How should I evaluate and manage a patient with unexplained microcytic anemia who may have thalassemia, including diagnostic workup, transfusion and iron‑chelation strategies, and curative options?

Evaluation and Management of Thalassemia

Initial Diagnostic Workup

Order hemoglobin electrophoresis when microcytosis persists despite normal iron studies (ferritin >30 μg/L and transferrin saturation >20%), or when the MCV is disproportionately low relative to the degree of anemia. 1

Key Discriminating Laboratory Features

• Low MCV with RDW ≤14.0% strongly suggests thalassemia minor, whereas RDW >14.0% points to iron deficiency anemia. 1, 2 Thalassemia trait produces uniform microcytosis because all red cells are similarly affected by the genetic defect, keeping RDW normal. 1

• Serum ferritin <30 μg/L combined with RDW >14% confirms iron deficiency anemia; proceed to evaluate bleeding sources rather than pursuing thalassemia workup. 1

• Ferritin >30 μg/L with RDW ≤14% indicates thalassemia trait and requires confirmatory hemoglobin electrophoresis. 1

• Transferrin saturation >20% with persistent microcytosis excludes iron deficiency and mandates hemoglobin electrophoresis. 1

Confirmatory Testing

• Hemoglobin electrophoresis identifies elevated HbA2 (>3.5%) in β-thalassemia trait and detects HbH in α-thalassemia variants. 3 This test should only be ordered after iron studies are completed, as concurrent iron deficiency can mask the elevated HbA2 pattern. 1

• Obtain peripheral blood smear to assess red cell morphology, looking for target cells, basophilic stippling, and uniform microcytosis characteristic of thalassemia. 1

• Measure complete blood count with attention to the hemoglobin-to-RBC ratio: thalassemia trait typically shows RBC count >5 million/μL despite low hemoglobin, whereas iron deficiency shows proportionally reduced RBC count. 1

Classification and Clinical Phenotypes

Thalassemia Minor (Trait)

• Patients are typically asymptomatic or experience mild fatigue and pallor, with hemoglobin 9-11 g/dL and MCV 55-75 fL. 4 This represents heterozygosity for one thalassemia gene and requires no treatment beyond genetic counseling. 4

• Do not prescribe iron supplementation for thalassemia trait—it is ineffective and risks iron overload. 5 Patients may undergo decades of unnecessary iron therapy when misdiagnosed. 5

Thalassemia Intermedia

• Patients present with moderate anemia (hemoglobin 7-10 g/dL), splenomegaly, hepatomegaly, and require only sporadic transfusions, usually beginning in adulthood. 4 This includes β-thalassemia intermedia (Rietti-Greppi-Micheli disease) and HbH disease (α-thalassemia intermedia). 4

• Physical growth and reproductive capacity remain normal or near-normal, with life expectancy extending to the fifth or sixth decade. 4

Thalassemia Major (Cooley's Anemia)

• Patients require lifelong regular red blood cell transfusions every 2-4 weeks to maintain hemoglobin >9-10 g/dL and suppress ineffective erythropoiesis. 3, 6 Without treatment, death occurs by age 3-4 years; with modern therapy, survival extends into the third decade or beyond. 4

• Transfusion-dependent patients develop severe iron overload requiring mandatory iron chelation therapy. 6, 7

Transfusion Strategy for Thalassemia Major

Transfusion Protocol

• Maintain pre-transfusion hemoglobin >9-10 g/dL through regular transfusions every 2-4 weeks to suppress endogenous erythropoiesis and prevent bone deformities from extramedullary hematopoiesis. 3, 8 This "hypertransfusion" regimen prevents the skeletal complications and growth retardation seen in undertransfused patients.

• Use leukoreduced, phenotypically matched red blood cells to minimize alloimmunization risk. 3 Alloimmunization occurs in 5-30% of chronically transfused patients and complicates future transfusion management.

• Monitor for transfusion reactions, particularly delayed hemolytic reactions and hyperhemolysis syndrome, which can occur even with matched units. 3

Splenectomy Considerations

• Consider splenectomy when transfusion requirements exceed 200-220 mL/kg/year of packed red cells, indicating hypersplenism. 4 Splenectomy reduces transfusion frequency but increases thrombotic risk and susceptibility to encapsulated bacterial infections. 3

• Defer splenectomy until after age 5-6 years to preserve immune function, and ensure pneumococcal, meningococcal, and Haemophilus influenzae vaccinations are current before surgery. 3

Iron Chelation Therapy

Indications and Timing

• Initiate iron chelation when serum ferritin exceeds 1,000 μg/L or after 10-20 transfusions, whichever comes first. 3, 9 Each unit of packed red cells delivers approximately 200-250 mg of iron, and the body has no physiologic mechanism to excrete excess iron.

• Monitor serum ferritin every 3 months and perform liver MRI (T2) annually to quantify hepatic and cardiac iron loading.* 3, 1 Cardiac iron overload (cardiac T2* <20 ms) is the leading cause of death in transfusion-dependent thalassemia.

Chelation Regimens

• Deferiprone (oral) 75-100 mg/kg/day divided three times daily is FDA-approved for transfusional iron overload in thalassemia syndromes. 9 Deferiprone has superior cardiac iron clearance compared to other chelators. 3

• Monitor absolute neutrophil count weekly during deferiprone therapy due to risk of agranulocytosis (0.5-1% incidence) and neutropenia. 9 Discontinue immediately if ANC falls below 1,500/μL.

• Alternative chelators include deferoxamine (subcutaneous infusion 20-40 mg/kg over 8-12 hours, 5-7 nights/week) or deferasirox (oral once daily 20-40 mg/kg). 3 Combination therapy with deferiprone plus deferoxamine may be used for severe iron overload.

• Target serum ferritin 500-1,000 μg/L in transfusion-dependent patients; do not over-chelate below 500 μg/L to avoid zinc deficiency and growth impairment. 1, 9

Monitoring for Chelation Toxicity

• Check liver enzymes (ALT, AST) monthly during chelation therapy, as transaminase elevations occur in 5-10% of patients. 9

• Monitor serum zinc levels and supplement if deficient, as all chelators can induce zinc deficiency. 9

• Perform annual ophthalmologic examination and audiometry to detect retinal toxicity and sensorineural hearing loss from deferoxamine. 3

Curative Treatment: Hematopoietic Stem Cell Transplantation

Indications and Patient Selection

• Hematopoietic stem cell transplantation (HSCT) is the only curative option for thalassemia major and should be considered in all patients with an HLA-identical sibling donor. 3, 7 Current outcomes show >90% overall survival and approximately 80% disease-free survival. 3

• Optimal timing is before age 7 years, before significant iron overload and hepatic fibrosis develop. 3 The Pesaro risk classification stratifies patients based on hepatomegaly, portal fibrosis, and adequacy of prior chelation; Class 1 patients (no adverse features) have >90% disease-free survival.

• Matched unrelated donor (MUD) transplantation is increasingly successful, with disease-free survival 65-85% in experienced centers. 3 Consider MUD transplantation for patients without sibling donors who have Class 1 or 2 risk features.

Transplant Outcomes and Complications

• Major complications include graft failure (5-10%), acute graft-versus-host disease (15-30%), and chronic GVHD (10-20%). 3 Transplant-related mortality is 5-10% in optimal-risk patients but rises to 15-30% in high-risk patients with advanced disease.

• Post-transplant monitoring includes chimerism studies, immunosuppression management, and surveillance for late effects including endocrine dysfunction and secondary malignancies. 3

Emerging and Investigational Therapies

• Hydroxyurea 10-20 mg/kg/day stimulates fetal hemoglobin (HbF) production and may reduce transfusion requirements in some patients with thalassemia intermedia. 7 Response is variable and unpredictable; trial for 3-6 months and continue only if transfusion needs decrease by ≥50%.

• Gene therapy with lentiviral vectors carrying functional β-globin genes has achieved transfusion independence in 70-90% of treated patients in recent trials. 8, 7 This approach is not yet widely available but represents a promising curative option for patients without suitable transplant donors.

Critical Pitfalls to Avoid

• Do not diagnose thalassemia trait as iron deficiency anemia based solely on microcytosis—always check iron studies first, then hemoglobin electrophoresis if iron replete. 1, 5 Misdiagnosis leads to years of ineffective iron therapy and delays genetic counseling.

• Do not undertransfuse patients with thalassemia major—maintaining hemoglobin >9-10 g/dL prevents skeletal deformities, growth failure, and extramedullary hematopoiesis. 3

• Do not delay iron chelation until clinical signs of overload appear—cardiac and hepatic iron deposition is often asymptomatic until irreversible damage occurs. 3, 6 Initiate chelation based on ferritin thresholds, not symptoms.

• Do not overlook cardiac iron assessment—serum ferritin correlates poorly with cardiac iron, and cardiac T2 MRI is mandatory for risk stratification.* 3

• Do not assume all patients with β-thalassemia trait are asymptomatic—some experience significant fatigue and exercise intolerance despite "mild" laboratory findings. 5

Genetic Counseling and Prevention

• Offer genetic counseling to all patients with confirmed thalassemia trait, emphasizing the 25% risk of thalassemia major if both partners carry a thalassemia gene. 4, 7 Partner screening should be performed before conception.

• Prenatal diagnosis via chorionic villus sampling (10-12 weeks) or amniocentesis (15-18 weeks) with DNA analysis can identify affected fetuses. 4, 7 Preimplantation genetic diagnosis is available for couples undergoing in vitro fertilization.

• Population screening programs in endemic regions (Mediterranean, Middle East, Southeast Asia) have successfully reduced thalassemia major births by 80-90%. 6, 7 However, migration has increased prevalence in Northern Europe and North America, requiring expanded screening efforts. 6