Abstract
BACKGROUND
In sickle cell disease (SCD), polymerization of hemoglobin S (HbS) leads to the formation of rigid, non-deformable sickled RBCs. Loss of RBC deformability, sickling and irreversible membrane damage causes abnormal blood rheology, and increases viscosity which contributes to vasoocclusion and other SCD pathophysiology. GBT440 (generic name voxelotor) is a novel anti-polymerization and anti-sickling agent currently undergoing clinical evaluation for the treatment of SCD.
OBJECTIVE
The purpose of this study was to determine the effects of GBT440 on deformability of sickle RBCs (SS RBCs) and the hyperviscosity of sickle cell blood (SS blood).
METHODS
The mechanical and rheological properties of GBT440-treated SS RBCs were measured using micropipette and filtration techniques. The viscosity of sickle blood was measured using a Wells-Brookfield cone/plate viscometer.
RESULTS
GBT440 restored movement of deoxygenated SS RBCs through a gel filtration column and reduced the pressure required to pass SS RBCs through a polycarbonate filter. Moreover, GBT440 decreased the membrane shear elastic modulus of SS RBCs assessed via micropipette aspiration and reduced the hyperviscosity of SS blood under deoxygenated conditions.
CONCLUSIONS
GBT440 maintains SS RBC deformability and improves SS blood viscosity by inhibiting HbS polymerization under deoxygenated conditions. These results further support development of GBT440 as a disease-modifying agent in SCD patients.
TY - JOUR
T1 - GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions.
AU - Dufu,Kobina,
AU - Patel,Mira,
AU - Oksenberg,Donna,
AU - Cabrales,Pedro,
PY - 2018/4/18/pubmed
PY - 2018/11/6/medline
PY - 2018/4/18/entrez
KW - Sickle cell disease
KW - red blood cell deformability
KW - sickling
KW - viscosity
SP - 95
EP - 105
JF - Clinical hemorheology and microcirculation
JO - Clin Hemorheol Microcirc
VL - 70
IS - 1
N2 - BACKGROUND: In sickle cell disease (SCD), polymerization of hemoglobin S (HbS) leads to the formation of rigid, non-deformable sickled RBCs. Loss of RBC deformability, sickling and irreversible membrane damage causes abnormal blood rheology, and increases viscosity which contributes to vasoocclusion and other SCD pathophysiology. GBT440 (generic name voxelotor) is a novel anti-polymerization and anti-sickling agent currently undergoing clinical evaluation for the treatment of SCD. OBJECTIVE: The purpose of this study was to determine the effects of GBT440 on deformability of sickle RBCs (SS RBCs) and the hyperviscosity of sickle cell blood (SS blood). METHODS: The mechanical and rheological properties of GBT440-treated SS RBCs were measured using micropipette and filtration techniques. The viscosity of sickle blood was measured using a Wells-Brookfield cone/plate viscometer. RESULTS: GBT440 restored movement of deoxygenated SS RBCs through a gel filtration column and reduced the pressure required to pass SS RBCs through a polycarbonate filter. Moreover, GBT440 decreased the membrane shear elastic modulus of SS RBCs assessed via micropipette aspiration and reduced the hyperviscosity of SS blood under deoxygenated conditions. CONCLUSIONS: GBT440 maintains SS RBC deformability and improves SS blood viscosity by inhibiting HbS polymerization under deoxygenated conditions. These results further support development of GBT440 as a disease-modifying agent in SCD patients.
SN - 1875-8622
UR - https://www.unboundmedicine.com/medline/citation/29660913/GBT440_improves_red_blood_cell_deformability_and_reduces_viscosity_of_sickle_cell_blood_under_deoxygenated_conditions_
DB - PRIME
DP - Unbound Medicine
ER -
