Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis

Percy, Melanie J.; Butt, Nauman N.; Crotty, Gerard; Drummond, Mark; Harrison, Claire; Jones, Gail; Turner, Matthew; Wallis, Jonathan P.; McMullin, Mary Frances

doi:10.3324/haematol.2009.008037

Cited by 47 publications

(28 citation statements)

References 10 publications

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“…Though the P50 values are well within normal range (22-28mmHg), but as compared to Indians, Kyrgyz had a higher mean P50 as compared to Indians representing a higher oxygen delivery. Additionally, our data rule-out the existence of abnormal Hb in either of the population group and the decrease in SpO 2 observed upon HA induction is due to increase in altitude Hb variants have been known to cause a reduction in oxygen supply to tissues (11). About 100 Hb variants are known in humans which can cause altered erythrocytosis (12).…”

Section: Discussionsupporting

confidence: 48%

"Analysis of Haemoglobin Variants and Oxygen Affinity in Indian and Kyrgyz Population Groups"

2017

IJCRR

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Aim:The hemoglobin (Hb) variants can alter the structure and biochemical functions of Hb along with affecting physiological properties of the individual. In normal adult RBC, Hb variants that exist are HbA1, HbA2, HbS and HbF. Mutations in globin chains can change the Hb-O 2 affinity which can alter the normal loading of oxygen in lungs and unloading in the tissues and also affect arterial oxygen saturation. Absence of abnormal Hbs rules out upto some extent presence of genetic or acquired facilitated oxygen affinity. Methodology:The study was undertaken to compare haemoglobin variants using HPLC in Indians (n=10) and Kyrgyz population groups (n=10). We estimated oxygen affinity (P50) from PO 2 , SO 2 and pH values using Lichtman equation and peripheral oxygen saturation (SpO 2 ) using pulse oximetry at basal and upon acute HA exposure to 4111m in both the population groups. Results:We obtained Hb fractions A1a, A1b, A1c and A2 within normal range and no HbF or HbS fractions were found in any volunteer from HPLC run. All the P50 values were well within normal range . No change in P50 was observed upon HA exposure in these two populations but Kyrgyz have been found to have a higher P50 compared to Indians at basal. Discussion and Conclusion:Since our data rule-out the existence of abnormal Hb variant in either of the population, thus the significant decrease in SpO 2 observed upon HA induction in both the groups is due to hypoxia at HA and higher P50 in Kyrgyz compared to Indians is population specific.

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Section: Discussionsupporting

confidence: 48%

"Analysis of Haemoglobin Variants and Oxygen Affinity in Indian and Kyrgyz Population Groups"

2017

IJCRR

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“…The reduced intrinsic O 2 affinity of feline Hb clearly compensates for the loss of DPG-mediated regulation of O 2 binding, otherwise the constitutively elevated blood-O 2 affinity would impair O 2 unloading to the cells of respiring tissues. This is evidenced by the fact that human Hb mutants with suppressed DPG sensitivity are invariably associated with erythrocytosis (often at clinically pathological levels) caused by inadequate tissue oxygenation (Percy et al, 2009). …”

Section: Allosteric Regulatory Control Of Feline Hbsmentioning

confidence: 99%

Genetically based low oxygen affinities of felid hemoglobins: lack of biochemical adaptation to high-altitude hypoxia in the snow leopard

Janečka

Nielsen

Andersen

et al. 2015

Journal of Experimental Biology

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Genetically based modifications of hemoglobin (Hb) function that increase blood-O 2 affinity are hallmarks of hypoxia adaptation in vertebrates. Among mammals, felid Hbs are unusual in that they have low intrinsic O 2 affinities and reduced sensitivities to the allosteric cofactor 2,3-diphosphoglycerate (DPG). This combination of features compromises the acclimatization capacity of blood-O 2 affinity and has led to the hypothesis that felids have a restricted physiological niche breadth relative to other mammals. In seeming defiance of this conjecture, the snow leopard (Panthera uncia) has an extraordinarily broad elevational distribution and occurs at elevations above 6000 m in the Himalayas. Here, we characterized structural and functional variation of big cat Hbs and investigated molecular mechanisms of Hb adaptation and allosteric regulation that may contribute to the extreme hypoxia tolerance of the snow leopard. Experiments revealed that purified Hbs from snow leopard and African lion exhibited equally low O 2 affinities and DPG sensitivities. Both properties are primarily attributable to a single amino acid substitution, β2His→Phe, which occurred in the common ancestor of Felidae. Given the low O 2 affinity and reduced regulatory capacity of feline Hbs, the extreme hypoxia tolerance of snow leopards must be attributable to compensatory modifications of other steps in the O 2 -transport pathway.

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“…A high-affinity hemoglobin should be ruled out in cases of erythrocytosis. 28 The conversion of 1,3 bisphosphoglycerate (BPG) to 2,3 BPG is catalyzed by the enzyme bisphosphoglycerate mutase. Hemoglobin is converted to a low oxygen affinity state by binding to 2,3 BPG and presence of 2,3 BPG shifts the oxygen affinity curve to the right.…”

Section: Other Congenital Secondary Erythrocytosesmentioning

confidence: 99%

Idiopathic erythrocytosis: a disappearing entity

McMullin¹

2009

Hematology

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Erythrocytosis results when there is an increased red cell mass and thus an increased hemoglobin. The causes can be divided into primary intrinsic defects of the erythroid progenitor cell and secondary defects, where factors external to the erythroid compartment are responsible. Both can then be further divided into congenital and acquired categories. Congenital causes include mutations of the erythropoietin receptor and defects of the oxygen-sensing pathway including VHL, PHD2 and HIF2A mutations. When fully investigated there remain a number of patients in whom no cause can be elucidated who are currently described as having idiopathic erythrocytosis. Investigation should start with a full history and examination. Having eliminated the common entity polycythemia vera, further direction for investigation is guided by the erythropoietin level. Clinical consequences of the various erythrocytoses are not clear, but in some groups thromboembolic events have been described in young patients. Evidence is lacking to define best management, but aspirin and venesection to a target hematocrit should be considered.T he average adult produces 2.3 × 10 6 red cells every second.1 These red cells contain hemoglobin (Hb), which is the means whereby oxygen is supplied to the tissues. There are precise homeostatic mechanisms to ensure sufficient, but not excess, red cell production. Any imbalance in the homeostatic mechanisms can lead to excess red cell production known as erythrocytosis.The exact extent of an erythrocytosis is ascertained by measuring the red cell mass. The red cell mass is defined as increased if it is greater than 125% above that expected for sex and body mass. 2 If this occurs, then the subject has an absolute erythrocytosis. The presence of an absolute erythrocytosis is reflected in the fact that the Hb and hematocrit (Hct) are also increased. The various parameters do not completely reflect each other as other factors may affect the measurements; however, an Hct of 0.60 or greater is always associated with an increased red cell mass. 3 An Hb above 18.5 g/dL in a male or 16.5 g/dL in a female or an Hct above 0.52 in a male or 0.48 in a female suggests that there is an erythrocytosis. It may be necessary to carry out a red cell mass to establish unequivocally that an absolute erythrocytosis is present. Classification of ErythrocytosesAn erythrocytosis can be classified depending on the identified cause. The main division is on the basis of primary causes, where an intrinsic defect in the erythroid progenitor cell is associated with an enhanced response to cytokines; or secondary, where the increased red cell production is driven by factors external to the erythroid compartment, such as increased erythropoietin (EPO) production for any reason. Primary and secondary causes can be classified further as either congenital or acquired ( Table 1). Primary Erythrocytosis Congenital Erythropoietin Receptor MutationsThe cytokine EPO binds to the EPO receptor on the surface of the erythroid cell. When this occurs a pho...

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Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis

Cited by 47 publications

References 10 publications

"Analysis of Haemoglobin Variants and Oxygen Affinity in Indian and Kyrgyz Population Groups"

"Analysis of Haemoglobin Variants and Oxygen Affinity in Indian and Kyrgyz Population Groups"

Genetically based low oxygen affinities of felid hemoglobins: lack of biochemical adaptation to high-altitude hypoxia in the snow leopard

Idiopathic erythrocytosis: a disappearing entity

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