What are the clinical presentation, diagnostic workup, and management of alpha thalassemia?

Alpha Thalassemia: Clinical Presentation, Diagnosis, and Management

Clinical Presentation

Alpha thalassemia presents along a spectrum determined by the number of deleted or mutated alpha-globin genes, ranging from asymptomatic carriers to lethal hydrops fetalis. 1, 2

Classification by Genotype and Phenotype

• Silent carrier (α-/αα): One gene deletion produces no symptoms, normal hemoglobin, but mild microcytosis (MCV typically 75-85 fL) 1, 3

• Alpha thalassemia trait (--/αα or α-/α-): Two gene deletions cause mild microcytic hypochromic anemia with MCV <80 fL, often <70 fL, normal or elevated RBC count, and RDW ≤14% 4, 1, 3

• HbH disease (--/α-): Three gene deletions produce moderate to severe hemolytic anemia with variable HbH levels (0.8-40%), chronic anemia requiring intermittent transfusions, and splenomegaly 1, 2

• Hemoglobin Bart's hydrops fetalis (--/--): All four genes deleted results in total absence of alpha-globin synthesis, intrauterine death or stillbirth, and severe fetal hydrops 1, 2

Geographic Distribution

• Alpha thalassemia is most prevalent in Southeast Asia (where it accounts for 28-55% of non-immune hydrops fetalis), Mediterranean countries, Africa, the Middle East, and the Indian subcontinent 4, 1

Diagnostic Workup

Initial Laboratory Evaluation

Begin with CBC focusing on MCV, MCH, and RDW to distinguish alpha thalassemia from iron deficiency anemia. 4, 3

• **MCV <80 fL with RDW ≤14%** strongly suggests thalassemia trait rather than iron deficiency (which shows RDW >14%) 4

• MCH is more reliable than MCV because it is less affected by specimen storage conditions and is consistently reduced in alpha thalassemia 5, 3

• RBC count is normal or elevated in thalassemia trait, distinguishing it from iron deficiency where RBC count is typically low 4

• Measure serum ferritin to exclude concurrent iron deficiency, as iron deficiency can mask thalassemia characteristics and falsely lower HbA2 levels 4

Critical Diagnostic Pitfall

If ferritin is below the reference range, provide iron replacement therapy before performing hemoglobin analysis, as iron deficiency falsely lowers HbA2 levels and can mask beta-thalassemia trait diagnosis. 4

Molecular Confirmation

• DNA testing is required to confirm the diagnosis, especially in silent carriers and alpha thalassemia trait where hemoglobin electrophoresis may be normal 1, 6

• Alpha-1 and alpha-2 globin gene sequencing detects both deletional and non-deletional mutations 7, 6

• Separate sequencing of fusion genes (such as the -α3.7 fusion gene) is essential because non-deletional mutations on fusion genes create different reproductive risks 7

Hemoglobin Analysis

• HbH disease shows 0.8-40% HbH on hemoglobin electrophoresis, with the percentage correlating with clinical severity 1

• Hemoglobin Bart's hydrops fetalis demonstrates Hb Bart's with total absence of HbF 1

• HbA2 levels are normal or slightly reduced in all forms of alpha thalassemia, unlike beta thalassemia trait where HbA2 is elevated 1

Prenatal Screening and Diagnosis

Maternal Screening Protocol

All pregnant women should undergo CBC screening with attention to MCV, as thalassemia carriers typically have MCV <80 fL. 4

• If maternal MCV <80 fL with RDW ≤14%, proceed with hemoglobin analysis and DNA testing 4

• Measure maternal ferritin to exclude iron deficiency before interpreting results 4

Partner Screening

When a pregnant woman is identified as an alpha thalassemia carrier, partner screening is mandatory to assess the risk of Hemoglobin Bart's hydrops fetalis. 8, 4

• Partner screening includes CBC with MCV measurement, and if MCV <80 fL, proceed with hemoglobin analysis and DNA testing 8, 4

• If both parents are carriers of two-gene deletions (α0-thalassemia), there is a 25% risk with each pregnancy of producing a fetus with Hemoglobin Bart's hydrops fetalis, which is typically fatal 8, 4

Prenatal Diagnostic Options

• Chorionic villus sampling at 10-13 weeks allows DNA-based testing for common deletions or point mutations 8, 4

• Amniocentesis at 15-20 weeks provides an alternative for DNA analysis 8, 4

• Ultrasound surveillance in late second and early third trimester detects hydrops fetalis in severe alpha thalassemia 8, 4

• Middle cerebral artery Doppler with peak systolic velocity >1.5 MoM screens for fetal anemia in at-risk pregnancies 9

Management

Alpha Thalassemia Trait (One or Two Gene Deletions)

Carriers of alpha thalassemia trait generally require no treatment. 1

• Genetic counseling is essential to explain carrier status, reproductive risks, and partner screening recommendations 4

• Avoid unnecessary iron supplementation, as these patients are not iron deficient and iron therapy provides no benefit 1

HbH Disease (Three Gene Deletions)

HbH disease requires intermittent transfusion therapy, particularly during intercurrent illness, pregnancy, or hemolytic crises. 1, 2

• Monitor CBC every 3-6 months to assess the degree of hemolytic anemia and determine transfusion needs 8

• Folic acid supplementation supports increased erythropoiesis 2

• Avoid oxidant drugs (sulfonamides, antimalarials) that precipitate hemolysis 2

• Splenectomy may be considered in patients with severe anemia and hypersplenism, though this increases thrombotic risk 8

HbH Disease in Pregnancy

Pregnant women with HbH disease require close hematologic monitoring and multidisciplinary management. 8

• Monitor CBC every 3-6 months throughout pregnancy to maintain adequate hemoglobin for optimal fetal growth 8

• Monthly fetal growth scans from viability ensure adequate fetal development 8

• Thromboprophylaxis with LMWH is indicated, particularly if the patient has undergone splenectomy 8

• Anticipate increased risk of gestational diabetes, preeclampsia, preterm birth (occurring in 9-33.3% of pregnancies), and cesarean delivery 8

• Manage pregnancies in expert centers with hematology, maternal-fetal medicine, and neonatology support 8

Hemoglobin Bart's Hydrops Fetalis (Four Gene Deletions)

Most pregnancies with Hemoglobin Bart's hydrops fetalis are terminated due to the lethal nature of the condition and increased maternal morbidity. 1

• Intrauterine transfusions may allow survival to delivery in selected cases, though long-term outcomes require lifelong transfusion and chelation therapy 2

• Maternal complications include mirror syndrome (maternal preeclampsia-like syndrome), polyhydramnios, and postpartum hemorrhage 1

Genetic Counseling Requirements

Provide clear, nondirective counseling covering the carrier state characteristics, disease risks to offspring, and all available reproductive options. 4

• Explain that if the partner is negative, the couple will be reassured with no risk of severe disease 4

• If both parents are carriers of two-gene deletions, emphasize the 25% risk with each pregnancy of Hemoglobin Bart's hydrops fetalis 4

• Discuss prenatal diagnosis options including CVS, amniocentesis, and the couple's autonomy in deciding whether to continue or terminate an affected pregnancy 4

• Consider ethnicity in risk assessment, as alpha thalassemia is most common in Southeast Asian populations where it represents a major cause of hydrops fetalis 4, 1

Critical Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency—alpha thalassemia trait shows MCV <80 fL with RDW ≤14% and normal/elevated RBC count, distinguishing it from iron deficiency 4

• Do not perform hemoglobin electrophoresis before correcting iron deficiency, as low iron falsely lowers HbA2 and can mask beta-thalassemia trait 4

• Do not fail to screen the partner when a pregnant woman is identified as a carrier, as this can result in missed diagnosis of at-risk pregnancies for Hemoglobin Bart's hydrops fetalis 8

• Do not rely on hemoglobin electrophoresis alone for alpha thalassemia diagnosis—molecular DNA testing is required for definitive diagnosis, especially in silent carriers 1, 6

• Do not overlook non-deletional mutations on fusion genes during molecular testing, as these create different reproductive risks than standard deletions 7