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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3472-3479.
Prepublished online as a Blood First Edition Paper on November 12, 2004; DOI 10.1182/blood-2004-06-2108.
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Submitted June 3, 2004
Accepted October 30, 2004
Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryoctes in myelodysplastic patients
Ewout J Houwerzijl, Nel R Blom, Johannes J van der Want, Henk Louwes, Mariet T Esselink, Jan W Smit, Edo Vellenga, and Joost T de Wolf*
Department of Hematology, University Hospital Groningen, Groningen, The Netherlands
Department of Hematology, University Hospital Groningen, Groningen, The Netherlands; Department of Cell Biology, Section for Electron Microscopy, University of Groningen, Groningen, The Netherlands
Department of Cell Biology, Section for Electron Microscopy, University of Groningen, Groningen, The Netherlands
Nuclear Medicine, Martini Hospital, Groningen, The Netherlands
* Corresponding author; email: j.th.m.de.wolf{at}int.azg.nl.
To investigate underlying mechanisms of thrombocytopenia in myelodysplastic syndrome (MDS), radiolabeled platelet studies were performed in 30 MDS patients with platelets <100 x 109/L. Furthermore, plasma thrombopoietin and glycocalicin-index (a parameter of platelet or megakaryocyte destruction) were determined. Mean platelet life (MPL), corrected for the degree of thrombocytopenia, was reduced in 15/30 patients (4.3 ± 0.9 days (mean ± SD) vs 6.0 ± 1.3, p=0.0003). Platelet production rate (PPR) was reduced in 25/30 patients (68 ± 34 x 109/d vs 220 ± 65, p<0.0001). Thrombopoietin levels were not significantly correlated with the PPR. However, the glycocalicin-index was significantly higher compared to controls (15 ± 16 vs 0.7 ± 0.2, p=0.001) and significantly correlated with the PPR (p=0.02, r=-0.5), but not with the MPL (p=1.8). Ultrastructural studies demonstrated necrosis-like programmed cell death (PCD) in mature and immature megakaryocytes (n=9). Immunohistochemistry of the bone marrow biopsies demonstrated no positive staining of MDS megakaryocytes for activated caspase-3 (n=24) or cathepsin D (n=21), while activated caspase-8 was demonstrated in a subgroup of patients (5/21) in <10% of megakaryocytes. These results indicate that the main cause of thrombocytopenia in MDS is caspase-3-independent necrosis-like PCD resulting in a decreased PPR in conjunction with an increased glycocalicin-index.
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