Rob Fijnheer

Meander Medisch Centrum, Amersfoort, Utrecht, Netherlands

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Publications (183)840.54 Total impact

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    ABSTRACT: Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder that results from the development of auto-antibodies against ADAMTS13. HLA-DRB1*11 provides a risk factor for the development of acquired TTP. Pulsing of antigen presenting cells from HLA-DRB1*11 and HLA-DRB1*03 positive individuals with ADAMTS13 resulted in presentation of peptides derived from the CUB-2 domain of ADAMTS13 with core sequences FINVAPHAR or ASYILIRD. In this study we assessed whether FINVAPHAR or ASYILIRD-reactive CD4+ T cells are present in peripheral blood mononuclear cells from HLA-DRB1*11 and HLA-DRB1*03 positive subjects with acquired TTP. The presence of ADAMTS13 reactive CD4+ T cells was addressed by flow cytometry and by the expression of the activation marker CD40L by CD4+ T cells. FINVAPHAR reactive CD4+ T cells were identified in a HLA-DRB1*11 positive patient during the acute phase of the disease whereas ASYILIRD-positive CD4+ T cells were identified in a DRB1*03 positive patient with acquired TTP. Frequencies of CUB2-domain-reactive CD4+ T cells ranged from 3.3 - 4.5%. Control peptides in which the anchor-residues were modified did not induce activation of CD4+ T cells. Taken together, our data provide evidence for the involvement of CUB2-domain reactive CD4+ T cells in the etiology of acquired TTP.
    No preview · Article · Jan 2016 · Blood
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    ABSTRACT: Von Willebrand factor (VWF) is one of the most important proteins of the hemostatic system. Its multimeric state is essential for its natural function to guide platelets to sites of injury. ADAMTS13 is the key protease that regulates the multimeric state of VWF. Without ADAMTS13, VWF multimers can grow to pathologically large sizes. This is a risk factor for the life-threatening condition thrombotic thrombocytopenic purpura (TTP). In this condition, VWF-rich thrombi occlude the microvasculature of various tissues. Intriguingly, a complete ADAMTS13 deficiency does not cause continuous TTP, either in patients or genetically targeted mice. Instead, TTP occurs in episodes of disease, separated by extended periods of remission. This indicates that regulating factors beyond ADAMTS13 are likely involved in this pathologic cascade of events. This raises the question of what really happens when ADAMTS13 is (temporarily) unavailable. In this review, we explore the possible role of complementary mechanisms that are capable of modifying the thrombogenic potential of VWF.
    Full-text · Article · Nov 2015 · Seminars in Thrombosis and Hemostasis
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    ABSTRACT: Objective: To determine pretreatment computed tomography observer agreement in patients with newly diagnosed lymphoma. Methods: Forty-nine computed tomography scans were reviewed by 3 experienced radiologists, with each scan assessed twice by 1 observer. Predefined nodal and extranodal regions were assessed, and Ann Arbor stages were assigned. K-statistics were defined as poor (κ < 0.2), fair (κ > 0.2 to κ ≤ 0.4), moderate (κ > 0.4 to κ ≤ 0.6), substantial (κ > 0.6 to κ ≤ 0.8), and almost perfect (κ > 0.8 to κ ≤ 1). Results: Nodal interobserver agreement varied from 0.09 for infraclavicular involvement to 0.95 for para-iliac involvement; intraobserver agreement was substantial to almost perfect, except for infraclavicular nodes. Extranodal interobserver agreement varied from 0.56 to 0.88; intraobserver agreement was substantial to almost perfect. Ann Arbor stage interobserver agreement varied from 0.57 to 0.69; intraobserver agreement was substantial. Conclusion: Computed tomography observer agreement in staging malignant lymphoma appears to be suboptimal.
    No preview · Article · Nov 2015 · Journal of Computer Assisted Tomography
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    ABSTRACT: Purpose: To determine the prognostic performance of tumor necrosis at FDG-PET in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Materials and methods: 108 patients with newly diagnosed DLBCL who underwent FDG-PET before R-CHOP therapy were retrospectively included. Lymphomatous sites at FDG-PET were assessed for the presence of a photopenic area, in keeping with tumor necrosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of tumor necrosis and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) with progression-free survival (PFS) and overall survival (OS). Results: On univariate Cox regression analysis, both tumor necrosis and higher NCCN-IPI risk groups were significantly associated with PFS (P=0.024 and P<0.001, respectively) and OS (P=0.034 and P<0.001, respectively). On multivariate Cox regression analysis, both tumor necrosis and the NCCN-IPI were independent significant predictors for PFS (P=0.007, hazard ratio: 2.723 [95% confidence interval: 1.324-5.597] and P<0.001, hazard ratio: 2.952 [95% confidence interval: 1.876-4.646], respectively) and OS (P=0.009, hazard ratio: 2.794 [95% confidence interval: 1.305-5.985] and P<0.001, hazard ratio: 2.813 [95% confidence interval: 1.724-4.587], respectively). Conclusion: Tumor necrosis at FDG-PET is an NCCN-IPI-independent predictor of outcome in DLBCL.
    No preview · Article · Oct 2015 · European journal of radiology
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    ABSTRACT: Objective: To directly correlate fluorine-18 fluoro-2-deoxy-D-glucose (F-FDG) uptake of the iliac crest, as determined with PET, with both spatially matched histological bone marrow parameters and laboratory markers in Hodgkin lymphoma patients without lymphomatous bone marrow involvement at bone marrow biopsy. Materials and methods: This retrospective study included 21 patients with newly diagnosed Hodgkin lymphoma who underwent F-FDG-PET and who had a lymphoma-negative bone marrow biopsy of the right posterior iliac crest. F-FDG-PET maximum standardized uptake value (SUVmax) was measured in the right posterior iliac crest and correlated to histological bone marrow parameters (cellularity, myeloid/erythroid ratio, degree of fibrosis, and reactive T- and B-lymphocytes) and laboratory markers (hemoglobin, C-reactive protein lactate dehydrogenase, and leukocyte and thrombocyte counts) using Pearson's correlation coefficient (R) for Gaussian data or Kendall's tau (τ) for non-Gaussian data. Results: There was a significant moderate correlation between F-FDG-PET SUVmax and cellularity of the iliac crest (R=0.519, P=0.016). Furthermore, there was a significant strong inverse correlation between F-FDG-PET SUVmax of the iliac crest and hemoglobin level (R=-0.661, P=0.001) and there was a significant moderate correlation between F-FDG-PET SUVmax of the iliac crest and C-reactive protein level (τ=0.441, P=0.007). All other correlations, including F-FDG-PET SUVmax of the right iliac crest versus reactive T- and B-lymphocytes in the bone marrow, were not significant. Conclusion: The observations suggest increased bone marrow F-FDG uptake to be caused by red marrow hyperplasia because of anemia in Hodgkin lymphoma. Increased bone marrow F-FDG uptake is unlikely to be caused by inflammatory bone marrow changes.
    No preview · Article · Oct 2015 · Nuclear Medicine Communications
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    Jan Voorberg · Fabian C Verbij · Rob Fijnheer

    Full-text · Article · Oct 2015 · EBioMedicine
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    ABSTRACT: Asymptomatic malaria infections are highly prevalent in malaria endemic regions and most of these infections remain undiagnosed and untreated. Whereas conventional malaria symptoms are by definition absent, little is known on the more subtle health consequences of these infections. The aim of our study was to analyze the hematologic, vascular and inflammatory effects of patent and subpatent asymptomatic malaria parasitemia in children and adults on the Indonesian island Sumba. Both children and adults with parasitemia had increased high-sensitive C-reactive protein levels compared to aparasitemic individuals. In addition, children, but not adults with parasitemia also had lower platelet counts and Hb levels and higher levels of von Willebrand factor and platelet factor-4, markers of endothelial and platelet activation, respectively. These findings suggest that asymptomatic malaria infections have subtle health consequences, especially in children, and should be regarded as potentially harmful. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Aug 2015 · The Journal of infection
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    ABSTRACT: There is a lack of data on the effect of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy on brain glucose metabolism of diffuse large B-cell lymphoma (DLBCL) patients, as measured by 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Moreover, the prognostic value of brain glucose metabolism measurements is currently unknown. To investigate the use of FDG-PET for measurement of brain glucose metabolism in R-CHOP-treated DLBCL patients, and to assess its prognostic value. This retrospective study included DLBCL patients who underwent FDG-PET including the brain. FDG-PET metabolic volume products (MVPs) of the entire brain, cerebral cortex, basal ganglia, and cerebellum were measured, before and after R-CHOP therapy. Whole-body total lesion glycolysis (TLG) was also measured. Thirty-eight patients were included, of whom 18 had an appropriate end-of-treatment FDG-PET scan. There were no significant differences (P > 0.199) between pre- and post-treatment brain glucose metabolism metrics. Low basal ganglia MVP was associated with a significantly worse progression-free survival (PFS) and overall survival (OS) (P = 0.020 and P = 0.032), and low cerebellar MVP was associated with a significantly worse OS (P = 0.034). There were non-significant very weak correlations between pretreatment brain glucose metabolism metrics and TLG. In the multivariate Cox regression, only the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) remained an independent predictor of PFS (hazard ratio 3.787, P = 0.007) and OS (hazard ratio 2.903, P = 0.0345). Brain glucose metabolism was not affected by R-CHOP therapy. Low pretreatment brain glucose metabolism was associated with a worse outcome, but did not surpass the predictive value of the NCCN-IPI. © The Foundation Acta Radiologica 2015.
    No preview · Article · Aug 2015 · Acta Radiologica
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    ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease, characterized by microangiopathic hemolytic anaemia and thrombocytopenia, resulting in neurologic and/or renal abnormalities. We report a 49-year-old patient with a history of thrombotic events, renal failure, and thrombocytopenia. Blood analysis demonstrated no ADAMTS13 activity in the absence of antibodies against ADAMTS13. The complete ADAMTS13 gene was sequenced, and two mutations were identified: one mutation on exon 24 (Arg1060Asp), which had previously been described, and a mutation on exon 27 (Met1260IlefsX34), which has not been reported. For these mutations, compound heterozygosity appears to be necessary to cause TTP, as family members of the patient display only one of the mutations and all displayed normal ADAMTS13 activity.
    No preview · Article · Aug 2015 · International journal of hematology
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    ABSTRACT: Purpose: To determine the prognostic value of pretreatment anemia, pretreatment elevated C-reactive protein (CRP) levels, and 6-month posttreatment anemia in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone (R-CHOP). Patients and methods: A total of 104 patients with newly diagnosed DLBCL were retrospectively included. Pretreatment hemoglobin and CRP levels and 6-month posttreatment hemoglobin levels were measured. Cox regression analyses were used to determine the associations of laboratory assessments and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) risk groups with progression-free survival (PFS) and overall survival (OS). Results: Pretreatment anemia, elevated pretreatment CRP levels, and higher risk NCCN-IPI groups were significantly associated with reduced PFS and OS (P = .001 and P = .003 for pretreatment anemia, P = .035 and P = .029 for elevated CRP, and P < .001 and P < .001 for higher risk NCCN-IPI groups). On multivariate Cox regression analysis, only the NCCN-IPI risk group remained as an independent significant predictor for PFS (P < .001) and OS (P < .001). In the subgroup of patients in complete remission 6 months after chemotherapy (n = 80), 6-month posttreatment anemia was significantly associated with reduced PFS (P = .046) but not OS (P = .062), and higher risk NCCN-IPI groups were significantly associated with both reduced PFS (P = .008) and OS (P = .017). On multivariate Cox regression analysis, only the NCCN-IPI group remained an independent significant predictor for PFS (P = .008) and OS (P = .017). Conclusion: Pretreatment anemia, pretreatment CRP levels, and 6-month posttreatment anemia are significantly associated with poor outcome, but were not proven to be of additional prognostic value to the current risk stratification index for DLBCL.
    No preview · Article · Aug 2015 · Clinical lymphoma, myeloma & leukemia
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    ABSTRACT: This study aimed to determine the prognostic value of residual anatomical disease, including its size and reduction relative to baseline, in diffuse large B-cell lymphoma patients who have F-fluoro-2-deoxy-D-glucose positron emission tomography-based complete response after first-line R-CHOP therapy. This retrospective study included 47 patients. In patients with computed tomography (CT)-based residual disease, the size of the largest residual lesion (Resmax) and the sum of the sizes of all residual lesions (Restotal) were measured, and their reductions relative to baseline (ΔResmax and ΔRestotal) were calculated. Patients with high-risk National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) scores had significantly lower progression-free survival (PFS) and overall survival (OS) than patients with low-risk NCCN-IPI scores (P = 0.032 and P = 0.022). In contrast, patients with residual lesions at CT had no significantly lower PFS and OS than those without (P = 0.531 and P = 0.801). In the subpopulation with CT-based residual disease, patients with high Resmax, high Restotal, low ΔResmax, and low ΔRestotal had no significantly different PFS and OS than those with low Resmax, low Restotal, high ΔResmax, and high ΔRestotal (P = 0.980 and P = 0.790, P = 0.423 and P = 0.229, P = 0.923 and P = 0.893, and P = 0.923 and P = 0.893, respectively). The NCCN-IPI retains its prognostic value in diffuse large B-cell lymphoma patients with F-fluoro-2-deoxy-D-glucose positron emission tomography-based complete response after first-line R-CHOP therapy. However, the presence of residual anatomical disease, including its size and reduction relative to baseline, has no prognostic value in these patients.
    No preview · Article · May 2015 · Journal of computer assisted tomography

  • No preview · Article · May 2015 · Acta oncologica (Stockholm, Sweden)
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    ABSTRACT: To assess the performance of whole-body MRI including diffusion-weighted imaging (whole-body MRI-DWI) for the detection of residual disease after completion of treatment in lymphoma patients. Twenty-six patients with lymphoma prospectively underwent whole-body MRI-DWI (1.5 Tesla MR) and 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/computed tomography (CT) for posttreatment evaluation which were visually assessed. Apparent diffusion coefficient (ADC) and FDG-PET/CT standardized uptake value measurements were performed in all residual lesions. An unblinded expert panel reviewed all cases and determined the presence or absence of posttreatment residual disease using all available imaging (except for whole-body MRI-DWI), clinical, and histopathological information with a follow-up of at least 6 months. The performance of whole-body MRI-DWI was compared with this panel reference standard. Five of 26 patients were diagnosed with residual disease. Sensitivity and specificity for detection of residual disease with whole-body MRI-DWI were 100% and 62%, respectively. By ROC analysis, the optimal threshold of ADC was 1.21 × 10(-3) mm(2) /s with sensitivity and specificity of 100% and 91.7%, respectively. Our initial results suggest that visual whole-body MRI-DWI analysis has a very good sensitivity for detecting viable residual lesions after completion of therapy but lacks specificity. ADC measurements could potentially increase the specificity of whole-body MRI. J. Magn. Reson. Imaging 2015. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · Journal of Magnetic Resonance Imaging

  • No preview · Article · Mar 2015 · American Journal of Hematology
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    ABSTRACT: Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.
    No preview · Article · Feb 2015 · Thrombosis and Haemostasis

  • No preview · Article · Feb 2015 · American Journal of Hematology
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    ABSTRACT: Accurate evaluation of the spleen is an important component of staging lymphoma, because this may have prognostic and therapeutic implications. To determine the diagnostic value of whole-body magnetic resonance imaging (MRI), including diffusion-weighted imaging (whole-body MRI-DWI) in the detection of splenic involvement in lymphoma. This IRB approved, prospective multicenter study included a total of 107 patients with newly diagnosed, histologically proven lymphoma who underwent 1.5 T whole-body MRI-DWI and FDG-PET/CT. Whole-body MRI-DWI and FDG-PET/CT were independently evaluated by a radiologist and a nuclear medicine physician, in a blinded manner. Splenic involvement at MRI was defined as splenic index > 725 cm(3) or discrete nodules. At FDG-PET/CT splenic involvement was defined as splenic uptake greater than liver uptake or hypodense nodules at contrast-enhanced CT. FDG-PET/CT augmented with follow-up imaging after treatment was used as reference standard. Splenic involvement was detected with FDG-PET/CT in 21 patients, all demonstrating response to treatment. The sensitivity, specificity, positive predictive value, and negative predictive value of whole-body MRI-DWI for the detection of splenic involvement were 85.7 %, 96.5 %, 85.7%, and 96.5%, respectively. Three out of six discrepancies were related to suboptimal criterion of splenic size used with whole-body MRI-DWI versus the size-independent FDG uptake. Whole-body MRI-DWI is reasonably accurate in the detection of splenic lymphomatous involvement. © The Foundation Acta Radiologica 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    No preview · Article · Feb 2015 · Acta Radiologica
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    ABSTRACT: To determine the prognostic value of tumor-induced cortical bone destruction at computed tomography (CT) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). This retrospective study included 105 patients with newly diagnosed DLBCL who had undergone CT and bone marrow biopsy (BMB) before R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone) chemo-immunotherapy. Cox regression analyses were used to determine the associations of cortical bone status at CT (absence vs. presence of tumor-induced cortical bone destruction), BMB findings (negative vs. positive for lymphomatous involvement), and dichotomized National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) strata (low risk vs. high risk) with progression-free survival (PFS) and overall survival (OS). Univariate Cox regression analysis indicated that cortical bone status at CT was no significant predictor of either PFS or OS (p = 0.358 and p = 0.560, respectively), whereas BMB findings (p = 0.002 and p = 0.013, respectively) and dichotomized NCCN-IPI risk strata (p = 0.002 and p = 0.003, respectively) were significant predictors of both PFS and OS. In the multivariate Cox proportional hazards model, only the dichotomized NCCN-IPI score was an independent predictive factor of PFS and OS (p = 0.004 and p = 0.003, respectively). The presence of tumor-induced cortical bone destruction at CT was not found to have any prognostic implications in newly diagnosed DLBCL.
    Preview · Article · Feb 2015 · Skeletal Radiology
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    ABSTRACT: This study compared CT-based and (18)F-fluoro-2-deoxy-D-glucose PET/CT (FDG-PET/CT)-based NCCN International Prognostic Index (NCCN-IPI) risk stratification in newly diagnosed diffuse large B-cell lymphoma (DLBCL). This retrospective study included 57 patients with newly diagnosed DLBCL who had undergone both (oral and intravenous contrast-enhanced full-dose) diagnostic CT and FDG-PET/CT. Diagnostic CT only and FDG-PET/CT were evaluated separately, and corresponding NCCN-IPI scores for the 2 datasets (NCCN-IPICT and NCCN-IPIPET/CT) were calculated. Percentages of agreement and weighted k statistic between NCCN-IPICT and NCCN-IPIPET/CT scoring with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk groups were calculated. In 47 of 57 patients (82.5%; 95% CI, 70.4-90.4), diagnostic CT alone was in agreement with FDG-PET/CT with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk NCCN-IPI groups, but not in the remaining 10 patients (17.5%; 95% CI, 9.6%-29.6%). All NCCN-IPI disagreements between diagnostic CT and FDG-PET/CT were from the detection of additional lesions by the latter, most of them being bone marrow lesions. Agreement between NCCN-IPICT and NCCN-IPIPET/CT with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk groups was considered good (k=0.771). Although agreement between NCCN-IPICT and NCCN-IPIPET/CT risk stratification is generally good, FDG-PET/CT results in higher NCCN-IPI risk stratifications in a non-negligible proportion of patients. Future studies should investigate the prognostic implications of these imaging-based differences in NCCN-IPI scoring. Copyright © 2015 by the National Comprehensive Cancer Network.
    No preview · Article · Feb 2015 · Journal of the National Comprehensive Cancer Network: JNCCN

  • No preview · Article · Jan 2015 · Circulation

Publication Stats

4k Citations
840.54 Total Impact Points

Institutions

  • 2009-2015
    • Meander Medisch Centrum
      Amersfoort, Utrecht, Netherlands
  • 1999-2015
    • University Medical Center Utrecht
      • • Department of Hematology
      • • Department of Clinical Chemistry and Haematology
      Utrecht, Utrecht, Netherlands
    • Medical University of Vienna
      • Department of Clinical Pharmacology
      Wien, Vienna, Austria
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2004-2012
    • Jeroen Bosch Ziekenhuis
      Hertogenbosch, North Brabant, Netherlands
  • 1996-2000
    • Utrecht University
      • • Department of Hematology
      • • Department of Neurology
      Utrecht, Utrecht, Netherlands
  • 1989-1991
    • University of Amsterdam
      • Central Laboratory of the Netherlands Red Cross Blood Transfusion Service
      Amsterdamo, North Holland, Netherlands
  • 1990
    • Hong Kong Red Cross Blood Transfusion Service
      Hong Kong, Hong Kong