What is the recommended management for alpha thalassemia based on genotype (silent carrier, trait, HbH disease, and hydrops fetalis)?

Alpha Thalassemia Management by Genotype

Management of alpha thalassemia is stratified by genotype severity: silent carriers and trait require no treatment, HbH disease needs monitoring with CBC every 3-6 months and iron chelation when ferritin exceeds 800 ng/mL, and hydrops fetalis is typically fatal requiring prenatal diagnosis and pregnancy termination counseling. 1

Silent Carrier (One Gene Deletion, -α/αα)

• No treatment is required for silent carriers, as they are asymptomatic with normal hemoglobin levels and only minimal microcytosis. 2
• Genetic counseling should be offered if the partner is also a carrier, as there is risk for more severe disease in offspring. 1
• Screen the partner with CBC and MCV measurement; if MCV <80 fL, proceed with hemoglobin analysis and DNA testing. 3

Alpha Thalassemia Trait (Two Gene Deletion, --/αα or -α/-α)

• No treatment is necessary as carriers are generally asymptomatic with mild microcytic anemia. 2
• Avoid inappropriate iron supplementation, as these patients have normal or elevated ferritin levels despite microcytosis. 4
• Genetic counseling is essential before conception to discuss the 25% risk of severe disease if the partner is also a carrier. 3
• Partner screening is mandatory when planning pregnancy, including CBC with MCV measurement, and if MCV <80 fL, proceed with hemoglobin analysis and DNA testing. 3

HbH Disease (Three Gene Deletion, --/-α)

Hematologic Monitoring

• Monitor CBC every 3-6 months to assess for worsening hemolytic anemia and determine transfusion needs, as HbH disease severity varies significantly. 1, 3
• Measure serum ferritin to exclude concurrent iron deficiency before initiating iron supplementation, as inappropriate iron supplementation can worsen hemosiderosis. 3
• Provide folic acid supplementation 1-5 mg daily to support erythropoiesis. 5

Iron Chelation Therapy

• Initiate iron chelation when liver iron concentration exceeds 5 mg Fe/g dry weight or serum ferritin consistently exceeds 800 ng/mL. 5
• Use deferasirox as first-line therapy at 5-10 mg/kg/day, as once-daily oral dosing improves adherence compared to subcutaneous deferoxamine. 5
• Alternative chelation options if deferasirox is not tolerated include deferiprone 75 mg/kg/day divided in 3 doses, which has superior cardiac iron removal if cardiac involvement develops. 5
• Deferoxamine 25-50 mg/kg subcutaneously 3-5 nights/week is less practical but can be considered as an alternative. 5

Cardiac Monitoring

• Perform annual cardiac MRI T2 monitoring* to detect cardiac iron before symptoms develop, with T2* <20 ms indicating cardiac iron loading. 5
• Switch to deferiprone 75 mg/kg/day if cardiac T2* falls below 20 ms, as it provides superior cardiac iron removal. 5
• Conduct echocardiography annually to assess left ventricular ejection fraction. 5

Transfusion Therapy

• Consider transfusions if hemoglobin drops below 7 g/dL or patient becomes symptomatic despite chelation. 5
• Initiate regular transfusions if hemoglobin consistently <7 g/dL with symptoms, development of cardiovascular complications, extramedullary hematopoiesis causing complications, or poor growth in children. 5

Infection Prevention

• Administer hepatitis B vaccination if not previously immunized. 5
• Screen for hepatitis B and C at baseline and annually. 5

Pregnancy Management in HbH Disease

• Pregnant women with HbH disease require CBC monitoring every 3-6 months throughout pregnancy to maintain adequate hemoglobin levels for optimal fetal growth. 3
• Ultrasound surveillance in the late second and early third trimester is critical to detect hydrops fetalis if the fetus has inherited severe alpha thalassemia. 3
• Middle cerebral artery Doppler should be used to assess for fetal anemia in cases of suspected hydrops fetalis. 3
• Monthly fetal growth monitoring scans from viability are recommended to ensure adequate fetal development. 3
• Prophylaxis with heparin or low-molecular-weight heparin is indicated, particularly if the patient has undergone splenectomy, as this significantly increases thrombotic risk. 3

Curative Options

• Consider hematopoietic stem cell transplantation (HSCT) as the only cure, ideally before age 14 years and before iron-related organ damage develops, if a matched donor is available. 5

Hemoglobin Bart's Hydrops Fetalis (Four Gene Deletion, --/--)

Prenatal Diagnosis

• Prenatal diagnosis is critical as this condition typically leads to fetal demise and is the most common cause of non-immune hydrops fetalis in Southeast Asian populations, accounting for 28-55% of cases. 1
• Prenatal diagnosis using amniocentesis or fetal blood sampling is recommended when both parents are carriers to detect this severe form. 1
• Middle cerebral artery Doppler is used to assess for fetal anemia in cases of suspected hydrops fetalis. 1

Management

• Most pregnancies are terminated due to the increased risk of both maternal and fetal morbidity, as this condition results in severe intrauterine hypoxia and non-immune hydrops fetalis presenting in late second or early third trimester. 1, 2
• Intrauterine transfusion is considered investigational and not generally recommended outside research settings. 1

Critical Pitfalls to Avoid

• Failure to consider ethnicity in the diagnostic approach (alpha thalassemia is more common in Southeast Asian, Mediterranean, Middle Eastern, and African populations) can lead to missed diagnoses. 1
• Failure to screen the partner for thalassemia carrier status can result in missed diagnosis of at-risk pregnancies for Hemoglobin Bart's hydrops fetalis. 3
• Delayed recognition of worsening anemia during pregnancy can compromise both maternal and fetal outcomes. 3
• Inappropriate iron supplementation in patients with normal or elevated ferritin can worsen iron overload. 3, 4