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Novel insights into the role of fetal hemoglobin in spleen function, red cell survival and ineffective erythropoiesis in sickle cell disease

Abstract : Sickle cell disease (SCD) is caused by a single point mutation in the β-globin gene generating sickle hemoglobin (HbS). Hypoxia drives HbS polymerization that is responsible for red blood cell (RBC) sickling and reduced deformability. In SCD, splenic dysfunction results in life-threatening complications, particularly in early childhood. During the course of the disease, the spleen functionally declines and anatomically disappears, although with great individual variability depending on modulating genetic and environmental factors. The key modulator of disease severity is fetal hemoglobin (HbF), as the presence of HbF inhibits HbS polymerization, thus delaying and preventing severe complications, ameliorating patients’ quality of life and increasing survival. There is a rather well characterized hetero cellular concentration of HbF and distribution in circulating RBCs but the role of HbF during erythropoiesis, is poorly documented. With the aim of better understanding the role of HbF in spleen function, red cell survival and ineffective erythropoiesis we investigated 1) the natural history of spleen dysfunction in SCD children, 2) the cellular expression and distribution of HbF in SCD children, in untreated patients and patients treated with Hydroxycarbamide and 3) ineffective erythropoiesis and the role of HbF during terminal erythropoiesis.We developed a flow cytometry high-throughput method to measure splenic filtration function and showed that splenic loss of function is present very early in life at 3-6 months in SCD children and further declines with age. We also highlighted that irreversibly sickled cells (ISCs) are a potential contributor to acute splenic sequestration (ASS) which in turn results in further loss of splenic function. In the second part of this work, we set up an original approach to determine HbF distribution per cell. Using a longitudinal cohort of patients treated with hydroxycarbamide (HC - an inducer of HbF), we showed that HC has a global positive impact on RBCs, by not only increasing HbF content but also by increasing the volume of all RBCs independent of HbF. We moreover showed that High F-cells are a more precise marker of HC efficacy. In the last part of the thesis, we showed for the first time clear evidence of ineffective erythropoiesis in SCD and revealed a new role of HbF during terminal erythropoiesis protecting erythroblasts from apoptosis. In conclusion, this work shows that HbF has an additional beneficial effect in SCD by not only conferring a preferential survival of F-cells in the circulation but also by decreasing ineffective erythropoiesis. Importantly, it suggests that the delay in hemoglobin switch in SCD might be also due to an enrichment in F-erythroblasts during terminal erythroid differentiation occurring very early in infancy, shortly after birth.
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Submitted on : Monday, February 1, 2021 - 1:26:07 PM
Last modification on : Tuesday, October 19, 2021 - 5:56:22 PM
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  • HAL Id : tel-03127209, version 1


Sara El Hoss. Novel insights into the role of fetal hemoglobin in spleen function, red cell survival and ineffective erythropoiesis in sickle cell disease. Tissues and Organs [q-bio.TO]. Université de Paris, 2019. English. ⟨NNT : 2019UNIP7140⟩. ⟨tel-03127209⟩



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