Sickle cell disease is a hereditary disorder in which the pathophysiology is driven by the aggregation of a mutant (sickle) hemoglobin (HbS). The self-assembly of deoxygenated sickle hemoglobin molecules into ordered fiber structures has consequences extending to the cellular and rheological levels, stiffening red blood cells and inducing pathological flow behavior. This review explores the current understanding of the molecular processes involved in the polymerization of hemoglobin in sickle cell disease and how the molecular phase transition creates quantifiable changes at the cellular and rheological scale, as well as, identifying knowledge gaps in the field that would improve our understanding of the disease and further improve treatment and management of the disease.
REFERENCES
1.
Alexy
, T.
, Pais
, E.
, Armstrong
, J. K.
, Meiselman
, H. J.
, Johnson
, C. S.
et al, “Rheologic behavior of sickle and normal red blood cell mixtures in sickle plasma: Implications for transfusion therapy
,” Transfusion
46
(6
), 912
–918
(2006
).2.
Ataga
, K. I.
, Kutlar
, A.
, Kanter
, J.
, Liles
, D.
, Cancado
, R.
et al, “Crizanlizumab for the prevention of pain crises in sickle cell disease
,” N. Engl. J. Med.
376
(5
), 429
–439
(2017
).3.
Ballas
, S. K.
, “Sickle cell disease: Classification of clinical complications and approaches to preventive and therapeutic management
,” Clin. Hemorheol. Microcirc.
68
(2–3
), 105
–128
(2018
).4.
Ballas
, S. K.
and Smith
, E. D.
, “Red blood cell changes during the evolution of the sickle cell painful crisis
,” Blood
79
(8
), 2154
–2163
(1992
).5.
Barabino
, G. A.
, Platt
, M. O.
, and Kaul
, D. K.
, “Sickle cell biomechanics
,” Annu. Rev. Biomed. Eng.
12
, 345
–367
(2010
).6.
Baum
, K. F.
, Dunn
, D. T.
, Maude
, G. H.
, and Serjeant
, G. R.
, “The painful crisis of homozygous sickle cell disease A study of risk factors
,” Arch. Intern. Med.
147
, 1231
–1234
(1987
).7.
Boisson
, C.
, Nader
, E.
, Renoux
, C.
, Gauthier
, A.
, Poutrel
, S.
et al, “Shear-stress-gradient and oxygen-gradient ektacytometry in sickle cell patients at steady state and during vaso-occlusive crises
,” Cells
11
(3
), 585
(2022
).8.
Bowers
, A. S.
, Reid
, H. L.
, Greenidge
, A.
, Landis
, C.
, and Reid
, M.
, “Blood viscosity and the expression of inflammatory and adhesion markers in homozygous sickle cell disease subjects with chronic leg ulcers
,” PLoS One
8
(7
), e68929
(2013
).9.
Briehl
, R. W.
, “Nucleation, fiber growth and melting, and domain formation and structure in sickle cell hemoglobin gels
,” J. Mol. Biol.
245
(5
), 710
–723
(1995
).10.
Brousse
, V.
, Buffet
, P.
, and Rees
, D.
, “The spleen and sickle cell disease: The sick(led) spleen
,” Br. J. Haematol.
166
(2
), 165
–176
(2014
).11.
Bucherer
, C.
, Ladjouzi
, J.
, Lacombe
, C.
, Leliévre
, J. C.
, Vandewalle
, H.
et al, “Effect of deoxygenation on rheological behavior of density separated sickle cell suspensions
,” Clin. Hemorheol. Microcirc.
12
(3
), 415
–425
(1992
).12.
Carragher
, B.
, Bluemke
, D. A.
, Gabriel
, B.
, Potel
, M. J.
, and Josephs
, R.
, “Structural analysis of polymers of sickle cell hemoglobin: I. Sickle hemoglobin fibers
,” J. Mol. Biol.
199
(2
), 315
–331
(1988
).13.
Caruso
, C.
, Cheng
, X.
, Michaud
, M. E.
, Szafraniec
, H. M.
, Thomas
, B. E.
et al, “Less deformable erythrocyte subpopulations biomechanically induce endothelial inflammation in sickle cell disease
,” Blood
144
, 2050
(2024
).14.
Castle
, B. T.
, Odde
, D. J.
, and Wood
, D. K.
, “Rapid and inefficient kinetics of sickle hemoglobin fiber growth
,” Sci. Adv.
5
(3
), eaau1086
(2019
).15.
Charache
, S.
, Dover
, G.
, Smith
, K.
, Talbot
, C. C.
, Moyer
, M.
et al, “Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex
,” Proc. Natl. Acad. Sci. U. S. A.
80
(15
), 4842
–4846
(1983
).16.
Charache
, S.
, Dover
, G. J.
, Moore
, R. D.
, Eckert
, S.
, Ballas
, S. K.
et al, “Hydroxyurea: Effects on hemoglobin F production in patients with sickle cell anemia [see comments]
,” Blood
79
(10
), 2555
–2565
(1992
).17.
Chien
, S.
, Sung
, K. L.
, Skalak
, R.
, Usami
, S.
, and Tözeren
, A.
, “Theoretical and experimental studies on viscoelastic properties of erythrocyte membrane
,” Biophys. J.
24
(2
), 463
–487
(1978
).18.
Chien
, S.
, Usami
, S.
, and Bertles
, J. F.
, “Abnormal rheology of oxygenated blood in sickle cell anemia
,” J. Clin. Invest.
49
(4
), 623
–634
(1970
).19.
Chien
, S.
, Usami
, S.
, Dellenback
, R. J.
, and Gregersen
, M. I.
, “Blood viscosity: Influence of erythrocyte deformation
,” New Series
157
(3790
), 827
–829
(1967
).20.
Christoph
, G. W.
, Hofrichter
, J.
, and Eaton
, W. A.
, “Understanding the shape of sickled red cells
,” Biophys. J.
88
(2
), 1371
–1376
(2005
).21.
Cieri-Hutcherson
, N. E.
, Hutcherson
, T. C.
, Conway-Habes
, E. E.
, Burns
, B. N.
, and White
, N. A.
, “Systematic review of l-glutamine for prevention of vaso-occlusive pain crisis in patients with sickle cell disease
,” in Pharmacotherapy
(Pharmacotherapy Publications, Inc.
, 2019
), Vol. 39
, Issue 11, pp. 1095
–1104
.22.
Clark
, M. R.
, Mohandas
, N.
, and Shohet
, S. B.
, “Deformability of oxygenated irreversibly sickled cells
,” J. Clin. Invest.
65
(1
), 189
–196
(1980
).23.
Connes
, P.
, “Blood rheology and vascular function in sickle cell trait and sickle cell disease: From pathophysiological mechanisms to clinical usefulness
,” Clin. Hemorheol. Microcirc.
86
(1–2
), 9
–27
(2024
).24.
Connes
, P.
, Alexy
, T.
, Detterich
, J.
, Romana
, M.
, Hardy-Dessources
, M. D.
et al, “The role of blood rheology in sickle cell disease
,” Blood Rev.
30
(2
), 111
–118
(2016
).25.
Darbari
, D. S.
, Sheehan
, V. A.
, and Ballas
, S. K.
, “The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management
,” Eur. J. Haematol.
105
(3
), 237
–246
(2020
).26.
De Souza
, D. C.
, Hebert
, N.
, Esrick
, E. B.
, Ciuculescu
, M. F.
, Archer
, N. M.
et al, “Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling
,” Nat. Commun.
14
(1
), 5850
(2023
).27.
Demers
, M.
, Sturtevant
, S.
, Guertin
, K. R.
, Gupta
, D.
, Desai
, K.
et al, “MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease
,” Blood Adv.
5
(5
), 1388
–1402
(2021
).28.
DeSimone
, J.
, Heller
, P.
, Hall
, L.
, and Zwiers
, D.
, “5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons
,” Proc. Natl. Acad. Sci. U. S. A.
79
(14
), 4428
–4431
(1982
).29.
Di Caprio
, G.
, Schonbrun
, E.
, Gonçalves
, B. P.
, Valdez
, J. M.
, Wood
, D. K.
et al, “High-throughput assessment of hemoglobin polymer in single red blood cells from sickle cell patients under controlled oxygen tension
,” Proc. Natl. Acad. Sci. U. S. A.
116
(50
), 25236
–25242
(2019
).30.
Du
, E.
, Diez-Silva
, M.
, Kato
, G. J.
, Dao
, M.
, and Suresh
, S.
, “Kinetics of sickle cell biorheology and implications for painful vasoocclusive crisis
,” Proc. Natl. Acad. Sci. U. S. A.
112
(5
), 1422
–1427
(2015
).31.
Dykes
, G.
, Crepeau
, R. H.
, and Edelstein
, S. J.
, “Three-dimensional reconstruction of the fibres of sickle cell haemoglobin
,” Nature
272
(5653
), 506
–510
(1978
).32.
Dykes
, G. W.
, Crepeau
, R. H.
, and Edelstein
, S. J.
, “Three-dimensional reconstruction of the 14-filament fibers of hemoglobin S
,” J. Mol. Biol.
130
(4
), 451
–472
(1979
).33.
Eaton
, W. A.
, “Impact of hemoglobin biophysical studies on molecular pathogenesis and drug therapy for sickle cell disease
,” in Molecular Aspects of Medicine
(Elsevier Ltd
., 2022
), Vol. 84
.34.
Eaton
, W. A.
and Hofrichter
, J.
, “Sickle cell hemoglobin polymerization
,” Adv. Protein Chem.
40
, 63
–279
(1990
).35.
El Hoss
, S.
, Cochet
, S.
, Marin
, M.
, Lapouméroulie
, C.
, Dussiot
, M.
et al, “Insights into determinants of spleen injury in sickle cell anemia
,” Blood Adv.
3
(15
), 2328
–2336
(2019
).36.
Esrick
, E. B.
, Lehmann
, L. E.
, Biffi
, A.
, Achebe
, M.
, Brendel
, C.
et al, “Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease
,” N. Engl. J. Med.
384
(3
), 205
–215
(2021
).37.
Evans
, E. A.
, “New membrane concept applied to the analysis of fluid shear- and micropipette-deformed red blood cells
,” Biophys. J.
13
(9
), 941
–954
(1973
).38.
Evans
, E. A.
, “Bending resistance and chemically induced moments in membrane bilayers
,” Biophys. J.
14
(12
), 923
–931
(1974
).39.
Evans
, E. A.
and Hochmuth
, R. M.
, “Membrane viscoelasticity
,” Biophys. J.
16
(1
), 1
–11
(1976
).40.
Ferrone
, F. A.
, Hofrichter
, J.
, Sunshine
, H. R.
, and Eaton
, W. A.
, “Kinetic studies on photolysis-induced gelation of sickle cell hemoglobin suggest a new mechanism
,” Biophys. J.
32
(1
), 361
–380
(1980
).41.
Green
, M. A.
, Noguchi
, C. T.
, Keidan
, A. J.
, Marwah
, S. S.
, and Stuart
, J.
, “Polymerization of sickle cell hemoglobin at arterial oxygen saturation impairs erythrocyte deformability
,” J. Clin. Invest.
81
(6
), 1669
–1674
(1988
).42.
Haire
, R. N.
, Tisel
, W. A.
, Niazi
, G.
, Rosenberg
, A.
, Gill
, S. J.
et al, “Hemoglobin solubility as a function of fractional oxygen saturation for hemoglobins in polyethylene glycol: A sickle hemoglobin model
,” Biochem. Biophys. Res. Commun.
101
(1
), 177
–182
(1981
).43.
Haydar
, F.
, David
, A.
, Domenica
, C. M.
, Yi-Shan
, C.
, Jennifer
, D.
et al, “CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia
,” N. Engl. J. Med.
384
(3
), 252
–260
(2021
).44.
Higgins
, J. M.
, Eddington
, D. T.
, Bhatia
, S. N.
, and Mahadevan
, L.
, “Statistical dynamics of flowing red blood cells by morphological image processing
,” PLoS Comput. Biol.
5
(2
), e1000288
(2009
).45.
Hofrichter
, J.
, Ross
, P. D.
, and Eaton
, W. A.
, “Kinetics and mechanism of deoxyhemoglobin S gelation: A new approach to understanding sickle cell disease
,” Proc. Natl. Acad. Sci. U. S. A.
71
(12
), 4864
–4868
(1974
).46.
Ingram
, V. M.
, “A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin
,” Nature
178
(4537
), 792
–794
(1956
).47.
Ingram
, V. M.
, “Gene mutations in human haemoglobin: The chemical difference between normal and sickle cell haemoglobin
,” Nature
180
(4581
), 326
–328
(1957
).48.
Itoh
, T.
, Chien
, S.
, and Usami
, S.
, “Deformability measurements on individual sickle cells using a new system with pO2 and temperature control
,” Blood
79
(8
), 2141
–2147
(1992
).49.
Jandl
, J. H.
, Simmons
, R. L.
, and Castle
, W. B.
, “Red cell filtration and the pathogenesis of certain hemolytic anemias
,” Blood
18
(2
), 133
–148
(1961
).50.
Kanter
, J.
, Walters
, M. C.
, Krishnamurti
, L.
, Mapara
, M. Y.
, Kwiatkowski
, J. L.
et al, “Biologic and clinical efficacy of lentiGlobin for sickle cell disease
,” N. Engl. J. Med.
386
(7
), 617
–628
(2022
).51.
Kato
, G. J.
, Piel
, F. B.
, Reid
, C. D.
, Gaston
, M. H.
, Ohene-Frempong
, K.
et al, “Sickle cell disease
,” Nat. Rev. Dis. Primers
4
, 18010
(2018
).52.
Kaul
, D. K.
, Fabry
, M. E.
, Windisch
, P.
, Baez
, S.
, and Nagel
, R. L.
, “Erythrocytes in sickle cell anemia are heterogeneous in their rheological and hemodynamic characteristics
,” J. Clin. Invest.
72
(1
), 22
–31
(1983
).53.
Keidan
, A. J.
, Noguchi
, C. T.
, Player
, M.
, Chalder
, S. M.
, and Stuart
, J.
, “Erythrocyte heterogeneity in sickle cell disease: Effect of deoxygenation on intracellular polymer formation and rheology of sub‐populations
,” Br. J. Haematol.
72
(2
), 254
–259
(1989
).54.
Kenny
, M. W.
, Meakin
, M.
, Worthington
, D. J.
, and Stuart
, J.
, “Erythrocyte deformability in sickle-cell crisis
,” Br. J. Haematol.
49
(1
), 103
–109
(1981
).55.
Kucukal
, E.
, Man
, Y.
, Hill
, A.
, Liu
, S.
, Bode
, A.
et al, “Whole blood viscosity and red blood cell adhesion: Potential biomarkers for targeted and curative therapies in sickle cell disease
,” Am. J. Hematol.
95
(11
), 1246
–1256
(2020
).56.
Kumar
, A.
and Graham
, M. D.
, “Margination and segregation in confined flows of blood and other multicomponent suspensions
,” Soft Matter
8
(41
), 10536
–10548
(2012
).57.
Lanzkron
, S.
, Carroll
, C. P.
, and Haywood
, C.
, “The burden of emergency department use for sickle-cell disease: An analysis of the national emergency department sample database
,” Am. J. Hematol.
85
(10
), 797
–799
(2010
).58.
Lettre
, G.
and Bauer
, D. E.
, “Fetal haemoglobin in sickle-cell disease: From genetic epidemiology to new therapeutic strategies
,” Lancet
387
(10037
), 2554
–2564
(2016
).59.
Liem
, R. I.
, “Balancing exercise risk and benefits: Lessons learned from sickle cell trait and sickle cell anemia
,” Hematol. Am. Soc. Hematol. Educ. Program
2018
(1
), 418
–425
(2018
).60.
Lu
, X.
, Wood
, D. K.
, and Higgins
, J. M.
, “Deoxygenation reduces sickle cell blood flow at arterial oxygen tension
,” Biophys. J.
110
(12
), 2751
–2758
(2016
).61.
Malfa
, R.
and Steinhardt
, J.
, “A temperature-dependent latent-period in the aggregation of sickle-cell deoxyhemoglobin
,” Biochem. Biophys. Res. Commun.
59
(3
), 887
–893
(1974
).62.
Man
, Y.
, Kucukal
, E.
, An
, R.
, Watson
, Q. D.
, Bosch
, J.
et al, “Microfluidic assessment of red blood cell mediated microvascular occlusion
,” Lab Chip
20
(12
), 2086
–2099
(2020
).63.
Metcalf
, B.
, Chuang
, C.
, Dufu
, K.
, Patel
, M. P.
, Silva-Garcia
, A.
et al, “Discovery of GBT440, an orally bioavailable R-state stabilizer of sickle cell hemoglobin
,” ACS Med. Chem. Lett.
8
(3
), 321
–326
(2017
).64.
Moffat
, K.
and Gibson
, Q. H.
, “The rates of polymerization and depolymerization of sickle cell hemoglobin
,” Biochem. Biophys. Res. Commun.
61
(1
), 237
–242
(1974
).65.
Mozzarelli
, A.
, Hofrichter
, J.
, and Eaton
, W. A.
, “Delay time of hemoglobin S polymerization prevents most cells from sickling in vivo
,” Science
237
(4814
), 500
–506
(1987
).66.
Ngo
, D.
, Aygun
, B.
, Akinsheye
, I.
, Hankins
, J. S.
, Bhan
, I.
et al, “Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin
,” Br. J. Haematol.
156
(2
), 259
–264
(2012
).67.
Ngo
, D.
, Bae
, H.
, Steinberg
, M. H.
, Sebastiani
, P.
, Solovieff
, N.
et al, “Fetal hemoglobin in sickle cell anemia: Genetic studies of the Arab-Indian haplotype
,” Blood Cells, Mol., Dis.
51
(1
), 22
–26
(2013
).68.
Nouraie
, M.
, Lee
, J. S.
, Zhang
, Y.
, Kanias
, T.
, Zhao
, X.
et al, “The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe
,” Haematologica
98
(3
), 464
–472
(2013
).69.
Ohene-Frempong
, K.
, Weiner
, S. J.
, Sleeper
, L. A.
, Miller
, S. T.
, Embury
, S.
et al, “Cerebrovascular accidents in sickle cell disease: Rates and risk factors
,” Blood
91
, 288
–294
(1998
).70.
Partanen
, M.
, Kang
, G.
, Wang
, W. C.
, Krull
, K.
, King
, A. A.
et al, “Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease
,” Br. J. Haematol.
189
(6
), 1192
–1203
(2020
).71.
Pauling
, L.
, Itano
, H. A.
, Singer
, S. J.
, and Wells
, I. C.
, “Sickle cell anemia, a molecular disease
,” Science
110
(2865
), 543
–548
(1949
).72.
Perazzo
, A.
, Peng
, Z.
, Young
, Y. N.
, Feng
, Z.
, Wood
, D. K.
et al, “The effect of rigid cells on blood viscosity: Linking rheology and sickle cell anemia
,” Soft Matter
18
(3
), 554
–565
(2022
).73.
Pfizer,
Pfizer Voluntarily Withdraws All Lots of Sickle Cell Disease Treatment OXBRYTA® (voxelotor) From Worldwide Markets
(September 25, 2024
), see https://www.pfizer.com/news/press-release/press-release-detail/pfizer-voluntarily-withdraws-all-lots-sickle-cell-disease74.
Piel
, F. B.
, Steinberg
, M. H.
, and Rees
, D. C.
, “Sickle cell disease
,” N. Engl. J. Med.
376
(16
), 1561
–1573
(2017
).75.
Platt
, O. S.
, Orkin
, S. H.
, Dover
, G.
, Beardsley
, G. P.
, Miller
, B.
et al, “Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia
,” J. Clin. Invest.
74
(2
), 652
–656
(1984
).76.
Platt
, O. S.
, Thorington
, B. D.
, Brambilla
, D. J.
, Milner
, P. F.
, Rosse
, W. F.
et al, “Pain in sickle cell disease
,” N. Engl. J. Med.
325
(1
), 11
–16
(1991
).77.
Qiang
, Y.
, Liu
, J.
, Dao
, M.
, and Du
, E.
, “In vitro assay for single-cell characterization of impaired deformability in red blood cells under recurrent episodes of hypoxia
,” Lab Chip
21
(18
), 3458
–3470
(2021
).78.
Qiang
, Y.
, Sissoko
, A.
, Liu
, Z. L.
, Dong
, T.
, Zheng
, F.
et al, “Microfluidic study of retention and elimination of abnormal red blood cells by human spleen with implications for sickle cell disease
,” Proc. Natl. Acad. Sci. U. S. A.
120
(6
), e2217607120
(2023
).79.
Ribeil
, J.-A.
, Hacein-Bey-Abina
, S.
, Payen
, E.
, Magnani
, A.
, Semeraro
, M.
et al, “Gene therapy in a patient with sickle cell disease
,” N. Engl. J. Med.
376
(9
), 848
–855
(2017
).80.
Rodgers
, D. W.
, Crepeau
, R. H.
, and Edelstein
, S. J.
, “Pairings and polarities of the 14 strands in sickle cell hemoglobin fibers
,” Proc. Natl. Acad. Sci. U. S. A.
84
(17
), 6157
–6161
(1987
).81.
Ross
, P. D.
, Hofrichter
, J.
, and Eaton
, W. A.
, “Thermodynamics of gelation of sickle cell deoxyhemoglobin
,” J. Mol. Biol.
115
(2
), 111
–134
(1977
).83.
Samuel
, R. E.
, Salmon
, E. D.
, and Briehl
, R. W.
, “Nucleation and growth of fibres and gel formation in sickle cell haemoglobin
,” Nature
345
(6278
), 833
–835
(1990
).82.
Sharma
, A.
, Boelens
, J.-J.
, Cancio
, M.
, Hankins, J.
S.
, Bhad
, P.
et al, “CRISPR-Cas9 editing of the HBG1 and HBG2 promoters to treat sickle cell disease
,” N. Engl. J. Med.
389
(9
), 820
–832
(2023
).84.
Sherwood
, J. M.
, Holmes
, D.
, Kaliviotis
, E.
, and Balabani
, S.
, “Spatial distributions of red blood cells significantly alter local haemodynamics
,” PLoS One
9
(6
), e100473
(2014
).85.
Singer
, K.
and Fisher
, B.
, “Studies on abnormal hemoglobins: V. The distribution of type S (sickle cell) hemoglobin and type F (alkali resistant) hemoglobin within the red cell population in sickle cell anemia
,” Blood
7
(12
), 1216
–1226
(1952
).86.
Singer
, K.
and Singer
, L.
, “Studies on abnormal hemoglobins: VIII. The gelling phenomenon of sickle cell hemoglobin: Its biologic and diagnostic significance
,” Blood
8
(11
), 1008
–1023
(1953
).87.
Solovieff
, N.
, Milton
, J. N.
, Hartley
, S. W.
, Sherva
, R.
, Sebastiani
, P.
et al, “Fetal hemoglobin in sickle cell anemia: Genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster
,” Blood
115
(9
), 1815
–1822
(2010
).88.
Song
, S. H.
, Kim
, J. H.
, Lee
, J. H.
, Yun
, Y. M.
, Choi
, D. H.
et al, “Elevated blood viscosity is associated with cerebral small vessel disease in patients with acute ischemic stroke
,” BMC Neurol.
17
(1
), 20
(2017
).89.
Sorette
, M. P.
, Lavenant
, M. G.
, and Clark
, M. R.
, “Ektacytometric measurement of sickle cell deformability as a continuous function of oxygen tension
,” Blood
69
(1
), 316
(1987
).90.
Steinberg
, M. H.
, Chui
, D. H. K.
, Dover
, G. J.
, Sebastiani
, P.
, Alsultan
, A.
et al, “Fetal hemoglobin in sickle cell anemia: A glass half full?
,” Blood
123
(4
), 481
(2014
).91.
Steinberg
, M. H.
and Nagel
, R. L.
, “Hemoglobins of the embryo, fetus, and adult
,” in Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management
, 2nd ed., edited by Steinberg
, M. H.
, Forget
, B. G.
, Higgs
, D. R.
, and Weatherall
, D. J.
(Cambridge University Press
, 2009
), pp. 119
–136
.92.
Sundd
, P.
, Gladwin
, M. T.
, and Novelli
, E. M.
“Pathophysiology of sickle cell disease
,” Annu. Rev. Pathol.: Mech. Dis.
14
(1
), 263
–292
(2019
).93.
Sunshine
, H. R.
, Hofrichter
, J.
, Ferrone
, F. A.
, and Eaton
, W. A.
, “Oxygen binding by sickle cell hemoglobin polymers
,” J. Mol. Biol.
158
(2
), 251
–273
(1982
).94.
Szafraniec
, H. M.
, Valdez
, J. M.
, Iffrig
, E.
, Lam
, W. A.
, Higgins
, J. M.
et al, “Feature tracking microfluidic analysis reveals differential roles of viscosity and friction in sickle cell blood
,” Lab Chip
22
, 1565
–1575 (
2022
).95.
Taylor
, V. I. J. G.
, Nolan
, V. G.
, Mendelsohn
, L.
, Kato
, G. J.
, Gladwin
, M. T.
et al, “Chronic hyper-hemolysis in sickle cell anemia: Association of vascular complications and mortality with less frequent vasoocclusive pain
,” PLoS One
3
(5
), e2095
(2008
).96.
Thomson
, A. M.
, McHugh
, T. A.
, Oron
, A. P.
, Teply
, C.
, Lonberg
, N.
et al, “Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: A systematic analysis from the Global Burden of Disease Study 2021
,” The Lancet Haematol.
10
(8
), e585
–e599
(2023
).97.
Tsai
, M.
, Kita
, A.
, Leach
, J.
, Rounsevell
, R.
, Huang
, J. N.
et al, “In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology
,” J. Clin. Invest.
122
(1
), 408
–418
(2012
).98.
Usami
, S.
, Chien
, S.
, Scholtz
, P. M.
, and Bertles
, J. F.
, “Effect of deoxygenation on blood rheology in sickle cell disease
,” Microvasc. Res.
9
(3
), 324
–334
(1975
).99.
Valdez
, J. M.
, Datta
, Y. H.
, Higgins
, J. M.
, and Wood
, D. K.
, “A microfluidic platform for simultaneous quantification of oxygen-dependent viscosity and shear thinning in sickle cell blood
,” APL Bioeng.
3
(4
), 046102
(2019
).100.
Vent-Schmidt
, J.
, Waltz
, X.
, Romana
, M.
, Hardy-Dessources
, M. D.
, Lemonne
, N.
et al, “Blood thixotropy in patients with sickle cell anaemia: Role of haematocrit and red blood cell rheological properties
,” PLoS One
9
(12
), e114412
(2014
).101.
Verduzco
, L. A.
and Nathan
, D. G.
, “Sickle cell disease and stroke
,” Blood
114
(25
), 5117
–5125
(2009
).102.
Vichinsky
, E.
, Hoppe
, C. C.
, Ataga
, K. I.
, Ware
, R. E.
, Nduba
, V.
et al, “A phase 3 randomized trial of voxelotor in sickle cell disease
,” N. Engl. J. Med.
381
(6
), 509
–519
(2019
).103.
Vunnam
, N.
, Hansen
, S.
, Williams
, D. C.
, Been
, M. O.
, Lo
, C. H.
et al, “Fluorescence lifetime measurement of prefibrillar sickle hemoglobin oligomers as a platform for drug discovery in sickle cell disease
,” Biomacromolecules
23
(9
), 3822
–3830
(2022
).104.
Wang
, Y.
, Garland
, J. S.
, Fellah
, S.
, Reis
, M. N.
, Parsons
, M. S.
et al, “Intracranial aneurysms in sickle cell disease are associated with hemodynamic stress and anemia
,” Blood Adv.
8
(18
), 4823
–4831
(2024
).105.
Weatherall
, M. W.
, Higgs
, D. R.
, Weiss
, H.
, Weatherall
, D. J.
, and Serjeant
, G. R.
, “Phenotype/genotype relationships in sickle cell disease: A pilot twin study
,” Clin. Lab. Haematol.
27
(6
), 384
–390
(2005
).106.
Williams
, D. C.
and Wood
, D. K.
, “High-throughput quantification of red blood cell deformability and oxygen saturation to probe mechanisms of sickle cell disease
,” Proc. Natl. Acad. Sci. U. S. A.
120
(48
), e2313755120
(2023
).107.
Wood
, D. K.
, Soriano
, A.
, Mahadevan
, L.
, Higgins
, J. M.
, and Bhatia
, S. N.
, “A biophysical indicator of vaso-occlusive risk in sickle cell disease
,” Sci. Transl. Med.
4
(123
), 123ra26
(2012
).108.
Yawn
, B. P.
, Buchanan
, G. R.
, Afenyi-Annan
, A. N.
, Ballas
, S. K.
, Hassell
, K. L.
et al, “Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members
,” JAMA
312
(10
), 1033
–1048
(2014
).109.
Yeom
, E.
, Kang
, Y. J.
, and Lee
, S.-J.
“Changes in velocity profile according to blood viscosity in a microchannel
,” Biomicrofluidics
8
(3
), 034110
(2014
).110.
Závodszky
, G.
, Van Rooij
, B.
, Czaja
, B.
, Azizi
, V.
, De Kanter
, D.
et al, “Red blood cell and platelet diffusivity and margination in the presence of cross-stream gradients in blood flows
,” Phys. Fluids
31
(3
), 031903
(2019
).111.
Zheng
, Y.
, Gossett
, J. M.
, Chen
, P. L.
, Barton
, M.
, Ryan
, M.
et al, “Proinflammatory state promotes red blood cell alloimmunization in pediatric patients with sickle cell disease
,” Blood Adv.
7
(17
), 4799
–4808
(2023
).© 2025 Author(s). Published under an exclusive license by AIP Publishing.
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