Rob Fijnheer

Publications (45)215.65 Total impact

• Article: Whole-body MRI for the detection of bone marrow involvement in lymphoma: prospective study in 116 patients and comparison with FDG-PET.

  Hugo J A Adams, Thomas C Kwee, Malou A Vermoolen, Bart de Keizer, John M H de Klerk, Judit A Adam, Rob Fijnheer, Marie José Kersten, Jaap Stoker, Rutger A J Nievelstein
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  ABSTRACT: OBJECTIVE: To assess and compare the value of whole-body MRI with FDG-PET for detecting bone marrow involvement in lymphoma. METHODS: A total of 116 patients with newly diagnosed lymphoma prospectively underwent whole-body MRI and blind bone marrow biopsy (BMB) of the posterior iliac crest. Of 116 patients, 80 also underwent FDG-PET. Patient-based sensitivities of whole-body MRI for detecting bone marrow involvement were calculated using BMB as reference standard and compared with FDG-PET in aggressive and indolent lymphomas separately. RESULTS: Sensitivity of whole-body MRI in all lymphomas was 45.5 % [95 % confidence interval (CI): 29.8-62.0 %]. Sensitivity of whole-body MRI in aggressive lymphoma [88.9 % (95 % CI: 54.3-100 %)] was significantly higher (P = 0.0029) than that in indolent lymphoma [23.5 % (95 % CI: 9.1-47.8 %)]. Sensitivity of FDG-PET in aggressive lymphoma [83.3 % (95 % CI: 41.8-98.9 %)] was also significantly higher (P = 0.026) than that in indolent lymphoma [12.5 % (95 % CI: 0-49.2 %)]. There were no significant differences in sensitivity between whole-body MRI and FDG-PET (P = 1.00) CONCLUSION: Sensitivity of whole-body MRI for detecting lymphomatous bone marrow involvement is too low to (partially) replace BMB. Sensitivity of whole-body MRI is significantly higher in aggressive lymphoma than in indolent lymphoma and is equal to FDG-PET in both entities. KEY POINTS : • Bone marrow involvement in lymphoma has prognostic and therapeutic implications. • Blind bone marrow biopsy (BMB) is standard for bone marrow assessment. • Neither whole-body MRI nor FDG-PET can yet replace BMB. • Both techniques have higher sensitivity in aggressive than in indolent lymphoma. • Both imaging techniques are complementary to BMB.
  European Radiology 04/2013; · 3.22 Impact Factor
• Article: Preferential HLA-DRB1*11 dependent presentation of CUB2 derived peptides by ADAMTS13 pulsed dendritic cells.

  Nicoletta Sorvillo, Simon D van Haren, Paul H Kaijen, Anja Ten Brinke, Rob Fijnheer, Alexander B Meijer, Jan Voorberg
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  ABSTRACT: Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13 derived peptides presented on MHC class II alleles from 17 healthy donors. Dendritic cells from a panel of both HLA-DRB1*11 positive and negative donors were pulsed with ADAMTS13 and the HLA-DR-presented peptide repertoire was analyzed by mass spectrometry. Interestingly, at low antigen concentrations HLA-DRB1*11 or DRB1*03 positive donors presented a limited number of CUB2 derived peptides. Pulsing of dendritic cells employing higher concentrations of ADAMTS13 resulted in presentation of larger numbers of ADAMTS13 derived peptides by both HLA-DRB1*11 positive and negative donors. Although the presented peptides were derived from several ADAMTS13 domains, inspection of the peptide-profiles revealed that CUB2 domain derived peptides were presented with a higher efficiency when compared to other peptides. Remarkably, dendritic cells from DRB1*11 donors pulsed with higher concentrations of ADAMTS13 present derivatives of a single CUB2 derived peptide. We hypothesize that functional presentation of CUB2 derived peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low affinity self-reactive CD4+ T cells.
  Blood 01/2013; · 9.90 Impact Factor
• Article: Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability.

  Meta Michels, André J A M van der Ven, Kis Djamiatun, Rob Fijnheer, Philip G de Groot, Arjan W Griffioen, Silvie Sebastian, Sultana M H Faradz, Quirijn de Mast
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  ABSTRACT: The pathogenesis of plasma leakage during dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is largely unknown. Angiopoietins are key regulators of vascular integrity: Angiopoietin-1 is stored in platelets and maintains vascular integrity, and endothelium-derived angiopoietin-2 promotes vascular leakage. We determined Angiopoietin-1 and Angiopoietin-2 levels in a cohort of children in Indonesia with DHF/DSS and related them to plasma leakage markers. Patients with DHF/DSS had reduced Angiopoietin-1 and increased Angiopoietin-2 plasma levels on the day of admission when compared with levels at discharge and in healthy controls. There was an inverse correlation between angiopoietin-1 and markers of plasma leakage and a positive correlation between angiopoietin-2 and markers of plasma leakage. Angiopoietin-1 levels followed the same trend as the soluble platelet activation marker P-selectin and correlated with platelet counts. Dengue-associated thrombocytopenia and endothelial activation are associated with an imbalance in angiopoietin-2: angiopoietin-1 plasma levels. This imbalance may contribute to the transient plasma leakage in DHF/DSS.
  The American journal of tropical medicine and hygiene 09/2012; · 2.59 Impact Factor
• Article: Indications for a protective function of beta2-glycoprotein I in thrombotic thrombocytopenic purpura.

  Vivian X Du, Gwen van Os, Johanna A Kremer Hovinga, Ilze Dienava-Verdoold, Jacques Wollersheim, Zaverio M Ruggeri, Rob Fijnheer, Philip G de Groot, Bas de Laat
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  ABSTRACT: It has been shown that β(2) -glycoprotein I (β(2) GPI) interacts with von Willebrand factor (VWF) in a glycoprotein (GP)Ib binding state. Given the presence of active VWF multimers in thrombotic thrombocytopenic purpura (TTP), we speculated that β(2) GPI might play a role in TTP. We found that β(2) GPI plasma levels were significantly lower in acute and remission TTP patients than in normal controls, showing a direct correlation with ADAMTS 13 levels and an inverse correlation with the extent of VWF activation. In vitro flow experiments demonstrated that β(2) GPI can block platelet adhesion to endothelial cell-derived VWF strings. We confirmed the direct binding of β(2) GPI to VWF by surface plasmon resonance, and determined that domain I of β(2) GPI is the binding site of VWF A1 domain. Adhesion of β(2) GPI to erythrocytes and platelets was increased in the presence of active VWF, indicating that β(2) GPI may be cleared from the circulation during TTP episodes together with blood cells. Our findings suggest that β(2) GPI may protect from the effects of hyper-functional VWF by inhibiting its interaction with platelets.
  British Journal of Haematology 08/2012; 159(1):94-103. · 4.94 Impact Factor
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  Available from: Kis Djamiatun

  Article: Severe dengue is associated with consumption of von Willebrand factor and its cleaving enzyme ADAMTS-13.

  Kis Djamiatun, Andre J A M van der Ven, Philip G de Groot, Sultana M H Faradz, D Hapsari, Wil M V Dolmans, Silvie Sebastian, Rob Fijnheer, Quirijn de Mast
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  ABSTRACT: Thrombocytopenia, bleeding and plasma leakage are cardinal features of severe dengue. Endothelial cell activation with exocytosis of Weibel-Palade bodies (WPBs) may play an etiological role in this condition. In a cohort of 73 Indonesian children with dengue hemorrhagic fever (DHF), of which 30 with dengue shock syndrome (DSS), we measured plasma levels of the WPB constituents von Willebrand factor antigen (VWF:Ag), VWF propeptide and osteoprotegerin (OPG), together with activity levels of the VWF-cleaving enzyme ADAMTS-13 and the amount of VWF in a platelet binding conformation (VWF activation factor). Compared with healthy controls (n = 17), children with DHF/DSS had significantly higher levels of VWF:Ag, VWF propeptide and OPG and decreased ADAMTS-13 activity. The VWF activation factor was also significantly higher in DHF/DSS and highest in children who died. There were significant differences in the kinetics of the various WPB constituents: VWF propeptide and OPG levels decreased toward discharge, while VWF:Ag levels were lower than expected at enrollment with plasma levels increasing toward discharge. Moreover, VWF propeptide levels correlated better with markers of disease severity (platelet count, liver enzymes, serum albumin and pleural effusion index) than corresponding VWF levels. Together, these findings suggest that there is consumption of VWF in DHF/DSS. In 4 out of 15 selected children with low ADAMTS-13 levels on admission, we found a remarkable reduction in the large and intermediate VWF multimers in the discharge blood samples, consistent with an acquired von Willebrand disease. These findings suggest that severe dengue is associated with exocytosis of WPBs with increased circulating levels of VWF:Ag, VWF propeptide and OPG. High circulating levels of VWF in its active conformation, together with low ADAMTS-13 activity levels, are likely to contribute to the thrombocytopenia and complications of dengue. During the convalescence phase, qualitative defects in VWF with loss of larger VWF multimers may develop.
  PLoS Neglected Tropical Diseases 05/2012; 6(5):e1628. · 4.69 Impact Factor
• Article: The macrophage mannose receptor promotes uptake of ADAMTS13 by dendritic cells.

  Nicoletta Sorvillo, Wouter Pos, Linda M van den Berg, Rob Fijnheer, Luisa Martinez-Pomares, Teunis B Geijtenbeek, Eszter Herczenik, Jan Voorberg
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  ABSTRACT: ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by cleaving ultra-large VWF multimers on the surfaces of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura. The formation of autoantibodies depends on the activation of CD4(+) T cells. This process requires immune recognition, endocytosis, and subsequent processing of ADAMTS13 into peptides that are presented on MHC class II molecules to CD4(+) T cells by dendritic cells (DCs). In the present study, we investigated endocytosis of recombinant ADAMTS13 by immature monocyte-derived DCs using flow cytometry and confocal microscopy. After incubation of fluorescently labeled ADAMTS13 with DCs, significant uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked by the addition of EGTA and mannan. ADAMTS13 endocytosis was decreased in the presence of a blocking mAb directed toward the macrophage mannose receptor (MR). Furthermore, siRNA silencing of MR reduced the uptake of ADAMTS13 by DCs. In addition, in vitro binding studies confirmed the interaction of ADAMTS13 with the carbohydrate recognition domains of MR. The results of the present study indicate that sugar moieties on ADAMTS13 interact with MR, thereby promoting its endocytosis by APCs.
  Blood 01/2012; 119(16):3828-35. · 9.90 Impact Factor
• Article: Plasma concentration of von Willebrand factor predicts mortality in patients on chronic renal replacement therapy.

  Nathalie C Péquériaux, Rob Fijnheer, Eugenie F Gemen, Arjan D Barendrecht, Friedo W Dekker, Raymond T Krediet, Jaap J Beutler, Elisabeth W Boeschoten, Mark Roest
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  ABSTRACT: Traditional cardiovascular risk factors do not explain the high incidence of cardiovascular mortality and morbidity in patients with end-stage renal disease. A prothrombotic state could accelerate the process of vascular disease in these patients. In this study, four platelet activation markers (NAP-2, P-selectin, GP1b and RANTES) and two endothelial cell activation markers (von Willebrand factor and its propeptide) were measured in 671 haemodialysis patients and 275 patients on continuous ambulatory peritoneal dialysis (PD). All were long-term dialysis patients. The risk of all-cause and cardiovascular mortality was assessed in relation to these markers after a mean follow-up time of 2.5 years. The von Willebrand factor showed a positive correlation with total mortality in the haemodialysis patients. In an unadjusted model, the hazard rate (HR) of total mortality was 2.4 [95% confidence interval (95% CI) 1.7-3.4] in the upper quartile of von Willebrand factor compared with the lowest quartile. It remained statistically significant (HR 1.8; 95% CI 1.2-2.6) after adjustment for traditional risk factors. In contrast, no significant correlation was found between von Willebrand factor levels and total mortality in PD patients. Finally, no relationship between platelet activation markers and total mortality was found in either the haemodialysis or the PD patients. It can be concluded that chronic endothelial cell activation, but not platelet activation, is related to all-cause mortality in end-stage renal disease patients on long-term dialysis.
  Nephrology Dialysis Transplantation 12/2011; 27(6):2452-7. · 3.40 Impact Factor
• Source

  Available from: Gestur Vidarsson

  Article: Residues Arg568 and Phe592 contribute to an antigenic surface for anti-ADAMTS13 antibodies in the spacer domain.

  Wouter Pos, Nicoletta Sorvillo, Rob Fijnheer, Hendrik B Feys, Paul H P Kaijen, Gestur Vidarsson, Jan Voorberg
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  ABSTRACT: The majority of patients diagnosed with thrombotic thrombocytopenic purpura have autoantibodies directed towards the spacer domain of ADAMTS13. In this study we explored the epitope specificity and immunoglobulin class and immunoglobulin G subclass distribution of anti-ADAMTS13 antibodies. The epitope specificity of anti-spacer domain antibodies was examined using plasma from 48 patients with acute acquired thrombotic thrombocytopenic purpura by means of immunoprecipitation of ADAMTS13 variants containing single or multiple alanine substitutions. Using similar methods, we also determined the presence of anti-TSP2-8 and CUB1-2 domain antibodies in this cohort of patients. Antibody profiling revealed that anti-ADAMTS13 immunoglobulin G1 and immunoglobulin G4 predominate in plasma of patients with acquired thrombotic thrombocytopenic purpura. Analysis of anti-spacer domain antibodies revealed that Arg568 and Phe592, in addition to residues Arg660, Tyr661, and Tyr665, also contribute to an antigenic surface in the spacer domain. The majority of patients (90%) lost reactivity towards the spacer domain following introduction of multiple alanine substitutions at Arg568, Phe592, Arg660, Tyr661 and Tyr665. Anti-TSP2-8 and anti-CUB1-2 domain-directed antibodies were present in, respectively, 17% and 35% of the patients' samples analyzed. Immunoglobulin G directed towards a single antigenic surface comprising residues Arg568, Phe592, Arg660, Tyr661 and Tyr665 predominates in the plasma of patients with acquired thrombotic thrombocytopenic purpura.
  Haematologica 06/2011; 96(11):1670-7. · 6.42 Impact Factor
• Article: MRI for staging lymphoma: whole-body or less?

  Thomas C Kwee, Erik M Akkerman, Rob Fijnheer, Marie José Kersten, József Zsíros, Inge Ludwig, Marc B Bierings, Malou A Vermoolen, Maarten S van Leeuwen, Jaap Stoker, Rutger A J Nievelstein
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  ABSTRACT: To assess whether whole-body MRI detects more clinically relevant lesions (i.e., leading to a change in Ann Arbor stage) than an MRI protocol that only includes the head/neck and trunk (i.e., from cranial vertex to groin, excluding the arms) in patients with lymphoma. One hundred consecutive patients with newly diagnosed lymphoma prospectively underwent T1-weighted and T2-weighted short inversion time inversion recovery whole-body MRI. The number of lymphomatous sites at MRI with a field of view (FOV) limited to the head/neck and trunk, and the additional number of lymphomatous sites at whole-body MRI and their influence on Ann Arbor stage were determined. At MRI with a FOV limited to the head/neck and trunk, 507 sites were classified as lymphomatous. At whole-body MRI, 7 additional sites outside the head/neck and trunk in 7 patients (7.0%; 95% confidence interval: 3.4-13.8%) were classified as lymphomatous, but Ann Arbor stage never changed. Whole-body MRI did not detect any clinically relevant lesions outside the FOV of an MRI protocol that only includes the head/neck and trunk. Therefore, it may be sufficient to only include the head/neck and trunk when using MRI for staging lymphoma.
  Journal of Magnetic Resonance Imaging 05/2011; 33(5):1144-50. · 2.70 Impact Factor
• Article: Magnetic resonance imaging of malignant lymphoma.

  Malou A Vermoolen, Marie José Kersten, Rob Fijnheer, Maarten S van Leeuwen, Thomas C Kwee, Rutger A J Nievelstein
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  ABSTRACT: Computed tomography (CT), (18)F-fluorodeoxyglucose (FDG)-PET and the hybrid FDG-PET/CT are the most commonly used diagnostic tools for the initial staging and treatment response assessment of malignant lymphomas. MRI techniques such as whole-body MRI and diffusion-weighted imaging may be good radiation-free alternatives to FDG-PET/CT, which may be particularly relevant for children. Diffusion-weighted imaging is characterized by high sensitivity for the detection of lesions and allows quantitative assessment of diffusion that may aid in the evaluation of malignant lymphomas. This article will review the value of these emerging MRI techniques for the staging and response assessment of malignant lymphoma. Furthermore, we will discuss some additional imaging techniques that are the subject of ongoing research and may have potential for future clinical application.
  Expert Review of Hematology 04/2011; 4(2):161-71. · 1.16 Impact Factor
• Article: Newly diagnosed lymphoma: initial results with whole-body T1-weighted, STIR, and diffusion-weighted MRI compared with 18F-FDG PET/CT.

  Henriëtte M E Quarles van Ufford, Thomas C Kwee, Frederik J Beek, Maarten S van Leeuwen, Taro Takahara, Rob Fijnheer, Rutger A J Nievelstein, John M H de Klerk
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  ABSTRACT: The purpose of this study was to compare whole-body MRI including diffusion-weighted imaging (DWI) with (18)F-FDG PET/CT in the staging of newly diagnosed lymphoma. Twenty-two consecutively registered patients with newly diagnosed lymphoma prospectively underwent whole-body MRI (22 with T1-weighted, STIR, and DWI sequences and 21 with T1-weighted and STIR sequences but not DWI) and FDG PET/CT. Whole-body MRI-DWI was independently evaluated by two blinded observers. Interobserver agreement was assessed, and whole-body MRI-DWI was compared with FDG PET/CT. The kappa values for interobserver agreement on whole-body MRI-DWI for all nodal regions together and for all extranodal regions together were 0.676 and 0.452. The kappa values for agreement between whole-body MRI-DWI and FDG PET/CT for all nodal regions together and for all extranodal regions together were 0.597 and 0.507. Ann Arbor stage according to whole-body MRI-DWI findings was concordant with that of FDG PET/CT findings in 77% (17/22) of patients. Understaging and overstaging relative to the findings with FDG PET/CT occurred in 0% (0/22) and 23% (5/22) of cases. In the care of 9% (2/22) of patients, overstaging with whole-body MRI-DWI relative to staging with FDG PET/CT would have had therapeutic consequences. Our early results indicate that overall interobserver agreement on whole-body MRI-DWI findings is moderate to good. Overall agreement between whole-body MRI-DWI and FDG PET/CT is moderate. In the care of patients with newly diagnosed lymphoma, staging with whole-body MRI-DWI does not result in underestimation of stage relative to the results with FDG PET/CT. In a minority of patients, reliance on whole-body MRI-DWI leads to clinically important overstaging relative to the results with FDG PET/CT. FDG PET/CT remains the reference standard for lymphoma staging until larger-scale studies show that use of whole-body MRI-DWI results in correct staging in this minority of cases.
  American Journal of Roentgenology 03/2011; 196(3):662-9. · 2.78 Impact Factor
• Article: ADC measurements in the evaluation of lymph nodes in patients with non-Hodgkin lymphoma: feasibility study.

  Thomas C Kwee, Inge Ludwig, Cuno S Uiterwaal, Henriette M E Quarles van Ufford, Malou A Vermoolen, Rob Fijnheer, Marc B Bierings, Rutger A J Nievelstein
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  ABSTRACT: To determine whether apparent diffusion coefficient (ADC) measurements allow discrimination of normal lymph nodes from lymphomatous lymph nodes, and indolent lymphomas from aggressive lymphomas in patients with non-Hodgkin lymphoma (NHL). Eighteen healthy volunteers and thirty-two patients with newly diagnosed NHL (indolent: n = 16; aggressive: n = 16) underwent diffusion-weighted imaging. ADCs of normal lymph nodes were compared to those of lymphomatous lymph nodes, and ADCs of indolent lymphomas were compared to those of aggressive lymphomas. Receiver operating characteristic (ROC) analysis was performed when ADCs were significantly different between two of the aforementioned groups. ADCs (in 10(-3) mm(2)/s) of lymphomatous lymph nodes (0.70 ± 0.22) were significantly lower (P < 0.0001) than those of normal lymph nodes (1.00 ± 0.15). Area under the ROC curve was 0.865. Sensitivity and specificity were 78.1 and 100% when using an optimal cutoff ADC value of 0.80. On the other hand, ADCs of indolent lymphomas (0.67 ± 0.21) were not significantly different (P = 0.2997) from those of aggressive lymphomas (0.74 ± 0.23). ADC measurements show promise as a highly specific tool for the discrimination of normal lymph nodes from lymphomatous lymph nodes, but appear to be of no utility in differentiating indolent from aggressive lymphomas.
  MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 02/2011; 24(1):1-8. · 1.88 Impact Factor
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  Available from: Meta Roestenberg

  Article: Thrombocytopenia in early malaria is associated with GP1b shedding in absence of systemic platelet activation and consumptive coagulopathy.

  Quirijn de Mast, Philip G de Groot, Waander L van Heerde, Meta Roestenberg, Jeroen F van Velzen, Bert Verbruggen, Mark Roest, Matthew McCall, An-Emmie Nieman, Josien Westendorp, Din Syafruddin, Rob Fijnheer, Edmee C van Dongen-Lases, Robert W Sauerwein, Andre J van der Ven
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  ABSTRACT: Thrombocytopenia develops early in malaria, but the underlying mechanisms remain incompletely understood. We studied the aetiology of malaria-associated thrombocytopenia in volunteers experimentally infected with Plasmodium falciparum malaria, in Indonesian malaria patients and in ex vivo studies. In experimental human malaria, the decrease in platelet counts was associated with a concurrent rise in young platelets (immature platelet fraction) and thrombopoietin. D-dimer concentrations were moderately elevated without a prolongation in the activated partial thromboplastin time or decrease in fibrinogen. There was no increase in expression of the platelet surface markers CD62P, PAC-1 and CD63 and in plasma concentrations of the platelet factors P-selectin, CXCR4, CXCL7, RANTES and CD40L. In contrast, concentrations of soluble glycoprotein-1b (sGP1b), the external domain of the platelet receptor for von Willebrand factor (VWF), increased early. Indonesian malaria patients also had elevated concentrations of sGP1b, which correlated with VWF concentrations. Finally, incubation of platelets with parasitized erythrocytes in vitro failed to induce platelet aggregation or activation. We concluded that neither compromised platelet production nor platelet activation or consumptive coagulopathy were responsible for the early thrombocytopenia in malaria. We hypothesize that the increase in sGP1b concentrations results from VWF-mediated GP1b shedding; a process that may prevent excessive adhesion of platelets and parasitized erythrocytes.
  British Journal of Haematology 10/2010; 151(5):495-503. · 4.94 Impact Factor
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  Available from: Rutger A J Nievelstein

  Article: Whole-body magnetic resonance imaging, including diffusion-weighted imaging, for diagnosing bone marrow involvement in malignant lymphoma.

  Thomas C Kwee, Rob Fijnheer, Inge Ludwig, Henriette M E Quarles van Ufford, Cuno S Uiterwaal, Marc B Bierings, Taro Takahara, Rutger A J Nievelstein
  British Journal of Haematology 05/2010; 149(4):628-30. · 4.94 Impact Factor
• Article: An autoantibody epitope comprising residues R660, Y661, and Y665 in the ADAMTS13 spacer domain identifies a binding site for the A2 domain of VWF.

  Wouter Pos, James T B Crawley, Rob Fijnheer, Jan Voorberg, David A Lane, Brenda M Luken
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  ABSTRACT: In the majority of patients with acquired thrombotic thrombocytopenic purpura (TTP), antibodies are directed toward the spacer domain of ADAMTS13. We have previously shown that region Y658-Y665 is involved. We now show that replacement of R660, Y661, or Y665 with alanine in ADAMTS13 reduced/abolished the binding of 2 previously isolated human monoclonal antibodies and polyclonal antibodies derived from plasma of 6 patients with acquired TTP. We investigated whether these residues also influenced cleavage of short von Willebrand factor (VWF) fragment substrate VWF115. An ADAMTS13 variant (R660A/Y661A/Y665A, ADAMTS13-RYY) showed a 12-fold reduced catalytic efficiency (k(cat)/K(m)) arising from greatly reduced (> 25-fold) binding, demonstrated by surface plasmon resonance. The influence of these residue changes on full-length VWF was determined with denaturing and flow assays. ADAMTS13-RYY had reduced activity in both, with proteolysis of VWF unaffected by autoantibody. Binding of ADAMTS13-RYY mutant to VWF was, however, similar to normal. Our results demonstrate that residues within Y658-Y665 of the ADAMTS13 spacer domain that are targeted by autoantibodies in TTP directly interact with a complementary exosite (E1660-R1668) within the VWF A2 domain. Residues R660, Y661, and Y665 are critical for proteolysis of short VWF substrates, but wider domain interactions also make important contributions to cleavage of full-length VWF.
  Blood 02/2010; 115(8):1640-9. · 9.90 Impact Factor
• Article: Whole‐body magnetic resonance imaging, including diffusion‐weighted imaging, for diagnosing bone marrow involvement in malignant lymphoma

  Thomas C. Kwee, Rob Fijnheer, Inge Ludwig, Henriette M.E. Quarles van Ufford, Cuno S. Uiterwaal, Marc B. Bierings, Taro Takahara, Rutger A.J. Nievelstein
  British Journal of Haematology 01/2010; 149(4):628 - 630. · 4.94 Impact Factor
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  Available from: PubMed Central

  Article: On the added value of baseline FDG-PET in malignant lymphoma.

  Henriette Quarles van Ufford, Otto Hoekstra, Marie de Haas, Rob Fijnheer, Shulamiet Wittebol, Bianca Tieks, Mark Kramer, John de Klerk
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  ABSTRACT: The added value of baseline positron emission tomography (PET) scans in therapy evaluation in malignant lymphoma is unclear. In guidelines, baseline PET is recommended but not mandatory except in lymphoma types with variable fluoro-D-glucose uptake. The aim of the present study was to test the hypothesis that adding baseline PET information decreases false positive readings with posttreatment PET and improves observer agreement. Forty-four patients (mean age 56 years, standard deviation 14) with malignant lymphoma were included. Two nuclear medicine physicians retrospectively and independently evaluated the posttreatment PET, 3 weeks later followed by paired reading of baseline and posttreatment PET. For each PET, 22 regions were classified as positive, negative, or equivocal, resulting in an overall PET score of positive, unclear, or negative. In case of discrepancies, consensus was reached. Addition of baseline to posttreatment PET evaluation affected the classification of metabolic response in 34% of malignant lymphoma patients treated with first-line chemotherapy. In one out of seven patients, addition of the baseline PET lead to opposite conclusions (95% confidence interval 4-14). False positivity was reduced by adding the baseline scan information, but the effect on false negativity was similar. In addition, the amount of unclear classifications halved after paired reading. Observer agreement did not improve upon adding the baseline PET data. Without any other clinical information, pretreatment PET facilitates changes the interpretation of a posttreatment PET in a third of the patients, resulting in both upgrading and downgrading of the posttreatment situation of a malignant lymphoma patient. If these results are confirmed for PET-computed tomography systems, they favor the addition of baseline PET to the current work-up of patients with malignant lymphoma.
  Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 10/2009; 12(2):225-32. · 2.47 Impact Factor
• Article: Whole-body MRI, including diffusion-weighted imaging, for the initial staging of malignant lymphoma: comparison to computed tomography.

  Thomas C Kwee, Henriette M E Quarles van Ufford, Frederik J Beek, Taro Takahara, Cuno S Uiterwaal, Marc B Bierings, Inge Ludwig, Rob Fijnheer, Rutger A J Nievelstein
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  ABSTRACT: To assess the value of whole-body magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), for the initial staging of malignant lymphoma, compared with computed tomography (CT). Thirty-one consecutive patients with newly diagnosed malignant lymphoma prospectively underwent whole-body MRI (T1-weighted and short inversion time inversion recovery [n = 31], and DWI [n = 28]) and CT. Ann Arbor stages were assigned by 1 radiologist according to whole-body MRI findings, and by another radiologist according to CT findings. Differences in staging between whole-body MRI (without and with DWI) and CT were resolved using other (imaging) studies (including 18F-fluoro-2-deoxyglucose positron emission tomography and bone marrow biopsy) and follow-up studies as reference standard. Staging results of whole-body MRI without DWI were equal to those of CT in 74% (23/31), higher in 26% (8/31), and lower in 0% (0/31) of patients, with correct/incorrect/unresolved overstaging relative to CT in 3, 2, and 2 patients, respectively, and incorrect staging of both modalities in 1 patient. Staging results of whole-body MRI with DWI were equal to those of CT in 75% (21/28), higher in 25% (7/28), and lower in 0% (0/28) of patients, with correct/incorrect overstaging relative to CT in 6 and 1 patient(s), respectively. Our results suggest that initial staging of malignant lymphoma using whole-body MRI (without DWI and with DWI) equals staging using CT in the majority of patients, whereas whole-body MRI never understaged relative to CT. Furthermore, whole-body MRI mostly correctly overstaged relative to CT, with a possible advantage of using DWI.
  Investigative radiology 09/2009; 44(10):683-90. · 4.85 Impact Factor
• Article: ADAMTS13 deficiency with elevated levels of ultra-large and active von Willebrand factor in P. falciparum and P. vivax malaria.

  Quirijn de Mast, Evelyn Groot, Puji B Asih, Din Syafruddin, Marije Oosting, Silvie Sebastian, Bart Ferwerda, Mihai G Netea, Philip G de Groot, Andre J A M van der Ven, Rob Fijnheer
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  ABSTRACT: A deficiency in ADAMTS13 (a von Willebrand factor [VWF] cleaving protease) is associated with accumulation of prothrombogenic unusually large VWF multimers (UL-VWF) in plasma. We studied VWF release and proteolysis in patients with symptomatic Plasmodium falciparum or P. vivax malaria on the Indonesian island Sumba. Malaria patients had significantly lower platelet counts and higher VWF concentrations and VWF activation factors than healthy hospital staff controls. The latter indicates that a higher amount of circulating VWF was in a conformation enabling spontaneous platelet binding. In addition, ADAMTS13 activity and antigen levels were reduced in both malaria groups, and this was associated with the appearance of UL-VWF. The mechanism behind this reduction and the role in malaria pathogenesis needs to be further elucidated. In malaria, endothelial cell activation with increased circulating amounts of active and ultra-large VWF, together with reduced VWF inactivation by ADAMTS13, may result in intravascular platelet aggregation, thrombocytopenia, and microvascular disease.
  The American journal of tropical medicine and hygiene 04/2009; 80(3):492-8. · 2.59 Impact Factor
• Article: Transient severe fetal heart rate abnormalities in a pregnancy complicated by thrombotic thrombocytopenic purpura.

  Sanne M Strasser, Anneke Kwee, Rob Fijnheer, Gerard H A Visser
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  ABSTRACT: Thrombotic thrombocytopenic purpura is a rare disease. However, in pregnant women it occurs more frequently. Thrombotic thrombocytopenic purpura may be a severe condition for both mother and fetus. This is a case of severe but temporary fetal heart rate abnormalities in a pregnancy complicated by thrombotic thrombocytopenic purpura. There was a remarkably good outcome despite indications of an impaired fetal condition for a period of at least 48 hours. Based on the literature regarding transient severe neurological symptoms in adults with thrombotic thrombocytopenic purpura, we hypothesize that the transient fetal heart rate abnormalities were most likely due to reversible microthrombi in the placenta.
  Obstetrics and Gynecology 03/2008; 111(2 Pt 2):517-21. · 4.73 Impact Factor