What is the initial workup and management for a patient suspected of having thalassemia?

Thalassemia Workup

Begin the workup by screening parents with mean corpuscular volume (MCV), as values <80 fL suggest possible thalassemia carrier status, followed by hemoglobin analysis and definitive DNA testing to identify specific genetic mutations. 1

Initial Laboratory Studies

Complete Blood Count Analysis

• Obtain CBC with differential focusing on red blood cell indices, specifically MCV and mean corpuscular hemoglobin (MCH) 2, 3
• Microcytosis (low MCV) and decreased hemoglobin content are hallmarks of all thalassemic red blood cells 3
• Note that MCV and MCH alone cannot discriminate between thalassemia trait and iron deficiency, nor between alpha and beta thalassemia types 3

Hemoglobin Analysis

• Perform hemoglobin analysis using either high-performance liquid chromatography (HPLC) or capillary zone electrophoresis (CE) 3
• Both systems provide qualitative and quantitative analysis of hemoglobin components for postnatal diagnosis 3
• Exercise caution with CE interpretation as Hemoglobin A2 is clearly separated from Hemoglobin E, and alpha-thalassemia gene interactions can affect Hb A2/E levels 3
• Measure Hemoglobin A2 and Hemoglobin F levels as part of the diagnostic workup 2

Peripheral Blood Smear

• Review peripheral blood smear for characteristic morphologic features including target cells, hypochromia, and microcytosis 2

Definitive Genetic Testing

DNA Analysis

• DNA testing for deletions or point mutations is the definitive diagnostic test to identify the specific genetic defect 1
• Alpha-thalassemia typically results from large gene deletions requiring specific molecular detection techniques 3
• Beta-thalassemia results from point mutations (over 200 identified), single nucleotide substitutions, or small deletions/insertions 4
• Next-generation sequencing (NGS) provides accurate diagnosis and can detect mutations that may be missed by conventional techniques, though cost remains a limitation 3

Cascade Testing Approach

• Test the affected family member first to identify the specific genetic mutation, followed by targeted testing of at-risk family members 1

Ethnicity-Based Risk Assessment

High-Risk Populations

• Consider ethnicity in the diagnostic approach, as alpha thalassemia is most prevalent in Southeast Asian, Mediterranean, Middle Eastern, and African populations 1
• Beta-thalassemia shows high carrier rates in Mediterranean populations 4
• Alpha thalassemia accounts for 28-55% of non-immune hydrops fetalis cases in Southeast Asian populations 1

Prenatal Considerations

When Both Parents Are Carriers

• Perform prenatal diagnosis using amniocentesis or fetal blood sampling when both parents are carriers to detect severe forms like Hemoglobin Bart's hydrops fetalis 1
• Use middle cerebral artery Doppler to assess for fetal anemia in suspected hydrops fetalis cases 1
• Hemoglobin Bart's hydrops fetalis (four-gene deletion) typically leads to fetal demise and presents in late second or early third trimester 1

Pre-Test Genetic Counseling

• Provide counseling on benefits including diagnosis confirmation and reproductive planning 1
• Discuss potential implications for family members and limitations of testing 1

Clinical Severity Classification

Transfusion-Dependent Thalassemia

• Includes beta-thalassemia major requiring regular lifelong blood transfusions to survive 2
• Beta-thalassemia major causes hemolytic anemia, poor growth, and skeletal abnormalities during infancy 5

Non-Transfusion-Dependent Thalassemia

• Includes thalassemia intermedia, carrier states, and Hemoglobin H disease (three-gene deletion alpha thalassemia) 2
• Monitor Hemoglobin H disease with CBC every 3-6 months to assess for worsening hemolytic anemia 1

Silent Carriers

• Alpha and beta thalassemia trait carriers are asymptomatic and require no treatment 5
• Carriers have normal life expectancy 5

Common Diagnostic Pitfalls

• Failure to consider ethnicity leads to missed diagnoses 1
• Relying solely on MCV and MCH without hemoglobin analysis or genetic testing results in incomplete diagnosis 3
• Misinterpreting CE results when Hemoglobin A2/E separation occurs in alpha-thalassemia gene interactions 3
• Confusing thalassemia trait with iron deficiency based on red blood cell indices alone 3