High circulating sclerostin is present in patients with thalassemia-associated osteoporosis and correlates with bone mineral density.

Osteoporosis is a severe complication of thalassemia. Sclerostin is a Wnt signaling inhibitor, which is produced by osteocytes and inhibits osteoblast function. Sclerostin is implicated in the pathogenesis of osteoporosis of different etiology. The aim of the study was to evaluate circulating sclerostin in 66 patients (median age 42 years) with thalassemia and osteoporosis who participated in a phase 2, randomized study (zoledronic acid vs. placebo) and the results were compared with those of 30 healthy controls (median age 44 years) without osteopenia/osteoporosis and 62 women with postmenopausal osteoporosis (median age 63 years). At baseline, thalassemic patients with osteoporosis had elevated circulating levels of sclerostin (median: 605 pg/ml, range: 22-1,227 pg/ml) compared to healthy controls without osteopenia/osteoporosis (250 pg/ml, 0-720 pg/ml, p<0.001) and reduced levels of sclerostin compared with postmenopausal women with osteoporosis (840 pg/ml, 181-1,704 pg/ml, p<0.001). Thalassemia patients had also increased serum dickkopf-1 (Dkk-1) and high bone turnover. Circulating sclerostin levels correlated with bone mineral density in lumbar spine (r=0.619, p<0.001), distal radius (r=0.401, p=0.001) and femoral neck (r=0.301, p=0.021). Zoledronic acid did not alter sclerostin levels after 12 months of therapy, although it reduced circulating Dkk-1. We conclude that circulating sclerostin is elevated in thalassemia patients with osteoporosis and correlated with their BMD, but it was not reduced post zoledronic acid administration. These findings suggest that high sclerostin may serve as a marker of increased osteocyte activity in thalassemia patients. Drugs targeting sclerostin may also be used in this difficult to treat disorder associated with bone loss.

Detection of CD55 and/or CD59 deficient red cell populations in patients with aplastic anaemia, myelodysplastic syndromes and myeloproliferative disorders.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal stem cell disorder characterized by intravascular haemolysis, venous thrombosis, marrow hypoplasia, frequent episodes of infection, and rarely leukaemic conversion. At the cellular level, PNH is characterized by the decrease or absence of glycosylphosphatidylinositol (GPI)-anchored molecules, such as CD55 and CD59, from the cell surface. PNH-like clones have been described in various haematological disorders. The link between PNH and aplastic anaemia (AA) has been established but the relationship of PNH with myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD) remains unclear. In this study, the presence of CD55 and/or CD59 defective (PNH-like) red cell populations was evaluated in 21 patients with AA, 133 with MDS, 197 with MPD, 7 with PNH and in 121 healthy blood donors using the Sephacryl Gel Test microtyping system. Red cell populations deficient in both molecules CD55 and CD59 were detected in 33.3% of AA patients, in 16.5% of MDS patients (50% with hypoplastic bone marrow), in 14.2% of MPD patients (more often in essential thrombocythemia, 21.2%) and in all PNH patients. CD55 deficient red cell populations were found in 14.2% of patients with AA, 12.7% of patients with MDS and 21.3% of patients with MPD. CD59 deficient populations were found in 9.5% of AA patients, 2.2% of MDS patients and 2% of MPD patients. These results indicate an association between PNH, AA and MDS or even between PNH and MPD. Further investigation is necessary to work out the mechanisms of this association, and to define classification criteria for borderline cases, where diagnosis is difficult.

Fetal Erythropoiesis after Allogeneic Bone Marrow Transplantation Estimated by the Peripheral Blood Erythrocytes Containing Hemoglobin F (F-cells).

During bone marrow engraftment following BMT there is a re-establishment of fetal erythropoiesis, expressed by the increase of F-cells. This seems to depend on several factors such as underlying disease, conditioning before therapy and other mechanisms concerning both the donor and the recipient bone marrow. The aim of this work was to study the factors influencing F-cell production during bone marrow engraftment following transplantation. We studied 28 patients who underwent allogeneic bone marrow transplantation, for various hematological malignancies (CML, AML, ALL, CMML and SAA). F-cells were estimated on peripheral blood smears by indirect immunofluorescence. Overall, there was an F-cell increase after BMT in comparison with values before BMT; this increase was significant on days 15-50 (p <.01). F-cell on days 18, 25, 32 and 40 following transplantation were significantly higher (p <.01) in patients who have had increased F-cell numbers post-chemotherapy before BMT, compared with the patients who did not show any increase of the F-cell number post chemotherapy. During the first month following transplantation (day 7 to day 40) patients who were transplanted from high F-cell donors failed to show any significant differences in their F-cell numbers in comparison to those transplanted from low F-cell donors. However, the F-cell increase became significantly higher in the former group between days 50 and 120. This observation implies that the stressed erythropoiesis of the initial phase does not allow revealing the varying F-cell production of the capacities donor bone marrow, while later, when the graft has settled, the high F-cell donors reveal this property of the host.

Detection of CD55- and/or CD59-deficient red cell populations in patients with lymphoproliferative syndromes.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria is an acquired clonal stem cell disorder characterized by the decrease or absence of glycosylphosphatidylinositol-anchored molecules from the surface of the affected cells, such as CD55 and CD59, resulting in chronic intravascular hemolysis, cytopenia and increased tendency to thrombosis. PNH-phenotype has been described in various hematological disorders, mainly in aplastic anemia and myelodysplastic syndromes, while it has been reported that complete deficiency of CD55 and CD59 has also been found in patients with lymphoproliferative syndromes, like non-Hodgkin's lymphomas. MATERIALS AND METHODS: The presence of CD55- and/or CD59-defective red cell populations was evaluated in 217 patients with lymphoproliferative syndromes. The study population included 87 patients with NHL, 55 with HD, 49 with CLL, 22 with ALL and four with hairy cell leukemia. One hundred and twenty-one healthy blood donors and seven patients with PNH were also studied as control groups. The sephacryl gel microtyping system was performed for the detection of CD55- and CD59-deficient red cell populations. Ham and sucrose lysis tests were also performed in all samples with CD55 or CD59 negative populations. RESULTS: Red cell populations deficient in both CD55 and CD59 molecules were detected in 9.2% of patients with lymphoproliferative syndromes (more often in ALL and nodular sclerosis type of HD) and in all PNH patients. CD55-deficient red cell populations were found in 8.7% of LPS patients (especially in low grade B-cell NHL), while CD59-deficient populations were found in only two patients with low grade B-cell NHL. CONCLUSION: These data indicate a possible association between paroxysmal nocturnal hemoglobinuria phenotype and lymphoproliferative syndromes, while further investigation is necessary to work out the mechanisms and the significance of the existence of this phenotype in these patients.