Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients.
To investigate underlying mechanisms of thrombocytopenia in myelodysplastic syndrome (MDS), radiolabeled platelet studies were performed in 30 MDS patients with platelet counts less than 100 x 10(9)/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 of 30 patients (4.3 +/- 0.9 days [mean +/- SD] vs 6.0 +/- 1.3, P = .0003). Platelet production rate (PPR) was reduced in 25 of 30 patients (68 +/- 34 x 10(9)/d vs 220 +/- 65, P < .0001). Thrombopoietin levels were not significantly correlated with the PPR. However, the glycocalicin index was significantly higher compared with controls (15 +/- 16 vs 0.7 +/- 0.2, P = .001) and significantly correlated with the PPR (P = .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 less than 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.
Houwerzijl
Ewout J
EJ
Department of Hematology, University Hospital Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. j.th.m.de.wolf@int.azg.nl
Blom
Nel R
NR
van der Want
Johannes J L
JJ
Louwes
Henk
H
Esselink
Mariet T
MT
Smit
Jan W
JW
Vellenga
Edo
E
de Wolf
Joost Th M
JT
D000368:Aged; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000473:pathology*; D001856:Bone Marrow Examination; D053148:Caspase 3; D020169:Caspases; D016922:Cellular Senescence; D005260:Female; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000473:pathology*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000150:complications / Q000473:pathology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000032:analysis; D013921:Thrombocytopenia / Q000209:etiology*; D013926:Thrombopoietin / Q000097:blood
D015415:Biomarkers; D019038:Platelet Glycoprotein GPIb-IX Complex; C023592:glycocalicin; D013926:Thrombopoietin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases