Adult HemoglobinEdit

Adult hemoglobin, abbreviated HbA, is the dominant form of hemoglobin in the circulating blood of healthy adults. It typically constitutes about 95–98 percent of total hemoglobin and serves as the primary carrier of oxygen from the lungs to tissues, while helping to shuttle carbon dioxide back to the lungs for exhalation. Structurally, HbA is a tetramer composed of two alpha globin chains and two beta globin chains (α2β2), each chain bound to a heme group that contains iron capable of binding one molecule of oxygen. In adult life a small fraction of hemoglobin exists as HbA2 (α2δ2) and fetal hemoglobin (HbF, α2γ2), but HbA remains the predominant form after infancy. For broader context, see hemoglobin and the discussions of globin gene clusters and heme chemistry.

The function of HbA is inseparable from the cellular environment in which red blood cells operate. Oxygen binding and release are governed by allosteric changes in the protein that enable cooperative binding; when one subunit binds oxygen, others become more likely to bind as well. This cooperative behavior, and its modulation by factors such as pH, carbon dioxide, and the molecule 2,3-bisphosphoglycerate (2,3-BPG), makes HbA an efficient transport system under varying physiological conditions. The Bohr effect describes how lower pH (in tissues where metabolism is higher) reduces HbA’s oxygen affinity, promoting release of oxygen where it is most needed. The reverse occurs in the lungs, where higher pH and lower CO2 levels favor oxygen uptake. See Oxygen dissociation curve, Bohr effect, 2,3-BPG, and red blood cell.

Structure and function

Tetrameric architecture and heme chemistry

HbA’s four globin chains form two identical pairs, creating a central region that houses four heme groups. Each heme contains iron that can reversibly bind one molecule of oxygen, allowing a single HbA tetramer to carry up to four oxygen molecules. The arrangement of the alpha and beta chains, and their interactions with the heme iron, give HbA its characteristic oxygen affinity and cooperative binding properties. For more on the chemistry of heme and iron, see heme and iron.

Allosteric regulation and gas transport

The oxygen affinity of HbA is tuned by allosteric effectors and the cellular milieu. 2,3-BPG, produced in red cells during glycolysis, binds to HbA and stabilizes the deoxygenated form, reducing oxygen affinity in tissues that require more oxygen delivery. Conversely, the lungs create conditions that favor oxygen binding and release. These dynamics are central to how HbA distributes oxygen and how high-altitude or disease states can influence oxygen delivery. See 2,3-BPG and Oxygen dissociation curve.

Life cycle and development

In humans, the majority of HbA production begins after birth, with a gradual switch from fetal Hb (HbF) to HbA as the dominant adult hemoglobin alongside a smallerHbA2 fraction. This developmental switch is governed by tightly regulated expression of the globin gene clusters on chromosomes 11 (β-like genes) and 16 (α-like genes). See fetal hemoglobin and globin gene cluster.

Genetics and development

Globin gene organization

The α-like globin genes reside on chromosome 16, while the β-like globin genes are on chromosome 11. The HbA tetramer is made from α and β globin chains produced in red blood cells, with regulation ensuring the timely expression of these genes as red cells mature. The locus control region and nearby regulatory elements coordinate tissue- and stage-specific expression of the globin genes. See globin gene cluster and regulatory elements.

HbA, HbA2, and HbF

Human adults carry predominantly HbA (α2β2). A smaller fraction is HbA2 (α2δ2), while HbF (α2γ2) persists at low levels in healthy adults but is elevated in certain disorders or hereditary contexts. The persistence of HbF in adults is a therapeutic target in some conditions, and variations in HbF levels can influence disease severity in disorders like sickle cell disease and β-thalassemia. See HbA2 and HbF.

Genetic variation and disease susceptibility

Hemoglobin gene variants arise through point mutations and other genetic changes. Some variants alter the stability or function of the hemoglobin molecule and can give rise to hemoglobinopathies or affect diagnostic measurements. Among the best known variants are HbS and HbC, which have clinical significance in populations with historical selective pressure from malaria. See hemoglobinopathy, sickle cell disease, and thalassemia.

Clinical significance

Hemoglobinopathies and thalassemias

Sickle cell disease (HbS) results from a mutation in the β-globin gene that causes polymerization of deoxygenated HbS, deforming red blood cells and leading to vaso-occlusive crises, hemolytic anemia, and multi-organ complications. See sickle cell disease and hemoglobin S.
Thalassemias involve reduced or absent synthesis of α or β globin chains, producing imbalanced globin production, anemia, and variable clinical outcomes. See thalassemia and beta-thalassemia.
Other variants such as HbC, HbE, and various unstable or hybrid forms can influence red cell physiology and disease presentation, depending on the specific mutations and genetic background. See hemoglobin C, hemoglobin E.

HbA1c and diagnostic practice

HbA1c, or glycated hemoglobin, reflects average blood glucose over the preceding two to three months and is widely used in diabetes management and diagnosis. However, HbA1c interpretation can be confounded by factors that alter red cell turnover or the structure of hemoglobin—such as anemia, iron deficiency, pregnancy, kidney disease, and hemoglobin variants. In some populations, certain hemoglobin variants interfere with some HbA1c assays, prompting calls for assay selection or supplementary diagnostic tests like fasting glucose or oral glucose tolerance tests. Proponents of a practical, outcome-focused approach argue for using HbA1c as one of several tools, rather than a solitary diagnostic criterion, balancing accuracy, cost, and accessibility. See HbA1c and glycated hemoglobin.

Measurement and laboratory approaches

Laboratories measure HbA and its variants using techniques such as high-performance liquid chromatography (HPLC), electrophoresis, capillary electrophoresis, and mass spectrometry. These methods differ in sensitivity to variants and their potential to misread or miss certain hemoglobin forms. Clinicians rely on a combination of methods and clinical judgment to interpret results in the context of symptoms and additional laboratory data. See electrophoresis, HPLC, and capillary electrophoresis.

Evolution and comparative biology

The HbA structure is a product of deep evolutionary history shared among many vertebrates, with diversification of globin genes enabling adaptation to diverse oxygen environments. In human populations, historical exposure to malaria has shaped the distribution of certain hemoglobin variants (such as HbS) and influenced regional health profiles. See evolutionary biology and malaria.