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α-thalassemia is a heterogeneous group of genetic erythrocyte disorders characterized by the absence or deficiency of hemoglobin's α-globin chains. Decreased α-globin synthesis causes a relative excess of β-globin chains, which damages erythroblasts and causes anemia. α-thalassemia has varied presentations, presenting silently in adult genetic carriers, but tends to be fatal in the fetal stage when all 4 α-globin chains are absent. Laboratory evaluation techniques can help diagnose the condition early and improve patients' life expectancy. This activity for healthcare professionals is designed to improve learners' competence in evaluating α-thalassemia and managing the condition based on laboratory findings. This activity also enhances learners' ability to collaborate effectively with interprofessional teams caring for α-thalassemia patients. Objectives: Apply learners' knowledge of α-thalassemia pathophysiology and classification in explaining patients' symptoms. Identify patients with α-thalassemia based on laboratory test results. Differentiate α-thalassemia from other erythrocyte disorders based on laboratory test results. Collaborate effectively with an interprofessional team in formulating short- and long-term care plans for patients with α-thalassemia. Access free multiple choice questions on this topic.

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.[1] "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.[2] α-thalassemia is a relatively common monogenic blood disorder found worldwide. α-globin production is regulated by 4 α genes located on chromosome 16.[3] α-thalassemia is usually caused by the affected allele's reduced (designated as α+) or complete absence (designated as α°) of globin chain production.[4] 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).[5] Hb Bart's can cause hydrops fetalis.

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).[5] 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 (see Image. Hemoglobin Electrophoresis Patterns of Hemoglobin Disorders).[6] 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.[7] 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. 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.[8] 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.[9]

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.[9] 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.[10] 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. 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.[11] The mother's pregnancy history may provide clues when evaluating patients with possible α-thalassemia.

The significant pathophysiological change in thalassemia is imbalanced globin chain production, resulting in RBC fragility. RBC precursors are thus easily destroyed in the bone marrow or peripheral blood. Symptoms include chronic anemia, splenomegaly, and skeletal deformities.[14] The blood picture is often similar to IDA, with slightly microcytic RBCs. Erythrocytes may be normal in the α-thalassemia silent carrier type. α-thalassemia 1 usually presents with mild anemia, slight RBC index decreases (mean corpuscular volume or MCV and mean corpuscular hemoglobin or MCH), hypochromia, microcytosis, and anisopoikilocytosis. HbA2 level is in the low to low-normal range (1.5%-2.5%). During the neonatal period, moderate amounts of Hb Bart's (3% to 8%) can be seen on blood films. A few (1:1,000-10,000 RBCs) intracellular hemoglobin precipitates forming Heinz inclusion bodies may also be detected. Hematological parameters should be reevaluated after iron supplementation. HbH disease generally occurs as NTDT, with α-globin synthesis reduced by about a quarter of the expected level. The presence of HbH, which contains β-globin chain homotetramers, can be detected by HPLC or electrophoresis.[15] HbH amount is between 3% and 30% and is associated with mild-to-severe microcytic or normocytic anemia. Elevated bilirubin levels arise due to a moderate hemolytic component.[16] The most severe α-thalassemia form is the homozygous α°-thalassemia state or Hb Bart's hydrops fetalis syndrome. The fetus cannot synthesize any α-globin chains to make HbF or HbA. Fetal blood shows the presence of only Hb Bart's (γ4) and some amount of embryonic Hemoglobin Portland (Hb Portland). Prenatal diagnosis is crucial for parental counseling in such cases.[17] TDT patients develop various complications due to systemic iron overload. Hemoglobin denaturation causes iron deposition in RBC membranes, resulting in membrane weakening and hemolysis. The concomitant effects of ineffective erythropoiesis, chronic anemia, and hypoxia increase gastrointestinal iron absorption. All these factors also cause increased iron deposition in tissues, resulting in hemosiderosis. Free iron generates reactive oxygen species, leading to free radical-mediated tissue damage, organ dysfunction, and subsequent organ failure. TDT patients require regular iron chelation therapy and iron level monitoring to avoid such complications.[18]

α-thalassemia diagnosis and management involve a collaborative effort from an interprofessional healthcare team. Members of the team may include the following: Hematologist: responsible for diagnosing and managing α-thalassemia, interpreting laboratory results, and overseeing treatment plans. Genetic counselor: provides information and counseling to individuals and families about the genetic aspects of α-thalassemia. This professional also helps assess the risk of transmitting the condition to the offspring, explains genetic test results, and assists with family planning decisions. Laboratory technologist: conducts various laboratory tests, including CBC, hemoglobin electrophoresis, molecular genetic testing, and other specialized assays, ensuring analytical accuracy and report timeliness. Pediatrician or internal medicine physician: involved in the overall care and management of individuals with α-thalassemia. Obstetrician/gynecologist: monitors high-risk pregnancies and addresses potential complications, such as fetal hydrops. Nurse practitioner: helps provide ongoing care, education, and support to individuals with α-thalassemia and their families. Pharmacist: collaborates with the healthcare team to manage medications, such as iron chelators or other supportive therapies. Transfusion specialist: may be involved in managing blood transfusions for individuals with more severe forms of α-thalassemia. Clinical geneticist: consulted for complex genetic cases or when additional expertise is required to interpret genetic testing results. Effective communication and collaboration among these professionals are crucial for providing comprehensive and coordinated care for individuals with α-thalassemia. A holistic, patient-centered approach helps ensure the best possible patient outcomes.