-D) antibodies, cross the placenta and mediate the destruction of RBCs via phagocytic IgG-Fc-receptors (FcγR). Clinical severity is not strictly related to titre and is more accurately predicted by the diagnostically-applied monocyte-based antibody-dependent cellular cytotoxicity (ADCC), a sensitive test with relatively low specificity. This suggests that other factors are involved in the pathogenesis of HDFN. Binding of IgG to FcγR requires the N-linked glycan at position 297 in the IgG-Fc-region, consisting of several different glycoforms. We therefore systematically analysed IgG-derived glycopeptides by mass spectrometry from 70 anti-D IgG1 antibodies purified from the plasma of alloimmunized pregnant women. This revealed a variable decrease in Fc-fucosylation in the majority of anti-D IgG1 (even down to 12%), whereas the total IgG of these patients remained highly fucosylated, like in healthy individuals (>90%). The degree of anti-D fucosylation correlated significantly with CD16 (FcγRIIIa)-mediated ADCC, in agreement with increased affinity of defucosylated IgG to human FcγRIIIa. Additionally, low anti-D fucosylation correlated significantly with low fetal-neonatal haemoglobin levels, thus with increased haemolysis, suggesting IgG-fucosylation to be an important pathological feature in HDFN with diagnostic potential.
    Full-text · Article · Jun 2014 · British Journal of Haematology
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    ABSTRACT: Genotyping is an important tool in the diagnosis of disorders involving allo-immunisation to antigens present on the membranes of platelets and neutrophils. To date 28 human platelet antigens (HPAs) have been indentified on six polymorphic glycoproteins on the surface of platelets. Antibodies against HPAs play a role in foetal and neonatal alloimmune thrombocytopenia (FNAIT), post-transfusion purpura (PTP) and refractoriness to donor platelets. The 11 human neutrophil antigens (HNAs) described to date have been indentified on five polymorphic proteins on the surface of granulocytes. Antibodies to HNAs are implicated with foetal and neonatal alloimmune neutropenia (FNAIN), autoimmune neutropenia (AIN) and transfusion related acute lung injury (TRALI). In this report, we will review the molecular basis and techniques currently available for the genotyping of human platelet and neutrophil antigens.
    No preview · Article · Apr 2014 · Transfusion and Apheresis Science
  • M. de Haas · K. Finning · E. Massey · D. J. Roberts
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    ABSTRACT: SUMMARY The new British Committee for Standards in Haematology (BCSH) guidelines for the use of anti-D immunoglobulin in pregnancy provide a welcome clarification of the use of anti-D in ectopic pregnancy and after red cell salvage during caesarean section, of dosing with different preparations and distinguishing non-immune and immune anti-D. The routine use of anti-D prophylaxis (RAADP) to prevent Rhesus (Rh) D alloimmunisation during the third trimester is well established and requires careful and well-audited local implementation to achieve the maximum public health benefit. In the UK, such scrutiny may be provided by the reporting of failed anti-D prophylaxis at women who have produced an immune anti-D that is detectable for the first time in the current pregnancy through the voluntary Serious Hazards of Transfusion reporting scheme (SHOT). Application of fetal RHD genotyping would avoid giving anti-D to RhD negative women carrying an RhD negative fetus. RAADP is directed by fetal RHD genotyping in some countries in Northern Europe led by the Netherlands and Denmark. The economic case for RAADP directed by fetal RHD genotyping needs to be carefully evaluated and in England is under consideration by National Institute for Health and Clinical Excellence (NICE). Possible future developments include the use of monoclonal anti-D preparations, now in advanced clinical trials, and also testing the hypothesis that directed RAADP from early in the second trimester may further reduce anti-D immunisation.
    No preview · Article · Feb 2014 · Transfusion Medicine
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    Full-text · Dataset · Jan 2014

Publication Stats

9k Citations
858.00 Total Impact Points


  • 2015
    • Leiden University Medical Centre
      • Department of Obstetrics
      Leyden, South Holland, Netherlands
  • 1994-2015
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Laboratory for Experimental and Clinical Immunology
      • • Central Laboratory of the Netherlands Red Cross Blood Transfusion Service
      Amsterdamo, North Holland, Netherlands
    • Hannover Medical School
      • Clinic for Immunology and Rheumatology
      Hanover, Lower Saxony, Germany
  • 2009-2014
    • Sanquin Blood Supply Foundation
      • Division of Diagnostic Services
      Amsterdamo, North Holland, Netherlands
  • 2011
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2010
    • Radboud University Nijmegen
      Nymegen, Gelderland, Netherlands
  • 2008
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 2006-2007
    • Nederlands Instituut voor onderzoek van de Gezondheidszorg
      Utrecht, Utrecht, Netherlands
  • 2004-2005
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2003
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 1993-2003
    • Netherlands Cancer Institute
      • • Center for Biomedical Genetics
      • • Division of Molecular Biology
      Amsterdamo, North Holland, Netherlands
  • 2002
    • Oxford University Hospitals NHS Trust
      • Department of Haematology
      Oxford, England, United Kingdom
  • 2001-2002
    • Hong Kong Red Cross Blood Transfusion Service
      Hong Kong, Hong Kong
  • 1999-2002
    • University of Groningen
      • Department of Applied Physics
      Groningen, Groningen, Netherlands
    • University of Wuerzburg
      • Department of Paediatrics
      Würzburg, Bavaria, Germany
  • 1994-2001
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Internal Medicine
      • • Academic Medical Center
      • • Department of Hematology
      Amsterdam, North Holland, Netherlands