ABSTRACT
The predictive value of clinical and platelet kinetic parameters for treatment outcome in idiopathic thrombocytopenic purpura (ITP) was investigated in 75 patients with platelets
Subject(s)
Blood Platelets/drug effects , Glucocorticoids/therapeutic use , Prednisone/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Thrombopoiesis/drug effects , Adolescent , Adult , Aged , Aged, 80 and over , Blood Platelets/physiology , Case-Control Studies , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/physiopathology , Purpura, Thrombocytopenic, Idiopathic/surgery , Remission Induction , Splenectomy , Thrombopoiesis/physiologyABSTRACT
Platelet kinetic studies in idiopathic thrombocytopenic purpura (ITP) have shown that in a subgroup of patients a shortened mean platelet life (MPL) is associated with a decreased platelet production rate (PPR). Other methods of studying certain aspects of thrombocytopoiesis are the plasma concentrations of thrombopoietin and glycocalicin.
Subject(s)
Platelet Glycoprotein GPIb-IX Complex/analysis , Purpura, Thrombocytopenic/blood , Thrombopoiesis , Thrombopoietin/blood , Adult , Aged , Blood Platelets/pathology , Bone Marrow/pathology , Cell Survival , Female , Humans , Male , Middle AgedABSTRACT
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.
Subject(s)
Apoptosis , Blood Platelets/pathology , Megakaryocytes/pathology , Myelodysplastic Syndromes/pathology , Thrombocytopenia/etiology , Aged , Biomarkers/blood , Bone Marrow Examination , Caspase 3 , Caspases , Cellular Senescence , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/complications , Platelet Glycoprotein GPIb-IX Complex/analysis , Thrombopoietin/bloodABSTRACT
To investigate whether altered megakaryocyte morphology contributes to reduced platelet production in idiopathic thrombocytopenic purpura (ITP), ultrastructural analysis of megakaryocytes was performed in 11 ITP patients. Ultrastructural abnormalities compatible with (para-)apoptosis were present in 78% +/- 14% of ITP megakaryocytes, which could be reversed by in vivo treatment with prednisone and intravenous immunoglobulin. Immunohistochemistry of bone marrow biopsies of ITP patients with extensive apoptosis showed an increased number of megakaryocytes with activated caspase-3 compared with normal (28% +/- 4% versus 0%). No difference, however, was observed in the number of bone marrow megakaryocyte colony-forming units (ITP, 118 +/- 93/105 bone marrow cells; versus controls, 128 +/- 101/105 bone marrow cells; P =.7). To demonstrate that circulating antibodies might affect megakaryocytes, suspension cultures of CD34+ cells were performed with ITP or normal plasma. Morphology compatible with (para-)apoptosis could be induced in cultured megakaryocytes with ITP plasma (2 of 10 samples positive for antiplatelet autoantibodies). Finally, the plasma glycocalicin index, a parameter of platelet and megakaryocyte destruction, was increased in ITP (57 +/- 70 versus 0.7 +/- 0.2; P =.009) and correlated with the proportion of megakaryocytes showing (para-) apoptotic ultrastructure (P =.02; r = 0.7). In conclusion, most ITP megakaryocytes show ultrastructural features of (para-) apoptosis, probably due to action of factors present in ITP plasma.