Family Medicine Board Review · Hematology · Source: AAFP 2022

Thalassemia: High-Yield Board Summary

Screening triggers, diagnosis pathway, alpha vs. beta subtypes side-by-side, iron chelation agents, and the complication monitoring schedule.

Screening Signs & Symptoms Diagnosis Treatment Iron Chelation Agents Complications Monitoring Beta-Thalassemia Subtypes Alpha-Thalassemia Subtypes

Screening

Patients with low MCV should be screened for thalassemia
Initial screening test: hemoglobin electrophoresis
Prenatal diagnosis: chorionic villus sampling at 10–12 weeks' gestation, or amniocentesis after 15 weeks' gestation

Board trap: low MCV in a board vignette isn't automatically iron deficiency — a normal/high RBC count with microcytosis and normal-to-elevated ferritin should trigger thalassemia screening instead.

Signs & Symptoms

Trait: asymptomatic
Intermedia/major: moderate-to-severe microcytic anemia → fatigue, lightheadedness, syncope; poor growth in children
Active hemolysis → hyperbilirubinemia, jaundice, gallstones
Chronic anemia → erythropoietin stimulation → bone marrow expansion: pseudotumors, frontal bossing, maxillary hypertrophy, malar prominence, depressed nasal bridge
Extramedullary hematopoiesis → hepatosplenomegaly

Exam pearl: the classic facial changes (frontal bossing, maxillary hypertrophy, malar prominence) are a direct consequence of marrow expansion from chronic erythropoietin drive — recognize this "thalassemic facies" pattern on boards.

Diagnosis

HPLC — primary diagnostic test
Genetic testing — confirms diagnosis and identifies mutations correlating with disease severity
Once diagnosed, assess iron overload further with T2*-weighted cardiac MRI or R2*-weighted liver MRI (liver biopsy rarely used)

Board trap: T2* cardiac MRI and R2* liver MRI are the noninvasive standards for quantifying iron burden — liver biopsy is a rarely-needed fallback, not first-line.

Treatment

Asymptomatic subtypes do not require treatment
Treatment goal: maintain Hb 9–10.5 g/dL to prevent extramedullary hematopoiesis

1. Transfusion Therapy

Usually every 2–5 weeks.
Non-transfusion-dependent patients may still need occasional transfusion for symptomatic anemia during pregnancy, before surgery, or during serious infection.

Risks of repeated transfusion: alloimmunization, transfusion reactions, transfusion-related infections, iron overload.

2. Iron Chelation Therapy

Recommended for TDT (transfusion-dependent thalassemia) if ferritin >1,000 ng/mL.
Recommended for NTDT (non-transfusion-dependent) if ferritin >800 ng/mL.

3. Other Therapies

Hydroxyurea — promotes HbF, may reduce transfusion frequency.
Stem cell transplantation — potentially curative; ideal candidate is <12 years old with a matching donor.

4. Luspatercept

Decreases overall transfusion burden in beta-thalassemia.

Board trap: the TDT vs. NTDT ferritin chelation cutoffs are different (1,000 vs. 800 ng/mL) — a favorite numeric detail to test directly.

Iron Chelation Therapy — Agent Comparison

Chelating Agent	Route	Considerations
Deferoxamine	Subcutaneous/IV infusion (typically prolonged, e.g., overnight)	Requires infusion pump/adherence burden; ototoxicity and retinal toxicity risk; growth retardation risk in children; historically the original standard agent
Deferasirox	Oral	GI upset; renal and hepatic toxicity monitoring required; more convenient adherence than deferoxamine
Deferiprone	Oral	Agranulocytosis/neutropenia risk — requires regular CBC monitoring; effective for cardiac iron removal

Board trap: deferiprone's defining safety concern is agranulocytosis — this single fact is a recurring board question (mandates routine CBC monitoring).

Complications of Thalassemia — Monitoring & Treatment

Complication	Monitoring Parameter	Age to Start	Frequency
Iron overload — cardiac	T2*-weighted cardiac MRI	Starting ~10 years	Annually (per severity)
Iron overload — hepatic	R2*-weighted liver MRI / ferritin	At diagnosis of transfusion dependence	Annually
Endocrinopathy (growth, thyroid, gonadal, diabetes)	Growth charts, TSH, glucose, pubertal staging	Childhood onward	Annually
Osteoporosis	DXA scan	Adolescence/adulthood	Periodic
Infection risk (post-splenectomy)	Clinical vigilance, vaccination status	After splenectomy	Ongoing

Pearl: the complication burden in thalassemia tracks directly with iron overload — cardiac iron is the leading cause of mortality, making T2* cardiac MRI monitoring especially high-yield.

Beta-Thalassemia Subtypes

β-Thalassemia Minor (Trait)

Definition: heterozygous — one normal beta globin allele + one thalassemic beta globin allele

Clinical: usually asymptomatic; palpable spleen very rare

Labs: microcytosis, Hb 100–140 g/L, MCV <70, Fe normal, RBC count normal

Smear: microcytosis, basophilic stippling

Hb electrophoresis: HbA2 increased to 3.5–5% (normal 1.5–3.5%)

Treatment: none required; genetic counseling for patient and family

β-Thalassemia Intermedia

Definition: clinical manifestations too mild for major, too severe for minor

Complications more common in intermedia than major: extramedullary hematopoiesis, leg ulcers, gallstones, thrombosis, growth retardation

Characterized by: Hb maintained ~7–10 g/dL without need for regular transfusions; variable splenomegaly; increased infection susceptibility; skeletal changes

β-Thalassemia Major

Definition: homozygous defect in both β-globin alleles, autosomal recessive

Death can result from: untreated anemia, infection, iron overload

Clinical: severe anemia at age 3–6 months; hepatosplenomegaly; extramedullary manifestations (thin bone cortex → increased fracture tendency); iron overload

Infection risk: anemic patients prone to bacterial infection; iron overload specifically increases risk for Yersinia, Klebsiella, and fungal infections

Bone: osteoporosis; radiologic changes from expanded marrow cavity; skull x-ray shows "hair-on-end" appearance; pathologic fractures common

Labs: severe microcytic anemia (Hb <60 g/L)

Smear: teardrop cells, target cells

Hb electrophoresis: HbA 0–10% (normal >95%); HbA2 >2.5%; HbF 90–100%

Treatment: regular blood transfusion (maintain Hb >10; 2–3 units every 4–6 weeks); folic acid 5 mg/day; iron chelation; splenectomy (after age 6, less frequently performed now); endocrine therapy; stem cell transplantation

Board trap: paradoxically, extramedullary hematopoiesis, leg ulcers, gallstones, and thrombosis are MORE common in intermedia than major — because major patients are transfused early and regularly (suppressing marrow drive), while intermedia patients are not.

Alpha-Thalassemia Subtypes (Gene Deletions)

Genotype	1 defective gene (αα/α−)	2 defective genes (cis: αα/−− or trans: α−/α−)	3 defective genes (α−/−−)	4 defective genes (−−/−−)
Name	Silent carrier	Alpha-thalassemia trait	HbH (β4) disease	Hb Barts (γ4) disease / hydrops fetalis
Clinical	Clinically silent; normal Hb, normal MCV	Decreased MCV, normal Hb	Presents in adults; decreased MCV, decreased Hb, splenomegaly, variable growth retardation, leg ulcers, infections	Usually incompatible with life
HPLC	Normal HPLC	Normal HPLC	Will show HbH	Will show Hb Barts
Treatment	No treatment required	No treatment required	Similar to β-thalassemia intermedia (no regular transfusion)	Usually incompatible with life

Board trap: HPLC is normal in 1- and 2-gene deletion alpha-thalassemia — it only becomes abnormal (showing HbH or Hb Barts) once 3 or 4 genes are deleted. Don't assume a normal HPLC excludes alpha-thalassemia trait/silent carrier.