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1. von Willebrand disease

Author

Seidizadeh, Omid, Eikenboom, Jeroen C. J., Denis, Cécile V., Flood, Veronica H., James, Paula, Lenting, Peter J., Baronciani, Luciano, O’Donnell, James S., Lillicrap, David, and Peyvandi, Flora

Published
2024
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4. Type 1 VWD classification revisited - novel insights from combined analysis of the LoVIC and WiN studies

Author

Poli Van Creveldkliniek Medisch, Child Health, Atiq, Ferdows, Blok, Robin, van Kwawegen, Calvin, Doherty, Dearbhla, Lavin, Michelle, van der Bom, Johanna G, O'Connell, Niamh M, de Meris, Joke, Ryan, Kevin, Schols, Saskia E M, Byrne, Mary B, Heubel-Moenen, Floor C J I, van Galen, Karin P M, Preston, Roger J S, Cnossen, Marjon H, Fijnvandraat, Karin, Baker, Ross Ian, Meijer, Karina, James, Paula D, Di Paola, Jorge, Eikenboom, Jeroen C J, Leebeek, Frank W G, O'Donnell, James S, Poli Van Creveldkliniek Medisch, Child Health, Atiq, Ferdows, Blok, Robin, van Kwawegen, Calvin, Doherty, Dearbhla, Lavin, Michelle, van der Bom, Johanna G, O'Connell, Niamh M, de Meris, Joke, Ryan, Kevin, Schols, Saskia E M, Byrne, Mary B, Heubel-Moenen, Floor C J I, van Galen, Karin P M, Preston, Roger J S, Cnossen, Marjon H, Fijnvandraat, Karin, Baker, Ross Ian, Meijer, Karina, James, Paula D, Di Paola, Jorge, Eikenboom, Jeroen C J, Leebeek, Frank W G, and O'Donnell, James S

Published
2024

5. The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A

Author

Poli Van Creveldkliniek Medisch, Regenerative Medicine and Stem Cells, Oomen, Ilja, Verhagen, Marieke, Miranda, Mariarosaria, Allacher, Peter, Beckers, Erik A M, Blijlevens, Nicole M A, van der Bom, Johanna G, Coppens, Michiel, Driessens, Mariëtte, Eikenboom, Jeroen C J, Fijnvandraat, Karin, Hassan, Shermarke, van Heerde, Waander L, Hooimeijer, H Louise, Jansen, Joop H, Kaijen, Paul, Leebeek, Frank W G, Meijer, Daniëlle, Paul, Helmut, Rijpma, Sanna R, Rosendaal, Frits R, Smit, Cees, van Vulpen, Lize F D, Voorberg, Jan, Schols, Saskia E M, Gouw, Samantha C, Poli Van Creveldkliniek Medisch, Regenerative Medicine and Stem Cells, Oomen, Ilja, Verhagen, Marieke, Miranda, Mariarosaria, Allacher, Peter, Beckers, Erik A M, Blijlevens, Nicole M A, van der Bom, Johanna G, Coppens, Michiel, Driessens, Mariëtte, Eikenboom, Jeroen C J, Fijnvandraat, Karin, Hassan, Shermarke, van Heerde, Waander L, Hooimeijer, H Louise, Jansen, Joop H, Kaijen, Paul, Leebeek, Frank W G, Meijer, Daniëlle, Paul, Helmut, Rijpma, Sanna R, Rosendaal, Frits R, Smit, Cees, van Vulpen, Lize F D, Voorberg, Jan, Schols, Saskia E M, and Gouw, Samantha C

Published
2024

6. The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A

Author

Oomen, Ilja, primary, Verhagen, Marieke, additional, Miranda, Mariarosaria, additional, Allacher, Peter, additional, Beckers, Erik A. M., additional, Blijlevens, Nicole M. A., additional, Bom, Johanna G. van der, additional, Coppens, Michiel, additional, Driessens, Mariëtte, additional, Eikenboom, Jeroen C. J., additional, Fijnvandraat, Karin, additional, Hassan, Shermarke, additional, van Heerde, Waander L., additional, Hooimeijer, H. Louise, additional, Jansen, Joop H., additional, Kaijen, Paul, additional, Leebeek, Frank W. G., additional, Meijer, Daniëlle, additional, Paul, Helmut, additional, Rijpma, Sanna R., additional, Rosendaal, Frits R., additional, Smit, Cees, additional, van Vulpen, Lize F. D., additional, Voorberg, Jan, additional, Schols, Saskia E. M., additional, and Gouw, Samantha C., additional

Published
2024
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8. SYMPHONYconsortium: Orchestrating personalized treatment for patients with bleeding disorders

Author

Cnossen, Marjon H., Moort, Iris, Reitsma, Simone H., Maat, Moniek P. M., Schutgens, Roger E. G., Urbanus, Rolf T., Lingsma, Hester F., Mathot, Ron A. A., Gouw, Samantha C., Meijer, Karina, Bredenoord, Annelien L., Graaf, Rieke, Fijnvandraat, Karin, Meijer, Alexander B., Akker, Emile, Bierings, Ruben, Eikenboom, Jeroen C. J., Biggelaar, Maartje, Haas, Masja, Voorberg, Jan, Leebeek, Frank W. G., Cnossen, Marjon H., Reitsma, Simone H., Haas, Masja, Biggelaar, Maartje, Leebeek, Frank W. G., Voorberg, Jan, Maat, Moniek P. M., Schutgens, Roger E. G., Urbanus, Rolf T., Lingsma, Hester F., Mathot, Ron A. A., Gouw, Samantha C., Meijer, Karina, Bredenoord, Annelien L., Graaf, Rieke, Fijnvandraat, Karin, Meijer, Alexander B., Akker, Emile, Bierings, Ruben, Eikenboom, Jeroen C. J., Moort, Iris, Arisz, Ryanne A., Zivkovic, Minka, Hoorn, E. Shannon, Bukkems, Laura H., Goedhart, Tine M. C. H. J., Romano, Lorenzo G. R., Al Arashi, Wala, Cloesmeijer, Michael E., Janssen, Alexander, Brands, Martijn R., Baas, Lieke, Castillo Alferez, Jessica, Zhang, Huan, Laan, Sebastiaan N. J., Boender, Johan, Bom, Johanna G., Bos, Mettine H. A., Burdorf, Lex, Coppens, Michiel, Driessens, Mariette, Fischer, Kathelijne F., Haverman, Lotte, Hazelzet, Jan A., Huisman, Elise J., Jansen, Natalie, Jong, Sean, Kruip, Marieke, Leeuwen, Nikki, Meer, Felix, Meijer, Stephan, Amstel, Hans Kristian Ploos, Polinder, Suzanne, Schols, Saskia E. M., Wijfjes, Guus, Kluft, Kees, Heerde, Waander L., Goedhart, Geertje, Uyl, Carin, Timp, Jasmijn, Stekelenburg, Anke, Moenen, Floor, Ypma, Paula, Nieuwenhuizen, Laurens, and Plat, Arnoud

Abstract

Treatment choices for individual patients with an inborn bleeding disorder are increasingly challenging due to increasing options and rising costs for society. We have initiated an integrated interdisciplinary national research program. The SYMPHONY consortium strives to orchestrate personalized treatment in patients with an inborn bleeding disorder, by unraveling the mechanisms behind interindividual variations of bleeding phenotype. The SYMPHONY consortium will investigate patients with an inborn bleeding disorder, both diagnosed and not yet diagnosed. Research questions are categorized under the themes: (1) diagnosis, (2) treatment, and (3) fundamental research, and consist of work packages addressing specific domains. Importantly, collaborations between patients and talented researchers from different areas of expertise promise to augment the impact of the SYMPHONY consortium, leading to unique interactions and intellectual property. SYMPHONY will perform research on all aspects of care, treatment individualization in patients with inborn bleeding disorders, as well as diagnostic innovations and results of molecular genetics and cellular model technology with regard to the hemostatic process. We believe that these research investments will lead to health‐care innovations with long‐term clinical and societal impact. This consortium has been made possible by a governmental, competitive grant from the Netherlands Organization for Scientific Research (NWO) within the framework of the NWA‐ORC Call grant agreement NWA.1160.18.038.

Published
2022
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9. Clinical value of early viscoelastometric point‐of‐care testing during postpartum hemorrhage for the prediction of severity of bleeding: A multicenter prospective cohort study in the Netherlands

Author

Ramler, Paul I., primary, Gillissen, Ada, additional, Henriquez, Dacia D. C. A., additional, Caram‐Deelder, Camila, additional, Markovski, Alexander A., additional, Maat, Moniek P. M., additional, Duvekot, Johannes J., additional, Eikenboom, Jeroen C. J., additional, Bloemenkamp, Kitty W. M., additional, Lith, Jan M. M., additional, Akker, Thomas, additional, and Bom, Johanna G, additional

Published
2021
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10. Population pharmacokinetics of the von Willebrand factor–factor VIII interaction in patients with von Willebrand disease

Author

Bukkems, Laura H., primary, Heijdra, Jessica M., additional, de Jager, Nico C. B., additional, Hazendonk, Hendrika C. A. M., additional, Fijnvandraat, Karin, additional, Meijer, Karina, additional, Eikenboom, Jeroen C. J., additional, Laros-van Gorkom, Britta A. P., additional, Leebeek, Frank W. G., additional, Cnossen, Marjon H., additional, and Mathôt, Ron A. A., additional

Published
2021
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11. Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms

Author

Cartwright, Ashley, Webster, Simon J, de Jong, Annika, Dirven, Richard J, Bloomer, Lisa D S, Al-Buhairan, Ahlam M, Budde, Ulrich, Halldén, Christer, Habart, David, Goudemand, Jenny, Peake, Ian R, Eikenboom, Jeroen C J, Goodeve, Anne C, Hampshire, Daniel J, Cartwright, Ashley, Webster, Simon J, de Jong, Annika, Dirven, Richard J, Bloomer, Lisa D S, Al-Buhairan, Ahlam M, Budde, Ulrich, Halldén, Christer, Habart, David, Goudemand, Jenny, Peake, Ian R, Eikenboom, Jeroen C J, Goodeve, Anne C, and Hampshire, Daniel J

Abstract

Copy number variation (CNV) is known to cause all von Willebrand disease (VWD) types, although the associated pathogenic mechanisms involved have not been extensively studied. Notably, in-frame CNV provides a unique opportunity to investigate how specific von Willebrand factor (VWF) domains influence the processing and packaging of the protein. Using multiplex ligation-dependent probe amplification, this study determined the extent to which CNV contributed to VWD in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease cohort, highlighting in-frame deletions of exons 3, 4-5, 32-34, and 33-34. Heterozygous in vitro recombinant VWF expression demonstrated that, although deletion of exons 3, 32-34, and 33-34 all resulted in significant reductions in total VWF (P < .0001, P < .001, and P < .01, respectively), only deletion of exons 3 and 32-34 had a significant impact on VWF secretion (P < .0001). High-resolution microscopy of heterozygous and homozygous deletions confirmed these observations, indicating that deletion of exons 3 and 32-34 severely impaired pseudo-Weibel-Palade body (WPB) formation, whereas deletion of exons 33-34 did not, with this variant still exhibiting pseudo-WPB formation similar to wild-type VWF. In-frame deletions in VWD, therefore, contribute to pathogenesis via moderate or severe defects in VWF biosynthesis and secretion.

Published
2020
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13. Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms

Author

Cartwright, Ashley, primary, Webster, Simon J., primary, de Jong, Annika, primary, Dirven, Richard J., primary, Bloomer, Lisa D. S., primary, AL-Buhairan, Ahlam M., primary, Budde, Ulrich, primary, Halldén, Christer, primary, Habart, David, primary, Goudemand, Jenny, primary, Peake, Ian R., primary, Eikenboom, Jeroen C. J., primary, Goodeve, Anne C., primary, and Hampshire, Daniel J., primary

Published
2020
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14. Lowering the increased intracellular pH of human-induced pluripotent stem cell-derived endothelial cells induces formation of mature Weibel-Palade bodies

Author

Tiemeier, Gesa L., primary, Koning, Rozemarijn, additional, Wang, Gangqi, additional, Kostidis, Sarantos, additional, Rietjens, Rosalie G. J., additional, Sol, Wendy M. P. J., additional, Dumas, Sébastien J., additional, Giera, Martin, additional, Berg, Cathelijne W., additional, Eikenboom, Jeroen C. J., additional, Berg, Bernard M., additional, Carmeliet, Peter, additional, and Rabelink, Ton J., additional

Published
2020
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24. The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance

Author

Mufti, Ahmad H, Ogiwara, Kenichi, Swystun, Laura L, Eikenboom, Jeroen C J, Budde, Ulrich, Hopman, Wilma M, Halldén, C, Goudemand, Jenny, Peake, Ian R, Goodeve, Anne C, Lillicrap, David, Hampshire, Daniel J, Mufti, Ahmad H, Ogiwara, Kenichi, Swystun, Laura L, Eikenboom, Jeroen C J, Budde, Ulrich, Hopman, Wilma M, Halldén, C, Goudemand, Jenny, Peake, Ian R, Goodeve, Anne C, Lillicrap, David, and Hampshire, Daniel J

Abstract

Plasma levels of von Willebrand factor (VWF) vary considerably in the general population and this variation has been linked to several genetic and environmental factors. Genetic factors include 2 common single nucleotide variants (SNVs) located in VWF, rs1063856 (c.2365A>G) and rs1063857 (c.2385T>C), although to date the mechanistic basis for their association with VWF level is unknown. Using genotypic/phenotypic information from a European healthy control population, in vitro analyses of recombinant VWF expressing both SNVs, and in vivo murine models, this study determined the precise nature of their association with VWF level and investigated the mechanism(s) involved. Possession of either SNV corresponded with a significant increase in plasma VWF in healthy controls (P < .0001). In vitro expression confirmed this observation and highlighted an independent effect for each SNV (P < .0001 and P < .01, respectively), despite close proximity and strong linkage disequilibrium between them both. The influence of c.2365A>G on VWF levels was also confirmed in vivo. This increase in VWF protein corresponded to an increase in VWF messenger RNA (mRNA) resulting, in part, from prolonged mRNA half-life. In addition, coinheritance of both SNVs was associated with a lower VWF propeptide-to-VWF antigen ratio in healthy controls (P < .05) and a longer VWF half-life in VWF knockout mice (P < .0001). Both SNVs therefore directly increase VWF plasma levels through a combined influence on VWF biosynthesis and clearance, and may have an impact on disease phenotype in both hemostatic and thrombotic disorders.

Published
2018
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26. The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study.

Author

Ypma, Paula F., Geloven, Nan, Kerkhoffs, Jean Louis H., Boekhorst, Peter, Zwaginga, Jaap J., Beckers, Erik A. M., Brand, Anneke, Meer, Pieter F., and Eikenboom, Jeroen C. J.

Subjects
HEMORRHAGE, THROMBOCYTOPENIA, BLOOD proteins, PLATELET count, COHORT analysis
Abstract

Summary: In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C‐reactive protein) and bleeding (WHO grading) in 88 patients with 116 on‐protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05–1·46, P‐value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C‐reactive protein (CRP) (95% CI 1·04–1·60, P‐value 0·02) after correction for morning platelet count. The 24 h post‐transfusion corrected count increment (CCI24) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI24. We report two inexpensive and easy‐to‐apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients. [ABSTRACT FROM AUTHOR]

Published
2020
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27. The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance

Author

Mufti, Ahmad H., primary, Ogiwara, Kenichi, additional, Swystun, Laura L., additional, Eikenboom, Jeroen C. J., additional, Budde, Ulrich, additional, Hopman, Wilma M., additional, Halldén, Christer, additional, Goudemand, Jenny, additional, Peake, Ian R., additional, Goodeve, Anne C., additional, Lillicrap, David, additional, and Hampshire, Daniel J., additional

Published
2018
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28. Von Willebrand's Disease.

Author

Leebeek, Frank W. G. and Eikenboom, Jeroen C. J.

Subjects
*VON Willebrand disease, *GENETIC disorder diagnosis, *HEMORRHAGIC diseases, *VON Willebrand factor, *THERAPEUTICS
Abstract

The article discusses the etiology and treatment for Von Willebrand disease, an inherited bleeding disorder due to defective platelet adhesion and aggregation among patient. A brief overview on the discovery of the disease by internist Erik von Willebrand in 1926 as hereditary pseudohemopilia is mentioned. Other topics include the diagnosis of the disease, the symptoms and its impact to the patient's quality of life.

Published
2016
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29. Intracellular Retention, Enhanced Clearance, and Defective FVIII Binding Are Common Features of Von Willebrand Factor D'-D3 Domain Mutations in Patients with Von Willebrand Disease Type 1 From the European Mcmdm-1VWD Study

Author

Schneppenheim, Reinhard, primary, Budde, Ulrich, additional, Batlle, Javier, additional, Castaman, Giancarlo, additional, Eikenboom, Jeroen C. J., additional, Federici, Augusto B., additional, Goudemand, Jenny, additional, Obser, Tobias, additional, Oyen, Florian, additional, Rodeghiero, Francesco, additional, Schneppenheim, Sonja, additional, Peake, Ian R., additional, and Goodeve, Anne C., additional

Published
2012
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33. Investigation of the Role of Copy Number Variation In the Pathogenesis of Type 1 Von Willebrand Disease

Author

Hampshire, Daniel J., primary, Bloomer, Lisa D., additional, Al-Buhairan, Ahlam M., additional, Coyle, Rachael E., additional, Vijzelaar, Raymon N. C. P., additional, Lillicrap, David, additional, James, Paula D., additional, Eikenboom, Jeroen C. J., additional, Schneppenheim, Reinhard, additional, Rodeghiero, Francesco, additional, Montgomery, Robert R., additional, Peake, Ian R., additional, and Goodeve, Anne C., additional

Published
2010
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34. Variations in glycosylation of von Willebrand factor with O-linked sialylated T antigen are associated with its plasma levels

Author

van Schooten, Carina J. M., primary, Denis, Cécile V., additional, Lisman, Ton, additional, Eikenboom, Jeroen C. J., additional, Leebeek, Frank W., additional, Goudemand, Jenny, additional, Fressinaud, Edith, additional, van den Berg, H. Marijke, additional, de Groot, Philip G., additional, and Lenting, Peter J., additional

Published
2006
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42. A patient with von Willebrand's disease characterized by a compound heterozygosity for a substitution of Arg by Gln in the putative factor‐VIII‐binding domain of von Willebrand factor (vWF) on one allele and very low levels of mRNA from the second vWF allele

Author

Peerlinck, Kathelijne, primary, Eikenboom, Jeroen C. J., additional, Ploos, Hans K., additional, Amstel, Van, additional, Sangtawesin, Wanida, additional, Arnout, Jef, additional, Reitsma, Pieter H., additional, Vermylen, Jos, additional, and Brieut, Ernest, additional

Published
1992
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45. Efficacy of recombinant activated Factor VII in patients with massive uncontrolled bleeding: a retrospective observational analysis.

Author

Berkhof, Farida F. and Eikenboom, Jeroen C. J.

Subjects
*BLOOD coagulation, *HEMORRHAGE, *BLOOD coagulation disorders, *HEMOPHILIA, *THERAPEUTICS, *IMMUNOGLOBULINS
Abstract

BACKGROUND: Recombinant activated Factor VII (rFVIIa) is a prohemostatic agent used for treatment of hemophilia patients with inhibiting antibodies. It has also been used in the context of massive uncontrolled blood loss, but the efficacy has not been proven. The aim of this study was to evaluate the effectiveness of rFVIIa in massive uncontrolled blood loss. STUDY DESIGN AND METHODS: In this retrospective observational analysis patients were included that had received rFVIIa between April 2004 and January 2008 in the context of bleeding that could not be controlled by conventional transfusion therapy. Data were retrieved from patient files, anesthesia reports, the electronic hospital information system, and the computer files of the hospital blood transfusion service. Baseline demographics, medication data, laboratory data, transfusion data, and surgical data were analyzed. RESULTS: In 32 patients with massive uncontrolled blood loss, a significant reduction in transfusion requirements was observed after infusion of rFVIIa, when comparing the transfusions before and up to 48 hours after infusion of rFVIIa. Mean red blood cell (RBC) transfusions showed a reduction of 20.1 units before rFVIIa to 8.7 after rFVIIa (mean difference, 11.4 units; 95% confidence interval [CI], 6.4-16.5) and fresh-frozen plasma (FFP) transfusions showed a reduction of 19.3 units before rFVIIa to 9.3 after rFVIIa (mean difference, 9.9 units; 95% CI, 4.2-15.6). Fifty-six percent of patients receiving rFVIIa for uncontrolled life-threatening bleeding were alive at discharge from the hospital. CONCLUSION: This study suggests that rFVIIa may play a role in patients with massive uncontrolled blood loss by reducing the amount of RBC and FFP transfusions and by improving the coagulation variables. [ABSTRACT FROM AUTHOR]

Published
2009
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47. The clinical impact of platelet refractoriness: correlation with bleeding and survival.

Author

Kerkhoffs, Jean-Louis H., Eikenboom, Jeroen C. J., van de Watering, Leo M. G., van Wordragen-Vlaswinkel, Rinie J., Wijermans, Pierre W., and Brand, Anneke

Subjects
*BLOOD platelet transfusion, *HEMORRHAGE complications, *THROMBOCYTOPENIA, *ANTINEOPLASTIC agents, *CLINICAL indications, *MULTIPLE regression analysis, *PATIENTS
Abstract

BACKGROUND: Despite supportive care with platelet (PLT) transfusions, bleeding complications occur in a substantial number of patients with thrombocytopenia due to cytotoxic therapy. Moreover, refractoriness to PLT transfusions remains a frequently encountered problem. The clinical impact of PLT transfusion failure was investigated in 117 patients, part of a randomized PLT transfusion trial, which excluded patients with HLA and/or HPA alloantibodies. STUDY DESIGN AND METHODS: Between October 2003 and April 2005, a multicenter randomized controlled trial, testing the clinical efficacy of PLTs stored in plasma compared to PLT additive solution (PAS II), was performed. Using multiple regression analysis of observational data of patients randomized in one of the participating centers, the occurrence of PLT transfusion refractoriness was analyzed for a relation with bleeding complications and patient survival. RESULTS: PLT transfusion failure occurred at least once in 49.6 percent of the patients. Mild to moderate bleeding complications occurred in 19 percent of the patients. PLT transfusion failure was, independently from thrombocytopenia, positively associated with bleeding complications (odds ratio, 3.4; 95% confidence interval, 1.1-11). Moreover, patients experiencing one or more 24-hour PLT transfusion failures had, compared to patients always showing a sufficient 24-hour increment, a significantly reduced median survival of 491 days (interquartile range [IQR], 156-858 days) versus 825 days (IQR, 355-996 days), respectively. In a Cox regression model, the effect on survival was independent of therapy, diagnosis, and age. CONCLUSION: Our results suggest that PLT transfusion failure might be a sensitive clinical marker for the occurrence of bleeding and impaired patient survival. PLT transfusion failure, bleeding complications, and decreased survival could be manifestations of a more severe degree of endothelial damage. [ABSTRACT FROM AUTHOR]

Published
2008
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50. Variations in glycosylation of von Willebrand factor with O-linked sialylated T antigen are associated with its plasma levels

Author

van Schooten, Carina J. M., Denis, Cécile V., Lisman, Ton, Eikenboom, Jeroen C. J., Leebeek, Frank W., Goudemand, Jenny, Fressinaud, Edith, van den Berg, H. Marijke, de Groot, Philip G., and Lenting, Peter J.

Abstract

The glycosylation profile of von Willebrand factor (VWF) is known to strongly influence its plasma levels. VWF contains several carbohydrate structures, including O-linked glycans that primarily consist of sialylated T antigen (NeuAc(α2-3)Gal-(β1-3)-[NeuAc(α2-6)]GalNAc). It is not yet known whether O-linked carbohydrates affect VWF levels. We developed an immunosorbent assay based on neuraminidase incubation allowing subsequent binding of peanut agglutinin (PNA) to desialylated O-linked T antigen on VWF. An inverse relation was found between PNA binding and VWF antigen levels in healthy individuals (n = 111; Pearson rank = −0.43; P < .001). A similar inverse association was observed in randomly selected plasma samples from our diagnostic laboratory: 252% ± 125% for VWF levels less than 0.5 U/mL (n = 15); 131% ± 36% for VWF levels between 0.5 and 1.5 U/mL (n = 32); and 92% ± 40% for VWF levels more than 1.5 U/mL (n = 19). Reduced or increased PNA binding was also observed in patients with increased (liver cirrhosis) or reduced (von Willebrand disease [VWD] type 1) VWF antigen levels, respectively. VWD type 1 patients further displayed increased ratios of propeptide over mature VWF antigen levels (0.38 ± 0.18 versus 0.17 ± 0.03 for patients and controls, respectively; P < .001), which is indicative of reduced VWF survival in these patients. Of interest, a linear relation between PNA binding and propeptide/VWF ratio was observed (Spearman rank = 0.47), suggesting a potential association between O-linked glycosylation and VWF survival. Finally, we detected a marked decrease in PNA binding in post-DDAVP (1-deamino-8-D-arginine vasopressin) samples from various patients, indicating that the O-linked glycosylation profile of VWF stored in endothelial storage organelles may differ from circulating VWF.

Published
2007
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