Hemoglobin is the chief erythrocyte protein that transports oxygen from the lungs to the tissues, carbon dioxide from the tissues to the lungs, and vasodilating nitrous oxide from nitrite to the blood vessels. Hemoglobin consists of α- and β-globins and an iron-bearing tetrapyrrole moiety. α- and β-globins influence oxygen loading and unloading and erythrocyte shape. Abnormal α- and β-globin result in hemoglobin dysfunction, misshapen erythrocytes, erythrocyte fragility, and the systemic symptoms seen in many hemoglobin disorders.

Thalassemia and hemoglobinopathies are collectively the most common Mendelian diseases found in humans. "Thalassemia" refers to quantitative deficiencies of one or more globin subunits, with α-thalassemia and β-thalassemia being defined as reduced or absent production of α-globin and β-globin chains, respectively.

α-thalassemia is a relatively common monogenic blood disorder found worldwide. α-globin production is regulated by 4 α genes located on chromosome 16. α-thalassemia is usually caused by the affected allele's reduced (designated as α+) or complete absence (designated as α°) of globin chain production.

The carrier state can either be an α+ (α-thalassemia 2 resulting from 1 α-globin gene deletion) or α° (α-thalassemia 1 resulting from the deletion of 2 α-globin genes) trait. α-Thalassemia 2 is an asymptomatic carrier state. The 2 other types of α-thalassemia are Hemoglobin H (or HbH, with deletion of 3 α-globin genes) and α-thalassemia major or Hemoglobin Bart's (or Hb Bart's, with deletion of all 4 α-globin genes). Hb Bart's can cause hydrops fetalis.

Thalassemia can be easily confused with iron deficiency anemia (IDA), which needs to be ruled out in a patient with low hemoglobin. Diagnostic tests like complete blood count (CBC) and hemoglobin analysis by high-performance liquid chromatography (HPLC) or electrophoresis may help identify the hemoglobin disorder in patients with chronic anemia (seeImage. Hemoglobin Electrophoresis Patterns of Hemoglobin Disorders). More advanced α-thalassemia mutation analytical techniques, such as allele-specific polymerase chain reaction (PCR), reverse dot blot (RDB) analysis, real-time PCR, and DNA sequencing, may also be useful for genetic counseling. Disease management, parental counseling, antenatal diagnosis, newborn screening, and complication prevention are critical for improving the patients' and their families' quality of life.

Types of α-Thalassemia

α-Thalassemia can be classified into 4 types based on the number of functional α-globin genes inherited. The severity of symptoms generally increases with the number of affected genes.

1. α-Thalassemia Silent Carrier (αα/α-): arises when 1 α gene is deleted, and α-globin-chain production is enough to ensure a normal hemoglobin synthesis. The patient remains asymptomatic, and the mutation is benign. However, mild anemia can sometimes occur, like increased stress or pregnancy. Patients can pass on the mutation to their progeny.

1. α-Thalassemia Minor (αα/–) or (α-/α-): occurs when 2 α genes are deleted. α-globin-chain production is reduced by half. In adults, faster red blood cell (RBC) production can compensate for the reduced α chain production to some extent, thus balancing the amount of α- and β-globin chains. Patients are usually asymptomatic, and anemia is often mild if present.

1. HbH Disease (α-/–): results from mating between an α-thalassemia silent carrier and an individual with α-thalassemia minor. HbH disease has 3 α gene deletions, manifesting as anemia of varying degrees. Non-transfusion-dependent (NTDT) or transfusion-dependent (TDT) thalassemia may arise. Excess β-globin chains aggregate to form HbH tetramers. HbH often precipitates within RBCs, damaging RBC membranes and resulting in hemolytic anemia. This disease has a broad phenotypic spectrum and may not be diagnosed until adulthood. Patients may present with splenomegaly, mild jaundice, and characteristic thalassemia-like bone changes due to extramedullary erythropoiesis. Patients may also develop gallstones and experience acute hemolytic episodes following infections or oxidant drug exposure.

1. α-Thalassemia Major (–/–): arises from homozygous states and produces the most severe and fatal form of α-thalassemia. This condition is also known as Hb Bart's hydrops fetalis, Hb Bart's, or hydrops fetalis. Excess fetal γ-globin production results from the complete lack of α-globin chains. However, γ-globin forms tetramers with high oxygen affinity and thus does not unload oxygen efficiently in tissues. Generalized edema occurs prenatally, accompanied by severe pleural and pericardial effusions. These manifestations arise from congestive cardiac failure due to severe anemia. Extramedullary erythropoiesis, hepatosplenomegaly, and a large placenta are also seen. The fetus is usually nonviable.

The mother's pregnancy history may provide clues when evaluating patients with possible α-thalassemia.

Disclosure:Anita Motiani declares no relevant financial relationships with ineligible companies.

Disclosure:Muhammad Zubair declares no relevant financial relationships with ineligible companies.

Disclosure:Amit Sonagra declares no relevant financial relationships with ineligible companies.