HbA₂: biology, clinical relevance and a possible target for ameliorating sickle cell disease

Abstract

SummaryHbA 2 , a tetramer of a-and d-globin chains, provides a diagnostic clue to the presence of b-thalassaemia trait. This minor haemoglobin, which forms about 2-3% of the total, has no known physiological role, but has the interesting property of preventing polymerization of deoxy-sickle haemoglobin. If it were possible to increase the level of HbA 2 sufficiently it could have a benefit in sickle cell disease similar to that of foetal haemoglobin. Moreover, HbA 2 is present in all erythrocytes, an advantage not found with foetal haemoglobin, which is heterocellularly expressed. The molecular basis of HbA 2 gene (HBD) expression is partially understood, and with new molecular tools, it might be possible to induce levels of HbA 2 that could be clinically important. However, high concentrations of this positively charged haemoglobin might damage the erythrocyte membrane; also, the reciprocal relationship of d-and c-globin gene (HBD and HBG1/2, respectively) expression might negate any benefit of increasing transcription of the former.

Pharmacoproteomics Profiling of Plasma From β‐Thalassemia Patients in Response to Hydroxyurea Treatment

“…It has been argued that there is a simultaneous increase of γ‐ and β‐globins that is compensated for by a concomitant increase of α‐globin, which is reflected by an increase in total Hb level and reduction in transfusion frequency. Similarly, δ‐globin induction might be clinically important, comparable to HbF . Because the pharmacological augmentation of HbF by increasing γ‐globin can correct the globin chain imbalance in β‐thalassemia patients while inhibiting HbS polymerization in SCD patients, it can be hypothesized that an increase in δ‐globin might play a similar protective role in β‐thalassemia, as observed in our study.…”

“…Similarly, δ-globin induction might be clinically important, comparable to HbF. 36 Because the pharmacological augmentation of HbF by increasing γ -globin can correct the globin chain imbalance in β-thalassemia patients while inhibiting HbS polymerization in SCD patients, 37 it can be hypothesized that an increase in δ-globin might play a similar protective role in β-thalassemia, as observed in our study. Indeed, δ-globin levels are higher at younger ages, which is depicted by increased HbA 2 levels 38 ; however, our data also indicate increased δ-globins in posttreated as well as in the responder cohort due to the effect of hydroxyurea therapy in β-thalassemia patients.…”

Hemoglobins emerging roles in mental disorders. Metabolical, genetical and immunological aspects

“…Increase of HbF levels may reflect compensatory changes against intermittent hypoxias, but in certain circumstances, this increase may act potentially harmful rather than acting beneficial. Considering that HbF and HbA2 is regulated in a reciprocal manner (Steinberg and Rodgers, 2015), higher HbF levels may also mean reduced benefitting from the protective effects of HbA2. HbF increases in response to anemia stress and hypobaric hypoxia (DeSimone et al, 1978), in adult humans exposed to high altitude hypoxia (Risso et al, 2012), in the fetuses of mothers who smoked (Bureau et al, 1983).…”

The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia

“…Several factors seem to be involved. First, HbA2 increases because of a post-transcriptional mechanism resulting from the β-globin deficit and the increased availability of α-globin chains [4]. Additionally, given that transcription factors of the globin genes are present in rate-limiting quantities, if there is inefficient binding to the altered or deleted β-promoters, more factors would be free to trigger the δ-promoter on the cis-locus by the locus control region (LCR) loop and on the trans-locus, and consequently increase the output of both δ-globin genes [1,5,6].…”