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Journal articles on the topic 'HemoglobinS Polymerization'

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Published: 5 June 2025

Last updated: 25 June 2025

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1

Li, Xianfeng, Urooj A. Mirza, Brian T. Chait, and James M. Manning. "Systematic Enhancement of Polymerization of Recombinant Sickle Hemoglobin Mutants: Implications for Transgenic Mouse Model for Sickle Cell Anemia." Blood 90, no. 11 (1997): 4620–27. http://dx.doi.org/10.1182/blood.v90.11.4620.

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Abstract To provide quantitative information on the sites that promote polymerization of sickle hemoglobin (HbS) after formation of the initial hydrophobic bond involving Val-6(β) [E6V(β)] and also to provide hemoglobins with an enhanced polymerization that could be used in a mouse model for sickle cell anemia, we have expressed recombinant double, triple, and quadruple HbS mutants with substitutions on both the α- and β-chains, E6V(β)/E121R(β), D75Y(α)/E6V(β)/E121R(β) and D6A(α)/D75Y(α)/E6V(β)/E121R(β). These recombinant hemoglobins were extensively characterized by high-performance liquid chromatography analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, isoelectric focusing, amino acid analysis, and mass spectroscopy. They retained the functional properties of the Hb tetramer and polymerized in a linear manner at progressively lower Hb concentration as a function of the degree of substitution, suggesting that these remote sites (αD6A, αD75Y, and βE121R) on the α- and β-chains exhibit additive, enhanced polymerization properties. The quadruple mutant has a polymerization concentration close to that of the purified SAD hemoglobin from transgenic mouse red blood cells consisting of HbS, Hb Antilles, and Hb D-Punjab. Normal mouse Hb increases the polymerization concentration of each mutant. Thus, the general approach of using recombinant Hbs as described here should prove useful in elucidating the quantitative aspects of the mechanism of HbS polymerization and in identifying the contribution of individual sites to the overall process. The strategy described here demonstrates the feasibility of a systematic approach to achieve future recombinant HbS mutants that could provide a new generation of the transgenic mouse model for sickle cell anemia.

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2

Li, Xianfeng, Urooj A. Mirza, Brian T. Chait, and James M. Manning. "Systematic Enhancement of Polymerization of Recombinant Sickle Hemoglobin Mutants: Implications for Transgenic Mouse Model for Sickle Cell Anemia." Blood 90, no. 11 (1997): 4620–27. http://dx.doi.org/10.1182/blood.v90.11.4620.4620_4620_4627.

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To provide quantitative information on the sites that promote polymerization of sickle hemoglobin (HbS) after formation of the initial hydrophobic bond involving Val-6(β) [E6V(β)] and also to provide hemoglobins with an enhanced polymerization that could be used in a mouse model for sickle cell anemia, we have expressed recombinant double, triple, and quadruple HbS mutants with substitutions on both the α- and β-chains, E6V(β)/E121R(β), D75Y(α)/E6V(β)/E121R(β) and D6A(α)/D75Y(α)/E6V(β)/E121R(β). These recombinant hemoglobins were extensively characterized by high-performance liquid chromatography analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, isoelectric focusing, amino acid analysis, and mass spectroscopy. They retained the functional properties of the Hb tetramer and polymerized in a linear manner at progressively lower Hb concentration as a function of the degree of substitution, suggesting that these remote sites (αD6A, αD75Y, and βE121R) on the α- and β-chains exhibit additive, enhanced polymerization properties. The quadruple mutant has a polymerization concentration close to that of the purified SAD hemoglobin from transgenic mouse red blood cells consisting of HbS, Hb Antilles, and Hb D-Punjab. Normal mouse Hb increases the polymerization concentration of each mutant. Thus, the general approach of using recombinant Hbs as described here should prove useful in elucidating the quantitative aspects of the mechanism of HbS polymerization and in identifying the contribution of individual sites to the overall process. The strategy described here demonstrates the feasibility of a systematic approach to achieve future recombinant HbS mutants that could provide a new generation of the transgenic mouse model for sickle cell anemia.

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3

Riccio, Alessia, Gaetano Mangiapia, Daniela Giordano, et al. "Polymerization of hemoglobins in Arctic fish: Lycodes reticulatus and Gadus morhua." IUBMB Life 63, no. 5 (2011): 346–54. http://dx.doi.org/10.1002/iub.450.

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4

Krzyszczyk, Paulina, Kishan Patel, Yixin Meng, et al. "Macrophage modulation by polymerized hemoglobins: Potential as a wound-healing therapy." TECHNOLOGY 07, no. 03n04 (2019): 84–97. http://dx.doi.org/10.1142/s2339547819500055.

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Chronic skin wounds are hypoxic and are stalled in a pro-inflammatory state. Hemoglobin (Hb)-based oxygen carriers have shown potential in increasing oxygen delivery to aid wound healing. Macrophages also take up Hb, thus altering their phenotype and the regulation of inflammation. Herein, we compared the effect of Hb and polymerized Hbs (PolyHbs) on the phenotype of human macrophages. Macrophages were incubated with Hb or different forms of PolyHbs, and the inflammatory secretion profile was analyzed. PolyHbs were produced by polymerizing Hb in the relaxed (R) or tense (T) quaternary state and by varying the molar ratio of the glutaraldehyde crosslinking agent to Hb. Hb decreased the secretion of most measured factors. PolyHb treatment led to generally similar secretion profiles; however, Hb had more similar trends to R-state PolyHb. Ingenuity pathway analysis predicted positive outcomes in wound healing and angiogenesis for T-state PolyHb prepared with a 30:1 (glutaraldehyde:Hb) polymerization ratio. When tested in diabetic mouse wounds, T-state PolyHb resulted in the greatest epidermal thickness and vascular endothelial CD31 staining. Thus, the effects of PolyHb on macrophages are affected by the polymerization ratio and the quaternary state, and T-state PolyHb yields secretion profiles that are most beneficial in wound healing.

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5

Adachi, K., E. Rappaport, H. S. Eck, P. Konitzer, J. Kim та S. Surrey. "Polymerization and Solubility of Recombinant Hemoglobins α2β26VAL(HB S) and α2β26LEU(HB LEU)". Hemoglobin 15, № 5 (1991): 417–30. http://dx.doi.org/10.3109/03630269108998861.

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6

Petersen, Asbjørn G., Steen V. Petersen, Sebastian Frische, et al. "Hemoglobin polymerization via disulfide bond formation in the hypoxia-tolerant turtle Trachemys scripta: implications for antioxidant defense and O2 transport." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 314, no. 1 (2018): R84—R93. http://dx.doi.org/10.1152/ajpregu.00024.2017.

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The ability of many reptilian hemoglobins (Hbs) to form high-molecular weight polymers, albeit known for decades, has not been investigated in detail. Given that turtle Hbs often contain a high number of cysteine (Cys), potentially contributing to the red blood cell defense against reactive oxygen species, we have examined whether polymerization of Hb could occur via intermolecular disulfide bonds in red blood cells of freshwater turtle Trachemys scripta, a species that is highly tolerant of hypoxia and oxidative stress. We find that one of the two Hb isoforms of the hemolysate HbA is prone to polymerization in vitro into linear flexible chains of different size that are visible by electron microscopy but not the HbD isoform. Polymerization of purified HbA is favored by hydrogen peroxide, a main cellular reactive oxygen species and a thiol oxidant, and inhibited by thiol reduction and alkylation, indicating that HbA polymerization is due to disulfide bonds. By using mass spectrometry, we identify Cys5 of the αA-subunit of HbA as specifically responsible for forming disulfide bonds between adjacent HbA tetramers. Polymerization of HbA does not affect oxygen affinity, cooperativity, and sensitivity to the allosteric cofactor ATP, indicating that HbA is still fully functional. Polymers also form in T. scripta blood after exposure to anoxia but not normoxia, indicating that they are of physiological relevance. Taken together, these results show that HbA polymers may form during oxidative stress and that Cys5αA of HbA is a key element of the antioxidant capacity of turtle red blood cells.

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7

Adachi, K., P. Konitzer, J. Kim, N. Welch, and S. Surrey. "Effects of beta 6 aromatic amino acids on polymerization and solubility of recombinant hemoglobins made in yeast." Journal of Biological Chemistry 268, no. 29 (1993): 21650–56. http://dx.doi.org/10.1016/s0021-9258(20)80591-2.

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8

Schaer, Dominik J., Christian A. Schaer, Paul W. Buehler, et al. "CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin." Blood 107, no. 1 (2006): 373–80. http://dx.doi.org/10.1182/blood-2005-03-1014.

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AbstractCD163 mediates the internalization of hemoglobin-haptoglobin (Hb-Hp) complexes by macrophages. Because Hp binding capacity is exhausted during severe hemolysis, an Hp-independent Hb-clearance pathway is presumed to exist. We demonstrate that Hb interacts efficiently with CD163 in the absence of Hp. Not only is Hb internalized into an endosomal compartment by CD163 as a result of active receptor-dependent endocytosis; it also inhibits the uptake of Hb-Hp complexes, suggesting a common receptor-binding site. Free Hb further induces heme oxygenase mRNA expression in CD163+ HEK293 cells, but not in CD163- cells. Additional evidence for Hp-independent Hb-CD163 interaction is provided by the demonstration that CD163 mediates the uptake of αα-DBBF crosslinked Hb, a chemically modified Hb that forms minimal Hp complexes. Moreover, certain modifications to Hb, such as polymerization or the attachment of specific functional groups (3 lysyl residues) to the β-Cys93 can reduce or enhance this pathway of uptake. In human macrophages, Hp-complex formation critically enhances Hb uptake at low (1 μg/mL), but not at high (greater than 100 μg/mL), ligand concentrations, lending support for a concentration-dependent biphasic model of macrophage Hb-clearance. These results identify CD163 as a scavenger receptor for native Hb and small-molecular-weight Hb-based blood substitutes after Hp depletion.

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9

Barnikol, W. K. R. "Influence of the Polymerization Step Alone on Oxygen Affinity and Cooperative During Production of Hyperpolymers from Native Hemoglobins with Crosslinkers." Artificial Cells, Blood Substitutes, and Biotechnology 22, no. 3 (1994): 725–31. http://dx.doi.org/10.3109/10731199409117904.

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10

Prabin, Kumar Jani, Mishra Swati, Ranjan Mishra Sruti, et al. "SICKLE CELL ANEMIA DISEASE TREATMENT ONGENETICS MOLECULAR LEVEL IN BASTER, CHHATTISGARH, A REVIEW." COMMUNITY PRACTITIONER 20, no. 09 (2023): 329–38. https://doi.org/10.5281/zenodo.8385187.

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<strong>Abstract </strong> SCA is a hereditary blood disorder considered by irregular haemoglobin causing in the production of sickle shaped red blood cell. Baster in Chhattisgarh a state in central Indian faces a significant problems of sickle cell anemia with a high prevalence among tribal population. This abstract highlight the genetic molecular level treatment methods in baster, Chhattisgarh to take SCA. The advent of molecular biology and genetic research has covered the way for innovatives therapeutics strategies for SCA. Which involve nucleotide substitution in beta globin gene. The genetics molecular level treatment is hematotropoietics stem cell transplantation also known as bone marrow transplantation in baster, Chhattisgarh. Effort are proceeding to expand the availability and accessibiIity of (HSCT) for a sickle cell anemia patients with an emphasis on increasing the number of suitable donor through awareness campaign. Conclusion genetics molecular level treatment approaches for a SCA in baster, Chhattisgarh are gaining momentum and hold great promises foe the management and potentials cure of this unbearable disease the addition of hematopoietics, stem cell transplantation gene therapy, along with continual research effort. Contributed for individual with SCA in baster, chhattisgarh and beyond.

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11

Weber, Roy E., Angela Fago, Hans Malte, Jay F. Storz, and Thomas A. Gorr. "Lack of conventional oxygen-linked proton and anion binding sites does not impair allosteric regulation of oxygen binding in dwarf caiman hemoglobin." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 305, no. 3 (2013): R300—R312. http://dx.doi.org/10.1152/ajpregu.00014.2013.

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In contrast to other vertebrate hemoglobins (Hbs) whose high intrinsic O2 affinities are reduced by red cell allosteric effectors (mainly protons, CO2, organic phosphates, and chloride ions), crocodilian Hbs exhibit low sensitivity to organic phosphates and high sensitivity to bicarbonate (HCO3−), which is believed to augment Hb-O2 unloading during diving and postprandial alkaline tides when blood HCO3− levels and metabolic rates increase. Examination of α- and β-globin amino acid sequences of dwarf caiman ( Paleosuchus palpebrosus) revealed a unique combination of substitutions at key effector binding sites compared with other vertebrate and crocodilian Hbs: β82Lys→Gln, β143His→Val, and β146His→Tyr. These substitutions delete positive charges and, along with other distinctive changes in residue charge and polarity, may be expected to disrupt allosteric regulation of Hb-O2 affinity. Strikingly, however, P. palpebrosus Hb shows a strong Bohr effect, and marked deoxygenation-linked binding of organic phosphates (ATP and DPG) and CO2 as carbamate (contrasting with HCO3− binding in other crocodilians). Unlike other Hbs, it polymerizes to large complexes in the oxygenated state. The highly unusual properties of P. palpebrosus Hb align with a high content of His residues (potential sites for oxygenation-linked proton binding) and distinctive surface Cys residues that may form intermolecular disulfide bridges upon polymerization. On the basis of its singular properties, P. palpebrosus Hb provides a unique opportunity for studies on structure-function coupling and the evolution of compensatory mechanisms for maintaining tissue O2 delivery in Hbs that lack conventional effector-binding residues.

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12

BRIEHL, ROBIN W., and ERIC S. MANN. "Hemoglobin S Polymerization." Annals of the New York Academy of Sciences 565, no. 1 Sickle Cell D (1989): 295–307. http://dx.doi.org/10.1111/j.1749-6632.1989.tb24177.x.

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13

Fabry, ME, A. Sengupta, SM Suzuka, et al. "A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-Antilles results in increased phenotypic severity." Blood 86, no. 6 (1995): 2419–28. http://dx.doi.org/10.1182/blood.v86.6.2419.bloodjournal8662419.

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We report on a second generation of transgenic mice produced by crossing a transgenic mouse line expressing high levels of human alpha and beta S chains (alpha H beta S [beta MDD]) with a line expressing human alpha and beta S-Antilles (beta SAnt). We hypothesized that mice expressing both hemoglobins (Hbs) would have a more severe phenotype because the reduced oxygen affinity and solubility of the beta S- Antilles might enhance the rate and extent of polymer formation. We obtained mice that expressed both beta S and beta S-Antilles. The doubly transgenic mice that are heterozygous for deletion of mouse beta Major (beta MD) occurred with reduced frequency and those that are homozygous for deletion of mouse beta Major (beta MDD) occurred at a much reduced frequency and suffered early mortality. Human alpha was 58% of all alpha globin for all animals, whereas beta S and beta S- Antilles were 34% and 28% of all beta globins for beta MD mice and 42% and 36% for beta MDD mice. Hematocrit, Hb, and mean corpuscular Hb were normal for all transgenic mice, but reticulocyte levels were higher for the doubly transgenic mice versus alpha H beta S [beta MDD] mice older than 30 days (10.0% +/- 1.0% v 4.3% +/- 0.4%; P < .001, mean +/- SE, n = 20 and n = 10, respectively) and control mice (3.9% +/- 0.4%). Reticulocytosis was more severe in mice less than 30 days old ( >> 20% for alpha H beta S beta S-Ant[beta MDD] mice). The median mean corpuscular hemoglobin concentration of doubly transgenic mice was higher than that of alpha H beta S[beta MDD] mice with a variable number of very dense cells. Delay times for polymerization of Hb in red blood cells from alpha H beta S beta S-Ant[beta MDD] mice were shorter than those of alpha H beta S[beta MDD] mice, and there were fewer cells with delay times greater than 100 seconds. Urine-concentrating ability in control mice under ambient conditions is 2,846 +/- 294 mOsm and was reduced 30% to 1,958 +/- 240 mOsm, P < 4 x 10(-8) in all mice expressing both transgenes. We conclude that doubly transgenic mice have a more severe phenotype than either of the two parental lines. These mice may be suitable for validating therapeutic intervention in sickle cell disease.

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14

Adachi, Kazuhiko, Jian Pang, Lattupally R. Reddy та ін. "Polymerization of Three Hemoglobin A2Variants Containing Valδ6and Inhibition of Hemoglobin S Polymerization by Hemoglobin A2". Journal of Biological Chemistry 271, № 40 (1996): 24557–63. http://dx.doi.org/10.1074/jbc.271.40.24557.

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15

Rao, M. Janardhan, K. Subramonia Iyer, and A. Seetharama Acharya. "Polymerization of Hemoglobin S." Journal of Biological Chemistry 270, no. 33 (1995): 19250–55. http://dx.doi.org/10.1074/jbc.270.33.19250.

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16

Stokes, Claire L., Christopher M. McKinney, and Christopher C. Silliman. "Complication Rates in Patients with Sickle Cell Disease Living Chronically at Moderate Altitude." Blood 124, no. 21 (2014): 4095. http://dx.doi.org/10.1182/blood.v124.21.4095.4095.

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Abstract Background: The increased risk of acute vaso-occlusive pain crisis and splenic infarction in children with sickle cell disease (SCD) acutely exposed to altitude has been well documented. However, little is known about complication rates in children chronically living at moderate altitude. We hypothesize that children with SCD experience more complications than children with SCD living at sea level. Methods: A retrospective chart review of all patients with sickle cell disease followed at the Children's Hospital Colorado between January 2001 and December 2010 was completed. Patients observed for less than one year were excluded from analysis. Incidence rates for vaso-occlusive crisis (VOC), acute chest syndrome (ACS), splenic sequestration, and stroke were calculated. Rate ratios and 95% confidence intervals were determined comparing to children with SCD from institutions located near sea level. Secondary measures looked at baseline hematologic indices collected at annual comprehensive care visits and percentage of patients with abnormal tricuspid regurgitation jet velocity (TRV). Two-tailed Student's t-tests were used to compare means of continuous variables. Results: 179 children were observed for a total of 1032.37 patient-years with demographics (Table 1). . At moderate altitude, patients with Hgb SS experienced about a 20% higher rate of VOC compared to historic controls with a rate ratio of 1.19 (1.03-1.39) (Table 2). Patients with Hgb SC had almost 3 times the number of admissions for splenic sequestration than those at sea level with a rate ratio of 2.93 (1.05-8.02). Incidence rates for ACS and stroke appeared to have been higher at moderate altitude than sea level, but did not reach statistical significance. There was also no difference in the percentage of patients with abnormal TRV. Baseline lab values were less than the 95%ile except for the hemoglobin of 11.7 for SC patients (Brown et al 1994). Discussion: The oxygen tension at an elevation of 5,280 feet (1,609 m) is 20% lower than at sea level due to the reduction in barometric pressure. Reduced oxygen tension may lead to increased hemoglobin S polymerization and red cell sickling. Hemoglobin SC patients have higher baseline hemoglobins, and their increase in splenic sequestration may be due to increased blood viscosity. Interestingly, the rate of ACS and pulmonary hypertension did not seem to be significantly elevated in our patients living at moderate altitude. This may be due to a lack of statistical power given the small size of this single institution study. Another limitation of this study is the comparison to data from multiple institutions near sea level which does not necessarily control for other possible contributing factors, e.g. climate. Also, VOC events were defined as hospitalizations requiring parenteral opioid administration, which is a stricter definition than used in the sea-level data. Thus, the risk ratio may be underestimated. Nevertheless, the data supports the anecdotal experience that patients living chronically at moderate altitude have increased sickle cell-related complication rates. Table 1 Table 1. Demographics Table 2 Table 2. Complication Incidence Rates 1 -compared to Gill et. al, Blood, 1995 2 - compared to Vichinsky et. al, Blood, 2012 3- compared to Brousse et. al, BJH, 1997 4- compared to Pashankar et. al, Pediatrics, 2007 5- compared to Quinn et. al, Blood, 2008 Disclosures No relevant conflicts of interest to declare.

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17

Hai, T. T., D. Nelson, D. Pereira, and A. Srnak. "Diaspirin Crosslinked Hemoglobin (DCLHbTM)Polymerization." Artificial Cells, Blood Substitutes, and Biotechnology 22, no. 3 (1994): 923–31. http://dx.doi.org/10.3109/10731199409117931.

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18

Sergunova, V. A., E. A. Manchenko, and O. Ye Gudkova. "Hemoglobin: Modification, Crystallization, Polymerization (Review)." General Reanimatology 12, no. 6 (2016): 49–63. http://dx.doi.org/10.15360/1813-9779-2016-6-49-63.

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19

Matsuhira, Takashi, Keizo Yamamoto, and Hiromi Sakai. "Ring-Opening Polymerization of Hemoglobin." Biomacromolecules 20, no. 4 (2019): 1592–602. http://dx.doi.org/10.1021/acs.biomac.8b01789.

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20

Ferrone, Frank A., James Hofrichter, and William A. Eaton. "Kinetics of sickle hemoglobin polymerization." Journal of Molecular Biology 183, no. 4 (1985): 591–610. http://dx.doi.org/10.1016/0022-2836(85)90174-3.

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21

Ferrone, Frank A., James Hofrichter, and William A. Eaton. "Kinetics of sickle hemoglobin polymerization." Journal of Molecular Biology 183, no. 4 (1985): 611–31. http://dx.doi.org/10.1016/0022-2836(85)90175-5.

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22

Hofrichter, James. "Kinetics of sickle hemoglobin polymerization." Journal of Molecular Biology 189, no. 3 (1986): 553–71. http://dx.doi.org/10.1016/0022-2836(86)90324-4.

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23

Sudha, Rajamani, Lavanya Anantharaman, Mylavarapu V. S. Sivaram, et al. "Linkage of Interactions in Sickle Hemoglobin Fiber Assembly." Journal of Biological Chemistry 279, no. 19 (2004): 20018–27. http://dx.doi.org/10.1074/jbc.m311562200.

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The AB and GH regions of the α-chain are located in spatial proximity and contain a cluster of intermolecular contact residues of the sickle hemoglobin (HbS) fiber. We have examined the role of dynamics of AB/GH region on HbS polymerization through simultaneous replacement of non-contact Ala19and Ala21of the AB corner with more flexible Gly or rigid α-aminoisobutyric acid (Aib) residues. The polymerization behavior of HbS with Aib substitutions was similar to the native HbS. In contrast, Gly substitutions inhibited HbS polymerization. Molecular dynamics simulation studies of α-chains indicated that coordinated motion of AB and GH region residues present in native (Ala) as well as in Aib mutant was disrupted in the Gly mutant. The inhibitory effect due to Gly substitutions was further explored in triple mutants that included mutation of an inter-doublestrand contact (αAsn78→ His or Gln) at the EF corner. Although the inhibitory effect of Gly substitutions in the triple mutant was unaffected in the presence of αGln78, His at this site almost abrogated its inhibitory potential. The polymerization studies of point mutants (αGln78→ His) indicated that the inhibitory effect due to Gly substitutions in the triple mutant was synergistically compensated for by the polymerization-enhancing activity of His78. Similar synergistic coupling, between αHis78and an intra-double-strand contact point (α16) mutation located in the AB region, was also observed. Thus, two conclusions are made: (i) Gly mutations at the AB corner inhibit HbS polymerization by perturbing the dynamics of the AB/GH region, and (ii) perturbations of AB region (through changes in dynamics of the AB/GH region or abolition of a specific fiber contact site) that influence HbS polymerization do so in concert with α78 site at the EF corner. The overall results provide insights about the interaction-linkage between distant regions of the HbS tetramer in fiber assembly.

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24

Budhiraja, Vikas, and J. David Hellums. "Effect of Hemoglobin Polymerization on Oxygen Transport in Hemoglobin Solutions." Microvascular Research 64, no. 2 (2002): 220–33. http://dx.doi.org/10.1006/mvre.2002.2418.

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25

ADACHI, K., J. KIM, and N. SHIBAYAMA. "Polymerization of Partially Liganded Hemoglobin S." Annals of the New York Academy of Sciences 565, no. 1 Sickle Cell D (1989): 356–57. http://dx.doi.org/10.1111/j.1749-6632.1989.tb24185.x.

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26

Weng, Weijun, Alexey Aprelev, Robin W. Briehl, and Frank A. Ferrone. "Universal Metastability of Sickle Hemoglobin Polymerization." Journal of Molecular Biology 377, no. 4 (2008): 1228–35. http://dx.doi.org/10.1016/j.jmb.2008.01.083.

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27

Rotter, Maria A., Haiyan Chu, Philip S. Low, and Frank A. Ferrone. "Band 3 catalyzes sickle hemoglobin polymerization." Biophysical Chemistry 146, no. 2-3 (2010): 55–59. http://dx.doi.org/10.1016/j.bpc.2009.10.004.

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28

Das, Rajdeep, Amrita Mitra, Gopa Mitra, et al. "Molecular insights of inhibition in sickle hemoglobin polymerization upon glutathionylation: hydrogen/deuterium exchange mass spectrometry and molecular dynamics simulation-based approach." Biochemical Journal 475, no. 13 (2018): 2153–66. http://dx.doi.org/10.1042/bcj20180306.

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In sickle cell anemia, polymerization of hemoglobin in its deoxy state leads to the formation of insoluble fibers that result in sickling of red blood cells. Stereo-specific binding of isopropyl group of βVal6, the mutated amino-acid residue of a tetrameric sickle hemoglobin molecule (HbS), with hydrophobic groove of another HbS tetramer initiates the polymerization. Glutathionylation of βCys93 in HbS was reported to inhibit the polymerization. However, the mechanism of inhibition in polymerization is unknown to date. In our study, the molecular insights of inhibition in polymerization were investigated by monitoring the conformational dynamics in solution phase using hydrogen/deuterium exchange-based mass spectrometry. The conformational rigidity imparted due to glutathionylation of HbS results in solvent shielding of βVal6 and perturbation in the conformation of hydrophobic groove of HbS. Additionally, molecular dynamics simulation trajectory showed that the stereo-specific localization of glutathione moiety in the hydrophobic groove across the globin subunit interface of tetrameric HbS might contribute to inhibition in polymerization. These conformational insights in the inhibition of HbS polymerization upon glutathionylation might be translated in the molecularly targeted therapeutic approaches for sickle cell anemia.

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29

Adachi, K., J. Pang, P. Konitzer, and S. Surrey. "Polymerization of recombinant hemoglobin F gamma E6V and hemoglobin F gamma E6V, gamma Q87T alone, and in mixtures with hemoglobin S." Blood 87, no. 4 (1996): 1617–24. http://dx.doi.org/10.1182/blood.v87.4.1617.bloodjournal8741617.

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To further understand determinants for Hemoglobin (Hb) S polymerization, as well as the inhibitory mechanism of Hb F on Hb S polymerization, Hb F variants containing Val-gamma 6 (Hb F gamma E6V) or Val-gamma 6, Thr-gamma 87 (Hb F gamma E6V, gamma Q87T) were expressed in yeast. The oxy form of Hb F gamma E6V was about 10-fold less stable to mechanical agitation than native oxy Hb F, which is similar to stability differences comparing oxy Hb S and oxy Hb A. Deoxy Hb F gamma E6V showed approximately 20-fold decreased solubility compared with native deoxy Hb F in high phosphate buffer and formed gels like deoxy Hb S in low phosphate buffer, indicating that the Val- gamma 6 substitution decreases solubility of Hb F like Val-beta 6 in deoxy Hb S. Oversaturated deoxy Hb F gamma E6V polymerized without a delay time in low and high phosphate buffers, in contrast to deoxy Hb S, which is accompanied by a distinct delay time before polymerization. Deoxy Hb F gamma E6V, gamma Q87T also polymerized without a delay time like deoxy Hb F gamma E6V. These results suggest that deoxy Hb F gamma E6V gamma Q87T polymers are different from those of deoxy Hb S, and that contact sites differ from those of deoxy Hb S, even though both have the same primary donor (A3) and acceptor sites in the EF helix. These results also suggest that other amino acids in addition to beta 6 Val and amino acids in the F helix are critical for nucleation- controlled polymerization of deoxy Hb S. 1:1 mixtures of deoxy Hb S and either Hb F variant polymerized with a delay time when the concentrations for the Hb S/Hb F gamma E6V and Hb S/Hb F gamma E6V, gamma Q87T mixtures were about 2- and 1.5-fold, respectively, higher than that for Hb S. Logarithmic plots of delay time versus concentration for Hb S/Hb F gamma E6V mixtures showed the same straight line as the line for Hb S/Hb S beta T87Q mixtures, but values for Hb S/Hb F gamma E6V, gamma Q87T mixtures were intermediate between those for Hb S and Hb S/Hb F gamma E6V mixtures. A 1:1 mixture of deoxy Hb A and Hb F gamma E6V, gamma Q87T also polymerized, but exhibited biphasic kinetics, when the concentration was increased to more than 3.5-fold higher than that required for Hb S polymer formation. These results suggest that Gin-gamma 87 is a critical amino acid for exclusion of FS hybrids (alpha 2 beta S gamma) from nuclei formation with Hb S. Our findings also show that Val-gamma 6 in hybrids that form in mixtures of the Hb F variants with either Hb S or Hb A interacts with the hydrophobic acceptor pocket on the EF helix of an adjacent tetramer containing Thr-beta 87.

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30

Bridges, KR, GD Barabino, C. Brugnara, et al. "A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy." Blood 88, no. 12 (1996): 4701–10. http://dx.doi.org/10.1182/blood.v88.12.4701.bloodjournal88124701.

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During 24 weeks of hydroxyurea treatment, we monitored red blood cell (RBC) parameters in three patients with sickle cell disease, including F-cell and F-reticulocyte profiles, distributions of delay times for intracellular polymerization, sickle erythrocyte adherence to human umbilical vein endothelial cells in a laminar flow chamber, RBC phthalate density profiles, mean corpuscular hemoglobin concentration and cation content, reticulocyte mean corpuscular hemoglobin concentration, 1H-nuclear magnetic resonance transverse relaxation rates of packed RBCs, and plasma membrane lateral and rotational mobilities of band 3 and glycophorins. Hydroxyurea increases the fraction of cells with sufficiently long delay times to escape the microcirculation before polymerization begins. Furthermore, high pretreatment adherence to human umbilical vein endothelial cells of sickle RBCs decreased to normal after only 2 weeks of hydroxyurea treatment, preceding the increase in fetal hemoglobin levels. The lower adhesion of sickle RBCs to endothelium would facilitate escape from the microcirculation before polymerization begins. Hydroxyurea shifted several biochemical and biophysical parameters of sickle erythrocytes toward values observed with hemoglobin SC disease, suggesting that hydroxyurea moderates sickle cell disease toward the milder, but still clinically significant, hemoglobin SC disease. The 50% reduction in sickle crises documented in the Multicenter Study of Hydroxyurea in Sickle Cell Disease is consistent with this degree of erythrocyte improvement.

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31

Ohiagu, Franklyn O., Paul C. Chikezie, and Chinwendu M. Chikezie. "Sickle hemoglobin polymerization and antisickling medicinal plants." Journal of Phytopharmacology 10, no. 2 (2021): 126–33. http://dx.doi.org/10.31254/phyto.2021.10209.

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Sickle cell disease (SCD) is a dilapidating disorder that is associated with organ destruction and decreased life expectancy. Therapeutic remedies that lead to fundamental cure of SCD such as, bone marrow and stem cell transplantations, as well as gene replacement therapy, are very costly and unaffordable to the disease sufferers in developing countries. In regions where these therapeutic approaches are possible, there are also limitations such as immunologic transplant rejection, difficulty in prognosis, difficulty in obtaining a suitable donor, end-organ dysfunction, and adverse health effects, especially among the older sufferers of this disease. The eagerness of researchers to develop new drugs for the amelioration of the crisis associated with SCD and a possible cure of the disease has led to the discovery of biomolecular agents that inhibit the mechanisms of HbS polymerization as well as medicinal plants with antisickling potentials. The antisickling potency of medicinal plants should be harnessed through research funding and efforts geared towards the discovery of molecules in such plants with HbS polymerization inhibitory effects.

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32

Vekilov, Peter G., Veseilina Uzunova, and Weichun Pan. "The Heme and Sickle Cell Hemoglobin Polymerization." Biophysical Journal 98, no. 3 (2010): 18a. http://dx.doi.org/10.1016/j.bpj.2009.12.107.

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33

Aprelev, Alexey, Weijun Weng, Mikhail Zakharov, et al. "Metastable Polymerization of Sickle Hemoglobin in Droplets." Journal of Molecular Biology 369, no. 5 (2007): 1170–74. http://dx.doi.org/10.1016/j.jmb.2007.04.030.

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34

Szabo, Attila. "Fluctuations in the polymerization of sickle hemoglobin." Journal of Molecular Biology 199, no. 3 (1988): 539–42. http://dx.doi.org/10.1016/0022-2836(88)90624-9.

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35

Ferrone, Frank A., and Maria A. Rotter. "Crowding and the polymerization of sickle hemoglobin." Journal of Molecular Recognition 17, no. 5 (2004): 497–504. http://dx.doi.org/10.1002/jmr.698.

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36

Dufu, Kobina, Donna Oksenberg, Brian Metcalf, and Uma Sinha. "GTx011, a Potent Allosteric Modifier Of Hemoglobin Oxygen Affinity, Delays Polymerization and Prevents Sickling." Blood 122, no. 21 (2013): 316. http://dx.doi.org/10.1182/blood.v122.21.316.316.

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Abstract Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene leading to formation of hemoglobin S (HbS). A primary and obligatory event in the molecular pathogenesis of SCD is the polymerization of deoxygenated HbS leading to sickling of red blood cells (RBCs). Prolonging the oxygenation of HbS should in principle delay polymerization relative to transit time through microcirculation, thus avoiding sickling. Discovered by Global Blood Therapeutics, GTx011 is a novel orally available small molecule that demonstrates desirable pharmacokinetics in multiple species. In addition, GTx011 binding to HbS produces concentration-dependent left shifts in partial oxygen pressure (p50) of oxygen equilibrium curves, indicating an increase in oxygen affinity. We report here that GTx011 delays in vitro polymerization and prevents sickling. GTx011 was evaluated in an adapted version of the polymerization assay described by Adachi et al. [Blood Cells (1982) 8:213-224]. Purified HbS (pre-incubated with GTx011) in 1.8 M potassium phosphate was passively de-oxygenated, followed by an induction of polymerization via temperature jump from 4°C to 37°C. Polymerization was quantified by measuring turbidity of the HbS solution under continued hypoxia. For sickling experiments, RBCs pre-incubated with GTx011 were subjected to hypoxia (pO2 of ∼30 mmHg) for 0.5 hr and subsequently imaged using a light microscope. In de-sickling experiments, RBCs were first sickled under hypoxia and then treated with GTx011 under continued hypoxia (2 hr) before acquiring images of cells. The percentage of sickled cells in each image was quantified using CellVigene software. GTx011 delayed HbS polymerization in a dose-dependent manner. The delay profile was similar to that of CO-liganded HbA, a well characterized intracellular inhibitor of HbS polymerization. Moreover, GTx011 prevented sickling of RBCs under hypoxia suggesting that GTx011 has the ability to prevent intracellular HbS polymerization. It should be noted that in this experimental system, RBCs were exposed to hypoxia for a relatively longer period of time than typical RBC transit times through microcirculation. Interestingly, GTx011 also reversed sickling of pre-sickled RBCs. The ability of GTx011 to de-sickle RBCs suggests that it may promote transition from the low affinity HbS (T-state HbS) into its high affinity conformer (R-state HbS), a form that is not incorporated into HbS polymers. Thus, by stabilizing the oxy (R) conformation of HbS, GTx011 has the potential to be a therapeutic agent for prevention of HbS polymerization and sickling in SCD patients. Table 1 Assay Polymerization Sickling De-sickling Unit DT cpd -DT HbS (min) (% sickled) (% sickled) [HbS] 50 µM ∼1 mM (20% HCT) ∼1 mM (20% HCT) [Cpd] 25 µM 50 µM 100 µM 1 mM 2 mM 5 mM 1 mM 2 mM 5 mM GTx011 3.9 12.8 22.9 41 33 28 57 34 31 5-HMF 1 1.8 6.3 76 65 50 97 96 89 No Cpd 0 0 0 85 85 85 96 96 96 Table 2 Assay Polymerization Unit DT HbS/HbA -DT HbS (min) [Hb] 50 µM % HbA-CO 20% 30% 40% HbA-CO 2.3 11.8 16.8 Disclosures: Dufu: Global Blood Therapeutics: Employment, Equity Ownership. Sinha:Global Blood Therapeutics: Employment, Equity Ownership.

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37

Demers, Melanie, Sarah Sturtevant, Kevin R. Guertin, et al. "MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease." Blood Advances 5, no. 5 (2021): 1388–402. http://dx.doi.org/10.1182/bloodadvances.2020003670.

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Abstract Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology. Dilution of HbS with nonsickling hemoglobin or hemoglobin with increased oxygen affinity, such as fetal hemoglobin or HbS bound to aromatic aldehydes, is clinically beneficial in decreasing polymerization. We investigated a novel alternate approach to modify HbS and decrease polymerization by inhibiting methionine aminopeptidase 2 (MetAP2), which cleaves the initiator methionine (iMet) from Val1 of α-globin and βS-globin. Kinetic studies with MetAP2 show that βS-globin is a fivefold better substrate than α-globin. Knockdown of MetAP2 in human umbilical cord blood–derived erythroid progenitor 2 cells shows more extensive modification of α-globin than β-globin, consistent with kinetic data. Treatment of human erythroid cells in vitro or Townes SCD mice in vivo with selective MetAP2 inhibitors extensively modifies both globins with N-terminal iMet and acetylated iMet. HbS modification by MetAP2 inhibition increases oxygen affinity, as measured by decreased oxygen tension at which hemoglobin is 50% saturated. Acetyl-iMet modification on βS-globin delays HbS polymerization under hypoxia. MetAP2 inhibitor–treated Townes mice reach 50% total HbS modification, significantly increasing the affinity of RBCs for oxygen, increasing whole blood single-cell RBC oxygen saturation, and decreasing fractional flow velocity losses in blood rheology under decreased oxygen pressures. Crystal structures of modified HbS variants show stabilization of the nonpolymerizing high O2–affinity R2 state, explaining modified HbS antisickling activity. Further study of MetAP2 inhibition as a potential therapeutic target for SCD is warranted.

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38

Ijoma, Ikechukwu Kingsley, and Vincent Egbulefu Ajiwe. "Methyl Ferulate Induced Conformational Changes of DeOxyHbS: Implication on Sickle Erythrocyte Polymerization." Mediterranean Journal of Chemistry 12, no. 1 (2022): 100. http://dx.doi.org/10.13171/mjc02208061631ijoma.

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<p class="10-OS-Abstract">Sickle cell disease (SCD) is a molecular disease caused by substituting glutamic acid with valine at the β-6 position of the hemoglobin, leading to the polymerization of erythrocytes that contain the hemoglobin afterward leads to severe clinical consequences. Polymerization of sickle hemoglobin occurs only in the deoxygenated form i.e only sickle deoxyhemoglobin (DeOxyHbS) polymerizes. SCD is predominant in children living in Africa, especially in West Africa. Therefore, molecular docking and molecular dynamic simulation studies were carried out on methyl ferulate isolated from <em>Ficus thonningii</em> leaves, a known antisickling plant used in Eastern Nigeria to manage SCD. The Harborne procedure was used for extraction, whereas the combination of column chromatography and flash chromatography was used for the isolation and purification of active principles of the leaves extract. The structure of methyl ferulate was determined based on nuclear magnetic resonance (NMR) analysis. A binding affinity of -5.8 kcal/mol indicated that methyl ferulate binds to DeOxyHbS and could interfere with the processes that trigger sickle hemoglobin polymerization <em>in vitro</em>. The observed variations in perturbation of both DeOxyHbS and FTH3-DeOxyHbS complex root mean square deviation (RMSD), the radius of gyration (R<sub>gyr</sub>), solvent accessible surface area (SASA), potential energy (PE), and Van der Waal’s (VDW) interactions were obtained from the molecular dynamic simulation studies of the binding site amino acid residue performed at 500 ps and suggest that in silico methyl ferulate binds with amino acid residues reported being involved in sickle hemoglobin polymerization and thus may possess antisickling potentials in vitro.</p>

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39

Sharma, Pranshu, Mayank Goyal, Ali M. Al-Khathaami, and Andrew Demchuk. "Internal Carotid Artery Septa in Sickle Cell Disease: Risk Factor for Stroke?" Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 35, no. 3 (2008): 378–80. http://dx.doi.org/10.1017/s031716710000901x.

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Sickle cell disease is a hemoglobinopathy occurring due to replacement of valine for glutamic acid at the sixth position of the beta globin chain. The altered hemoglobin structure makes it prone for polymerization during hypoxic and infective stress. Polymerization of the hemoglobin molecule leads to sickling of the red blood cells in the vessels causing thrombosisvasoocclusive crises. Although abdomen and extremities are more often involved, silent cerebral infarcts and stroke can occur in up to 25-29% of patients and is the major cause of morbidity and mortality.

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40

Maier-Redelsperger, M., CT Noguchi, M. de Montalembert, et al. "Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease." Blood 84, no. 9 (1994): 3182–88. http://dx.doi.org/10.1182/blood.v84.9.3182.3182.

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Abstract Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.

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41

Maier-Redelsperger, M., CT Noguchi, M. de Montalembert, et al. "Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease." Blood 84, no. 9 (1994): 3182–88. http://dx.doi.org/10.1182/blood.v84.9.3182.bloodjournal8493182.

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Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.

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42

Garel, M. C., C. Domenget, J. Caburi-Martin, C. Prehu, F. Galacteros, and Y. Beuzard. "Covalent binding of glutathione to hemoglobin. I. Inhibition of hemoglobin S polymerization." Journal of Biological Chemistry 261, no. 31 (1986): 14704–9. http://dx.doi.org/10.1016/s0021-9258(18)66928-5.

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43

Falcón Dieguez, José Ernesto, Pablo Rodi, Manuel A. Lores Guevara, and Ana Maria Gennaro. "Spin Label Studies of the Hemoglobin–Membrane Interaction During Sickle Hemoglobin Polymerization." Applied Magnetic Resonance 38, no. 4 (2010): 443–53. http://dx.doi.org/10.1007/s00723-010-0138-8.

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44

Steinberg, Martin H., David H. K. Chui, George J. Dover, Paola Sebastiani, and Abdulrahman Alsultan. "Fetal hemoglobin in sickle cell anemia: a glass half full?" Blood 123, no. 4 (2014): 481–85. http://dx.doi.org/10.1182/blood-2013-09-528067.

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Abstract Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia by inhibiting deoxy sickle hemoglobin (HbS) polymerization. The blood concentration of HbF, or the number of cells with detectable HbF (F-cells), does not measure the amount of HbF/F-cell. Even patients with high HbF can have severe disease because HbF is unevenly distributed among F-cells, and some cells might have insufficient concentrations to inhibit HbS polymerization. With mean HbF levels of 5%, 10%, 20%, and 30%, the distribution of HbF/F-cell can greatly vary, even if the mean is constant. For example, with 20% HbF, as few as 1% and as many as 24% of cells can have polymer-inhibiting, or protective, levels of HbF of ∼10 pg; with lower HbF, few or no protected cells can be present. Only when the total HbF concentration is near 30% is it possible for the number of protected cells to approach 70%. Rather than the total number of F-cells or the concentration of HbF in the hemolysate, HbF/F-cell and the proportion of F-cells that have enough HbF to thwart HbS polymerization is the most critical predictor of the likelihood of severe sickle cell disease.

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45

Noguchi, C. T., and A. N. Schechter. "Sickle Hemoglobin Polymerization in Solution and in Cells." Annual Review of Biophysics and Biophysical Chemistry 14, no. 1 (1985): 239–63. http://dx.doi.org/10.1146/annurev.bb.14.060185.001323.

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46

NOGUCHI, C. "S12.3. Sickle hemoglobin polymerization: thermodynamics and therapeutic implications." Biorheology 32, no. 2-3 (1995): 149–50. http://dx.doi.org/10.1016/0006-355x(95)92013-z.

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47

MAKHIJANI, V., and G. COKELET. "S12.4. Simulation of physiologic intracellular hemoglobin S polymerization." Biorheology 32, no. 2-3 (1995): 150. http://dx.doi.org/10.1016/0006-355x(95)92014-2.

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48

Kuypers, Frans A. "Hemoglobin S Polymerization and Red Cell Membrane Changes." Hematology/Oncology Clinics of North America 28, no. 2 (2014): 155–79. http://dx.doi.org/10.1016/j.hoc.2013.12.002.

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49

Li, Weiming, Miaomiao Chen, Huayu Xiong, et al. "Surface protein imprinted magnetic nanoparticles for specific recognition of bovine hemoglobin." New Journal of Chemistry 40, no. 1 (2016): 564–70. http://dx.doi.org/10.1039/c5nj02879e.

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50

Mendonça-Reis, Evelyn, Camila Cristina Guimarães-Nobre, Lyzes Rosa Teixeira-Alves, Leandro Miranda-Alves, and Clemilson Berto-Junior. "TSH Receptor Reduces Hemoglobin S Polymerization and Increases Deformability and Adhesion of Sickle Erythrocytes." Anemia 2024 (April 2, 2024): 1–8. http://dx.doi.org/10.1155/2024/7924015.

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SCD is a hereditary disorder caused by genetic mutation in the beta-globin gene, resulting in abnormal hemoglobin, HbS that forms sickle-shaped erythrocytes under hypoxia. Patients with SCD have endocrine disorders and it was described that 7% of these patients have clinical hypothyroidism. Recent studies have shown that mature erythrocytes possess TSH receptors. Thus, we aimed to assess the effects of TSH on SCD erythrocytes. The experiments were conducted using different concentrations of TSH (1, 2, 3, and 5 mIU/L). In HbS polymerization assay, erythrocytes were exposed to TSH in hypoxia to induce polymerization, and measurements were taken for 30 minutes. The deformability assay was made using Sephacryl-S 500 columns to separate deformable from nondeformable cells. Static adhesion test utilized thrombospondin to assess erythrocyte adhesion in the presence of TSH. TSH at all contractions were able to reduce polymerization of HbS and increase deformability. The static adhesion of erythrocytes at the lowest concentrations of 1 and 2 mIU/L were increased, but at higher contractions of 3 and 5 mIU/L, static adhesion was not modulated. The results suggest that TSH has potential involvement in the pathophysiology of sickle cell disease by inhibiting HbS polymerization, positively modulating deformability and impacting static adhesion to thrombospondin.

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