PMID- 34197597
OWN - NLM
STAT- MEDLINE
DCOM- 20211213
LR  - 20221001
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 138
IP  - 13
DP  - 2021 Sep 30
TI  - Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin.
PG  - 1172-1181
LID - 10.1182/blood.2021012070 [doi]
AB  - 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.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Henry, Eric R
AU  - Henry ER
AUID- ORCID: 0000-0002-5648-8696
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Metaferia, Belhu
AU  - Metaferia B
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Li, Quan
AU  - Li Q
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Harper, Julia
AU  - Harper J
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Best, Robert B
AU  - Best RB
AUID- ORCID: 0000-0002-7893-3543
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Glass, Kristen E
AU  - Glass KE
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Cellmer, Troy
AU  - Cellmer T
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Dunkelberger, Emily B
AU  - Dunkelberger EB
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
FAU - Conrey, Anna
AU  - Conrey A
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD; and.
FAU - Thein, Swee Lay
AU  - Thein SL
AUID- ORCID: 0000-0002-9835-6501
AD  - Sickle Cell Branch, National Heart, Lung, and Blood Institute, National 
      Institutes of Health, Bethesda, MD; and.
FAU - Bunn, H Franklin
AU  - Bunn HF
AD  - Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
FAU - Eaton, William A
AU  - Eaton WA
AD  - Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institutes of Health, Bethesda, MD.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antisickling Agents)
RN  - 0 (Benzaldehydes)
RN  - 0 (Hemoglobin, Sickle)
RN  - 0 (Pyrazines)
RN  - 0 (Pyrazoles)
RN  - 3ZO554A4Q8 (voxelotor)
RN  - S88TT14065 (Oxygen)
SB  - IM
CIN - Blood. 2021 Sep 30;138(13):1094-1095. PMID: 34591098
CIN - Transfusion. 2022 Jul;62(7):1462-1464. PMID: 35815728
MH  - Anemia, Sickle Cell/blood/*drug therapy/metabolism
MH  - Antisickling Agents/pharmacology/*therapeutic use
MH  - Benzaldehydes/pharmacology/*therapeutic use
MH  - Erythrocytes/drug effects/metabolism
MH  - Hemoglobin, Sickle/chemistry/*metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Oxygen/blood/*metabolism
MH  - Pyrazines/pharmacology/*therapeutic use
MH  - Pyrazoles/pharmacology/*therapeutic use
PMC - PMC8570057
EDAT- 2021/07/02 06:00
MHDA- 2021/12/15 06:00
PMCR- 2022/09/30
CRDT- 2021/07/01 17:27
PHST- 2021/04/28 00:00 [received]
PHST- 2021/06/30 00:00 [accepted]
PHST- 2021/07/02 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/07/01 17:27 [entrez]
PHST- 2022/09/30 00:00 [pmc-release]
AID - S0006-4971(21)01299-4 [pii]
AID - 2021/BLD2021012070 [pii]
AID - 10.1182/blood.2021012070 [doi]
PST - ppublish
SO  - Blood. 2021 Sep 30;138(13):1172-1181. doi: 10.1182/blood.2021012070.