Simultaneous polymerization and adhesion under hypoxia in sickle cell disease

Papageorgiou, Dimitrios; Abidi, Sabia Z.; Chang, Hung-Yu; Li, Xuejin; Kato, Gregory J.; Karniadakis, George Em; Suresh, S.; Dao, Ming

doi:10.1073/pnas.1807405115

Cited by 61 publications

(59 citation statements)

References 47 publications

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“…Exacerbating the hypoxia‐induced polymerization is the inherent low‐affinity of HbS, presumably due to high levels of 2,3‐diphosphoglycerate (2,3‐DPG) present in sickle RBCs . These sickled RBCs have strongly reduced deformability and show increased adherence to vascular endothelium, leading to vaso‐occlusive crises . Hydroxyurea (HU), regular blood transfusion, and L‐glutamine are the main treatment options in SCD, with allogeneic hematopoietic stem cell transplantation being the only curative therapy currently available .…”

Section: Introductionmentioning

confidence: 99%

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

et al. 2019

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In sickle cell disease (SCD), sickle hemoglobin (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These sickled RBCs have strongly reduced deformability, leading to vaso‐occlusive crises and chronic hemolytic anemia. To date, there are no reliable laboratory parameters or assays capable of predicting disease severity or monitoring treatment effects. We here report on the oxygenscan, a newly developed method to measure RBC deformability (expressed as Elongation Index ‐ EI) as a function of pO2. Upon a standardized, 22 minute, automated cycle of deoxygenation (pO2 median 16 mmHg ± 0.17) and reoxygenation, a number of clinically relevant parameters are produced in a highly reproducible manner (coefficients of variation <5%). In particular, physiological modulators of oxygen affinity, such as, pH and 2,3‐diphosphoglycerate showed a significant correlation (respectively R = ‑0.993 and R = 0.980) with Point of Sickling (PoS5%), which is defined as the pO2 where a 5% decrease in EI is observed during deoxygenation. Furthermore, in vitro treatment with antisickling agents, including GBT440, which alter the oxygen affinity of hemoglobin, caused a reproducible left‐shift of the PoS, indicating improved deformability at lower oxygen tensions. When RBCs from 21 SCD patients were analyzed, we observed a significantly higher PoS in untreated homozygous SCD patients compared to treated patients and other genotypes. We conclude that the oxygenscan is a state‐of‐the‐art technique that allows for rapid analysis of sickling behavior in SCD patients. The method is promising for personalized treatment, development of new treatment strategies and could have potential in prediction of complications.

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Section: Introductionmentioning

confidence: 99%

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

et al. 2019

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“…Structurally, the net effect of this Asn-Lys substitution is the removal of the α 2 β 2 -stabilizing Lys132-Glu7 salt bridge, highlighting the perturbation of local electrostatic equilibrium by SCD-linked mutations such as K132N and E6V, too. Previous molecular dynamics simulation studies also suggest that Hb-S polymerization is favoured by inter-facial electrostatic interactions (18), and is inhibited when subjected to hypoxic (low pH environment) conditions, where the side chain of Glu6 gets neutralized and the electrostatic repulsion mechanism disappears. This molecular dynamics simulation study provides a direct support that the electrostatic repulsion mechanism, previously described in (16,19,20), is a key biophysical basis for Hb-S polymerization in RBC sickling, too.…”

Section: Why Is the Electrostatic Repulsion Mechanism So Important Here?mentioning

confidence: 94%

Biophysical Basis of Hb-S Polymerization in Red Blood Cell Sickling

2019

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Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by the Glu6Val mutation in the β chain (Hb) of the oxygen-carrying hemoglobin protein in sicklemia patients. In the molecular pathogenesis of SCD, the sickle hemoglobin (Hb-S) polymerization is a major driver for structural deformation of red blood cells, i.e. red blood cell (RBC) sickling. Biophysically, it still remains elusive how this SCD-linked E6V mutation leads to Hb-S polymerization in RBC sickling. Therefore, with a comprehensive set of analysis of experimental Hb structures, this letter highlights electrostatic repulsion as a key biophysical mechanism of Hb-S polymerization in RBC sickling, which provides atomic-level insights into the functional impact of the SCD-linked E6V substitution from a biophysical point of view. SIGNIFICANCE During the past 25 years, a total of 104 Hb-related structures have been deposited in PDB. For the first time, this article presents a comprehensive set of electrostatic analysis of the 104 experimental structures, highlighting electrostatic repulsion as a fundamental biophysical mechanism for Hb-S polymerization in RBC sickling. The structural and electrostatic analysis here also provides biophysical insights into the functional impact of the SCD-linked E6V substitution.

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“…Recently, Papageorgiou et al [ 116 ] showed the unique adhesion dynamics of sickle reticulocytes (under hypoxia) (see Figure 6 a–f), the HbS fiber projections can extensively grow outward of the cell boundary, creating multiple adhesion sites. They also showed that not only in reticulocytes, but also in young erythrocytes, adhesion and HbS polymerization can work synergistically to increase the number of adhesion binding sites while the cell is adhered on the surface within minutes.…”

Section: Sickle Cell Diseasementioning

confidence: 99%

“…The aforementioned mechanisms may prove to be factors in initiating or promoting SCD vaso-occlusion. Furthermore, Papageorgiou et al [ 116 ] suggested a connection between polymerization, adhesion, and SS-RBC maturation, which resulted in the following descending order of the degree of adhesion susceptibility under hypoxia: sickle reticulocytes in the circulation ⇒ mature SS-RBCs with low density and high deformability ⇒ mature SS-RBCs with high density and low deformability ⇒ irreversibly-sickled cells.…”

Section: Sickle Cell Diseasementioning

confidence: 99%

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Synergistic Integration of Laboratory and Numerical Approaches in Studies of the Biomechanics of Diseased Red Blood Cells

Papageorgiou

Chang

et al. 2018

Biosensors

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In red blood cell (RBC) disorders, such as sickle cell disease, hereditary spherocytosis, and diabetes, alterations to the size and shape of RBCs due to either mutations of RBC proteins or changes to the extracellular environment, lead to compromised cell deformability, impaired cell stability, and increased propensity to aggregate. Numerous laboratory approaches have been implemented to elucidate the pathogenesis of RBC disorders. Concurrently, computational RBC models have been developed to simulate the dynamics of RBCs under physiological and pathological conditions. In this work, we review recent laboratory and computational studies of disordered RBCs. Distinguished from previous reviews, we emphasize how experimental techniques and computational modeling can be synergically integrated to improve the understanding of the pathophysiology of hematological disorders.

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Simultaneous polymerization and adhesion under hypoxia in sickle cell disease

Cited by 61 publications

References 47 publications

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

Biophysical Basis of Hb-S Polymerization in Red Blood Cell Sickling

Synergistic Integration of Laboratory and Numerical Approaches in Studies of the Biomechanics of Diseased Red Blood Cells

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