Gelation of sickle cell hemoglobin in mixtures with normal adult and fetal hemoglobins

Sunshine, Helen R.; Hofrichter, James; Eaton, William A.

doi:10.1016/0022-2836(79)90402-9

Cited by 134 publications

(89 citation statements)

References 49 publications

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“…2,36 The association between %HbF and the presence and burden of WMCs described here is highly consistent with the known antipolymerization dose-response effect of %HbF. 35,37 The lack of a protective effect of the SEN haplotype on the presence of WMCs despite a higher %HbF is consistent with the lack of a protective effect of this haplotype against silent infarcts in children reported in a previous study. 15 Haplotypes are of interest more because of their geographic origin than as a causal explanation.…”

Section: 35supporting

confidence: 88%

Low fetal hemoglobin percentage is associated with silent brain lesions in adults with homozygous sickle cell disease

et al. 2017

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Key Points• Low %HbF is independently associated with silent WMCs on brain imaging in adults with SCD.• Our results highlight the potential use of therapeutic strategies inducing HbF expression in SCD patients with silent white matter changes.Silent white matter changes (WMCs) on brain imaging are common in individuals with sickle cell disease (SCD) and are associated with cognitive deficits in children. We investigated the factors predictive of WMCs in adults with homozygous SCD and no history of neurological conditions. Patients were recruited from a cohort of adults with homozygous SCD followed up at an adult sickle cell referral center for which steady-state measurements of biological parameters and magnetic resonance imaging scans of the brain were available.WMCs were rated by consensus, on a validated age-related WMC scale.

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Section: 35supporting

confidence: 88%

Low fetal hemoglobin percentage is associated with silent brain lesions in adults with homozygous sickle cell disease

et al. 2017

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“…When HbS concentration exceeds its solubility threshold deoxygenation induces polymerization of HbS tetramers, rigidifying and ultimately deforming red blood cells (34). Polymerization of HbS is affected primarily by Hb concentration and composition (relative amounts of HbS, HbF, and HbA forms), but is also modulated by pH, temperature, phosphate concentration, and ligand pressure (35)(36)(37). Interestingly, non-polymerized solution-phase HbS follows the same equilibrium ligand-binding curve as HbA (38) and demonstrates similar ligand-binding kinetics (39 -41).…”

mentioning

confidence: 99%

Nitrite Reductase Activity of Hemoglobin S (Sickle) Provides Insight into Contributions of Heme Redox Potential Versus Ligand Affinity

Grubina

Basu

Tiso

et al. 2008

Journal of Biological Chemistry

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Hemoglobin A (HbA) is an allosterically regulated nitrite reductase that reduces nitrite to NO under physiological hypoxia. The efficiency of this reaction is modulated by two intrinsic and opposing properties: availability of unliganded ferrous hemes and R-state character of the hemoglobin tetramer. Nitrite is reduced by deoxygenated ferrous hemes, such that heme deoxygenation increases the rate of NO generation. However, heme reactivity with nitrite, represented by its bimolecular rate constant, is greatest when the tetramer is in the R quaternary state. The mechanism underlying the higher reactivity of R-state hemes remains elusive. It can be due to the lower heme redox potential of R-state ferrous hemes or could reflect the high ligand affinity geometry of R-state tetramers that facilitates nitrite binding. We evaluated the nitrite reductase activity of unpolymerized sickle hemoglobin (HbS), whose oxygen affinity and cooperativity profile are equal to those of HbA, but whose heme iron has a lower redox potential. We now report that HbS exhibits allosteric nitrite reductase activity with competing proton and redox Bohr effects. In addition, we found that solution phase HbS reduces nitrite to NO significantly faster than HbA, supporting the thesis that heme electronics (i.e. redox potential) contributes to the high reactivity of R-state deoxy-hemes with nitrite. From a pathophysiological standpoint, under conditions where HbS polymers form, the rate of nitrite reduction is reduced compared with HbA and solution-phase HbS, indicating that HbS polymers reduce nitrite more slowly.The various redox reactions catalyzed by ferrous hemes of the heme-globins (primarily hemoglobin and myoglobin) have interested scientists for over 150 years (1). In 1901, while studying the mechanism of meat curing, John Haldane described the ability of nitrite to oxidize hemoglobin (Hb) 5 to methemoglobin (met-Hb) and generate iron-nitrosyl-hemoglobin (iron-nitrosyl-Hb) in sections of meat not exposed to air (2), although he was most likely observing the analogous reaction with myoglobin (Mb). The reaction of nitrite with deoxyhemoglobin (deoxy-Hb) was further characterized by Brooks in 1937 (3) and by Doyle and colleagues in 1981 (4). Recent work has demonstrated that deoxy-Hb can effectively catalyze the reduction of nitrite to NO along physiological oxygen and pH gradients (5-9). This reaction has been implicated in nitrite-and deoxy-Hb-dependent vasodilation in vivo (5, 10 -12) and in vitro (5, 13), as well as in nitrite-mediated cytoprotection following ischemia-reperfusion injury (14 -17). An analogous reaction of nitrite with deoxymyoglobin (deoxy-Mb) has been associated with the regulation of cardiomyocyte respiration during physiological and pathological hypoxia (18,19).In an anaerobic environment nitrite is reduced to NO as deoxy-Hb is oxidized to met-Hb (Equation 1) (6,20). NO generated in this reaction can then be bound by other ferrous deoxy-hemes to form iron-nitrosyl-Hb (Equation 2) (21).Importantly, this reaction is a...

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“…The equilibrium constant, K , for the polymer phase in the reaction Hb (solution) + = Hb(H2 0 )n (polymer) is given by [51]:…”

Section: Experimental Conditions For Polymerisation Of Hbsmentioning

confidence: 99%

“…The kinetics of fibre formation and polymerisation are extremely important and have played a central role in understanding the physical chemistry o f HbS polymerisation as well as the pathophysiology o f the SCA to subsequently improve therapeutic strategies A large variety o f techniques have been used to monitor the process of polymer formation, including nuclear magnetic resonance [53,54], viscosity [55][56][57], turbidity [21,51,58], linear birefringence [25,59,60], light scattering [20, 60. 61] and transverse relaxation times [62], and the results from all o f these techniques show the same basic kinetic features o f polymerisation.…”

Section: Kinetics Of Hbs Polymerisationmentioning

confidence: 99%

Electrochemical modulation of sickle cell haemoglobin polymerisation

Iqbal

McKendry

Horton

et al. 2007

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Gelation of sickle cell hemoglobin in mixtures with normal adult and fetal hemoglobins

Cited by 134 publications

References 49 publications

Low fetal hemoglobin percentage is associated with silent brain lesions in adults with homozygous sickle cell disease

Low fetal hemoglobin percentage is associated with silent brain lesions in adults with homozygous sickle cell disease

Nitrite Reductase Activity of Hemoglobin S (Sickle) Provides Insight into Contributions of Heme Redox Potential Versus Ligand Affinity

Electrochemical modulation of sickle cell haemoglobin polymerisation

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