What are the diagnosis and treatment options for alpha thalassemia?

Alpha Thalassemia Diagnosis and Treatment

Diagnosis

Alpha thalassemia should be suspected in any patient presenting with microcytic anemia (MCV <80 fL) and normal or elevated ferritin levels, distinguishing it from iron deficiency anemia. 1

Initial Laboratory Evaluation

• Complete Blood Count (CBC) with specific attention to:

  • MCV typically below 80 fL and often below the 5th percentile for age 2, 3
  • RBC count normal or elevated (unlike iron deficiency where it is low) 2, 3, 4
  • Red cell distribution width (RDW) ≤14.0% suggests thalassemia trait, while RDW >14.0% suggests iron deficiency 2, 3, 4

• Serum ferritin measurement is mandatory to exclude concurrent iron deficiency, as iron deficiency can mask thalassemia trait characteristics and falsely lower HbA2 levels 2, 4

Critical Diagnostic Pitfall

If iron deficiency is present (ferritin below reference range), provide iron replacement therapy BEFORE performing hemoglobin analysis, as iron deficiency falsely lowers HbA2 levels and masks beta-thalassemia trait diagnosis 2, 4

Confirmatory Testing

• Peripheral blood smear examination to confirm size, shape, and color of red blood cells 4
• Reticulocyte count to distinguish decreased production from increased destruction 4
• Hemoglobin electrophoresis may reveal common characteristics but has limitations 1
• Genetic testing (DNA analysis) is required to confirm the diagnosis, as it definitively identifies gene deletions or mutations 1, 5

Severity Classification by Genotype

Alpha thalassemia severity correlates directly with the number of deleted alpha-globin genes (normal complement is 4 genes) 5:

• Silent carrier (1 gene deletion): Asymptomatic, no treatment needed 5
• Alpha thalassemia trait (2 gene deletions): Asymptomatic, no treatment needed 5
• HbH disease (3 gene deletions): Variable severity with moderate to severe anemia, HbH present 0.8-40% 5, 6
• Alpha thalassemia major/Bart's hydrops fetalis (4 gene deletions): Historically fatal at birth 5, 7

Prenatal Diagnosis for At-Risk Couples

When both parents are identified as carriers, prenatal diagnosis options include 2:

• Chorionic villus sampling (CVS) at 10-13 weeks for DNA-based testing to detect deletions or mutations 2
• Amniocentesis at 15-20 weeks as alternative for DNA analysis 2
• Ultrasound surveillance in late second and early third trimester can detect hydrops fetalis in severe alpha thalassemia 2
• DNA testing for alpha-thalassemia should be performed when parental MCV is <80 fL in workup of non-immune hydrops fetalis, as alpha thalassemia is the most common cause (28-55% of cases) in Southeast Asian populations 2, 3

Treatment

Alpha Thalassemia Trait and Silent Carrier

No treatment is required for carriers of alpha thalassemia trait or silent carriers, but genetic counseling is essential for reproductive planning 5

HbH Disease (3 Gene Deletions)

Treatment varies based on clinical severity 5, 6:

• Mild forms: Monitoring only without intervention 1
• Moderate to severe forms: Intermittent transfusion therapy, especially during intercurrent illness 8, 5
• Avoid oxidative medications that can precipitate hemolysis 5

Iron chelation therapy is necessary for patients receiving chronic transfusions to prevent iron overload complications including cirrhosis, heart failure, and endocrinopathies 1, 8

Alpha Thalassemia Major (Bart's Hydrops Fetalis)

Early, serial intrauterine transfusions have transformed outcomes, with improved neurocognitive functioning and fewer congenital anomalies compared to historical outcomes 7

Postnatal management requires:

• Aggressive transfusion protocols (different from standard thalassemia protocols) to suppress ineffective erythropoiesis and hemoglobin Bart's formation 7
• Iron chelation may be safely administered after one year of age with monitoring, including quantitative liver iron measurements 7
• Hematopoietic cell transplantation (HCT) offers potential cure for patients surviving on chronic transfusion therapy 7

Emerging Therapies

New therapeutic approaches under investigation include 7:

• In-utero stem cell transplantation using maternal stem cells
• Phase 1 gene therapy trials evaluating reactivation of embryonic α-globin (zeta) gene
• Gene therapy encoding the α-globin gene

Genetic Counseling Requirements

Provide clear, nondirective counseling covering: the carrier state characteristics, disease risks to offspring (25% risk if both parents are carriers), disease characteristics, and all available options including no further action or prenatal diagnosis 2

Partner screening is mandatory when one parent is identified as a carrier, including CBC with MCV measurement, and if MCV <80 fL, proceed with hemoglobin analysis 2

Monitoring for Complications

Complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition, affecting skeletal system, endocrine organs, heart, and liver 1, 8

Regular monitoring should include:

• Iron overload assessment (even in non-transfusion-dependent patients) 8
• Cardiac function evaluation 8
• Endocrine function screening 8
• Hepatic assessment 8