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IHP-Loaded Red Blood Cells as Preventive Therapy In Sickle Cell Disease
Abstract 1625 Sickle cell disease (SCD) is a genetic disorder characterized by abnormal hemoglobin S (HbS) that polymerizes under hypoxic conditions leading to sickled-shape red blood cells (RBCs). Vaso-occlusive crisis (VOC) is one of the major clinical manifestations of the disease, very painful f...
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Published in: | Blood 2010-11, Vol.116 (21), p.1625-1625 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Abstract 1625
Sickle cell disease (SCD) is a genetic disorder characterized by abnormal hemoglobin S (HbS) that polymerizes under hypoxic conditions leading to sickled-shape red blood cells (RBCs). Vaso-occlusive crisis (VOC) is one of the major clinical manifestations of the disease, very painful for patients and causing irreversible organ damages. RBC exchange is commonly used as preventive and curative treatment of the disease. However, the therapeutic action of RBC exchange only relies on the removal of HbS-containing RBCs (SS-RBCs) and their transient replacement by normal RBCs (AA-RBCs). Recent works have shown that sickled reticulocytes, activated platelets and leukocytes play a critical role in the onset of VOC. They aggregate with endothelial cells creating local hypoxia, enhancing sickling and thus capillary blockade. Oxygen deprivation that occurs in venous capillaries may widely contribute to the severity of the occlusion. Therefore, increasing the oxygenation level in capillaries could help to prevent SS-RBCs from sickling and avoid crisis. This may be possible by transfusing patients with AA-RBCs loaded with Inositol HexaPhosphate (IHP), an allosteric effector that binds tightly to hemoglobin. The resulting suspension (IHP-RBCs) has the ability to increase oxygen release by 2 to 3 fold compared to normal AA-RBCs. The objective of the present study was to evaluate in vivo the benefit of using IHP-RBCs treatment in SCD. We used BERK transgenic mouse model that fully mimics human SCD in childhood with specific features of splenomegaly, reticulocytosis and leukocytosis. IHP-RBCs were prepared by loading IHP into murine C57BL6J RBCs using reversible hypotonic lysis method. RBCs subjected to reversible hypotonic lysis but without IHP were used as control suspension. Study was designed with repeated RBC exchanges scheduled every 2 weeks. First RBC exchange using IHP-RBCs or control suspension was performed on 6–7 week-old mice followed by 2 further injections. Mice were sacrificed one week after last RBC exchange and critical hematological parameters (reticulocyte, leukocyte, platelet counts and sickled cells) as well as serum inflammation markers were used as readouts to evaluate the risk of VOC. The first study was performed in normoxic conditions. After the therapy, approximately 42% of mouse RBCs had been replaced by IHP-RBCs or control suspension. Strong reduction of spleen weight (50%) and circulating sickled RBCs was observed in both cases du |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood.V116.21.1625.1625 |