Abstract
The consequences of sickle cell disease (SCD) include ongoing hematopoietic stress, hemolysis, vascular damage, and effect of chronic therapies, such as blood transfusions and hydroxyurea, on hematopoietic stem and progenitor cell (HSPC) have been poorly characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients, stratified by treatment and control cohorts. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, a two to five-fold increase in CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors, and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a as well as high levels CD49f antigen expression. These findings were present to varying degrees in all patients with SCD, including those on chronic therapy and those who were therapy naive. HU treatment appeared to normalize many of these parameters. Chronic stress erythropoiesis and inflammation incited by SCD and HU therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.
Highlights
Hematopoiesis in patients with sickle ccell disease (SCD) is associated with erythroid hyperplasia, reticulocytosis, and ineffective erythropoiesis starting at the immature erythroblast stage in the bone marrow (BM) [1,2,3,4]
Analysis of hematological and red blood cells (RBC) parameters revealed that the HU treated group had significantly higher levels of HbF, mean corpuscular volume (MCV), erythropoietin (EPO), and platelets compared to the naive and transfusion groups, while the transfusion group had significantly higher levels of bilirubin and ferritin compared to the HU group (Table 1 and Figure S1)
In this study we report on the composition of HSC in patients with sickle cell disease (SCD) under different clinical conditions: Naïve, on chronic transfusion and on HU
Summary
Hematopoiesis in patients with sickle ccell disease (SCD) is associated with erythroid hyperplasia, reticulocytosis, and ineffective erythropoiesis starting at the immature erythroblast stage in the bone marrow (BM) [1,2,3,4]. The consequences of SCD on stem and progenitor cells have not been fully characterized. Using a functional assay to characterize hematopoiesis, Hara et al reported in 1977 that there were more burst forming unit-erythroid (BFU-E) cells circulating in the peripheral blood (PB) of patients with SCD compared to healthy individuals [5]. Croizat et al expanded upon these results and observed increased numbers of BFU-Es, in a subset of SCD patients with low. In 2003, the number of circulating CD34+ CD38− HSPCs was shown to be slightly higher in steady state SCD patients as compared to controls, but dramatically higher during vaso-occlusive crises by Lamming et al [8]. At the level of BM, Uchida et al observed lower levels of CD34+ cells in SCD patients treated with HU as compared to “steady-state” or SCD patients without treatment [9], suggesting that some of the discrepancies in the previous reports might have been caused by the lack of stratification of the patients by treatment modality
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