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Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin.
Blood. 2021 09 30; 138(13):1172-1181.Blood

Abstract

The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the US Food and Drug Administration approval in 2019 of voxelotor, the only antisickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the nonpolymerizing, high oxygen affinity R (oxy) conformation of hemoglobin S (HbS). Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. In this study, we used the allosteric model of Monod, Wyman, and Changeux to simulate whole-blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with results of experiments using a new robust assay, which shows the large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. However, reduction of sickling mitigates red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal Hb or decrease mean corpuscular hemoglobin concentration (MCHC) should be more therapeutically effective than drugs that increase oxygen affinity.

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Authors+Show Affiliations

Henry ER
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Metaferia B
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Li Q
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Harper J
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Best RB
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Glass KE
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Cellmer T
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Dunkelberger EB
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Conrey A
Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and.
Thein SL
Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and.
Bunn HF
Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Eaton WA
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

MeSH

Anemia, Sickle CellAntisickling AgentsBenzaldehydesErythrocytesHemoglobin, SickleHumansModels, MolecularOxygenPyrazinesPyrazoles

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

34197597

Citation

Henry, Eric R., et al. "Treatment of Sickle Cell Disease By Increasing Oxygen Affinity of Hemoglobin." Blood, vol. 138, no. 13, 2021, pp. 1172-1181.
Henry ER, Metaferia B, Li Q, et al. Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin. Blood. 2021;138(13):1172-1181.
Henry, E. R., Metaferia, B., Li, Q., Harper, J., Best, R. B., Glass, K. E., Cellmer, T., Dunkelberger, E. B., Conrey, A., Thein, S. L., Bunn, H. F., & Eaton, W. A. (2021). Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin. Blood, 138(13), 1172-1181. https://doi.org/10.1182/blood.2021012070
Henry ER, et al. Treatment of Sickle Cell Disease By Increasing Oxygen Affinity of Hemoglobin. Blood. 2021 09 30;138(13):1172-1181. PubMed PMID: 34197597.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin. AU - Henry,Eric R, AU - Metaferia,Belhu, AU - Li,Quan, AU - Harper,Julia, AU - Best,Robert B, AU - Glass,Kristen E, AU - Cellmer,Troy, AU - Dunkelberger,Emily B, AU - Conrey,Anna, AU - Thein,Swee Lay, AU - Bunn,H Franklin, AU - Eaton,William A, PY - 2021/04/28/received PY - 2021/06/30/accepted PY - 2021/7/2/pubmed PY - 2021/12/15/medline PY - 2021/7/1/entrez SP - 1172 EP - 1181 JF - Blood JO - Blood VL - 138 IS - 13 N2 - The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the US Food and Drug Administration approval in 2019 of voxelotor, the only antisickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the nonpolymerizing, high oxygen affinity R (oxy) conformation of hemoglobin S (HbS). Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. In this study, we used the allosteric model of Monod, Wyman, and Changeux to simulate whole-blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with results of experiments using a new robust assay, which shows the large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. However, reduction of sickling mitigates red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal Hb or decrease mean corpuscular hemoglobin concentration (MCHC) should be more therapeutically effective than drugs that increase oxygen affinity. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/34197597/Treatment_of_sickle_cell_disease_by_increasing_oxygen_affinity_of_hemoglobin_ DB - PRIME DP - Unbound Medicine ER -