Eduovisual
Blood & Lymphoreticular
Thalassemia: alpha and beta, transfusion and chelation
— Alpha thalassemia: deletions of α-globin genes on chromosome 16 (4 genes total, 2 per chromosome)
— Beta thalassemia: point mutations in β-globin gene on chromosome 11 (β⁰ = absent, β⁺ = reduced)
— Microcytic anemia (MCV often <75) with normal or elevated RBC count and normal iron studies
— Persistent microcytosis despite adequate iron repletion in primary care
— Ethnic background: Mediterranean, Middle Eastern, Southeast Asian, African, South Asian
— Family history of anemia, splenectomy, or transfusion dependence
— Routine prenatal screening flagging microcytosis in one or both parents
— Incidental finding on preoperative CBC or annual physical
— Silent carrier (1 α gene deleted) → asymptomatic, normal CBC
— Alpha trait (2 deleted) → mild microcytosis, no anemia
— HbH disease (3 deleted) → moderate hemolytic anemia, splenomegaly
— Hb Bart's/hydrops fetalis (4 deleted) → in utero death unless transfused
— β-thal minor → mild microcytic anemia, often mistaken for iron deficiency
— β-thal intermedia → transfusion as needed
— β-thal major (Cooley anemia) → transfusion-dependent by age 1–2
Board pearl: A patient with microcytic anemia and Mentzer index (MCV/RBC) <13 suggests thalassemia; >13 suggests iron deficiency. Always order ferritin before chasing thalassemia workup, because empiric iron in a thalassemia carrier wastes resources and risks iron overload.
Step 3 management: In an ambulatory adult with new microcytic anemia, the first move is iron studies + reticulocyte count, not immediate hemoglobin electrophoresis — establish iron status first to avoid misdiagnosis.
— Presents at 6–24 months as fetal Hb (HbF) declines and β-chain demand rises
— Failure to thrive, pallor, jaundice, hepatosplenomegaly, irritability
— Skeletal changes: frontal bossing, maxillary hyperplasia ("chipmunk facies"), pathologic fractures from marrow expansion
— Without transfusion: death in early childhood from anemia or high-output heart failure
— Presents later in childhood or adolescence
— Mild–moderate anemia, growth delay, bone deformities, leg ulcers, extramedullary hematopoiesis (paravertebral masses, cord compression)
— Pulmonary hypertension, thrombosis risk (especially post-splenectomy)
— Usually asymptomatic; identified incidentally
— Mild microcytic anemia (Hb 10–13), MCV 60–75
— Mild splenomegaly in some; otherwise normal exam
— HbH disease: Moderate anemia (Hb 7–10), jaundice, splenomegaly, gallstones, episodic hemolysis with oxidant stress, fever, or pregnancy
— Hb Bart's (hydrops fetalis): Severe in utero anemia, pleural/pericardial effusions, anasarca; maternal preeclampsia ("mirror syndrome"); typically fatal without intrauterine transfusion
— Ancestry (Southeast Asian → α; Mediterranean → β)
— Age at onset of anemia (infancy vs adolescence vs adult)
— Prior transfusions and chelation history
— Splenectomy and resulting thrombosis/infection risk
— Family screening results, consanguinity
— Symptoms of iron overload: fatigue, arthralgias, impotence, amenorrhea, glucose intolerance, cardiac symptoms
Key distinction: A young child with severe anemia + hepatosplenomegaly + characteristic facies → β-thal major. An adult Southeast Asian with chronic mild–moderate hemolytic anemia and gallstones → HbH disease.
Board pearl: Always ask transfusion-dependent patients about endocrine symptoms — hypogonadism is often the earliest clinical sign of iron overload, predating cardiac dysfunction by years.
— Pallor of conjunctivae, palmar creases, nail beds
— Scleral icterus and mild jaundice from chronic hemolysis
— Growth retardation and delayed puberty in transfusion-dependent children
— Bronze/slate-gray skin from iron overload + increased melanin (chronic transfusion)
— Frontal bossing, prominent maxilla with overbite, depressed nasal bridge
— "Hair-on-end" skull on imaging from marrow expansion
— Dental malocclusion
— Splenomegaly (often massive in untreated disease or post–HbH hemolytic crisis)
— Hepatomegaly from extramedullary hematopoiesis and iron deposition
— RUQ tenderness from pigmented gallstones (calcium bilirubinate)
— Tachycardia, displaced PMI, S3 gallop, JVD, peripheral edema in advanced disease
— High-output state in severe untreated anemia: bounding pulses, wide pulse pressure, flow murmur
— Signs of pulmonary hypertension (loud P2, RV heave) in β-thal intermedia and post-splenectomy patients
— Bone pain, pathologic fractures
— Spinal cord compression from paraspinal extramedullary masses (rare but exam-classic in β-thal intermedia)
— Leg ulcers over malleoli (chronic hemolysis)
— Loss of axillary/pubic hair, testicular atrophy, gynecomastia
— Acanthosis nigricans (insulin resistance from iron-induced diabetes)
— Short stature, delayed bone age
Step 3 management: On any transfusion-dependent thalassemia (TDT) visit, document growth parameters, Tanner stage, cardiac exam, liver size, and signs of endocrinopathy — these drive surveillance ordering.
Board pearl: A TDT patient with new-onset heart failure, arrhythmia, or syncope should be presumed to have cardiac siderosis until cardiac T2* MRI proves otherwise — this is a medical emergency requiring intensified chelation.
— Microcytic, hypochromic anemia: MCV typically 55–75 fL
— RBC count often normal or elevated (distinct from iron deficiency, where RBC is low)
— RDW normal or mildly elevated (vs significantly elevated in IDA)
— Smear: target cells, basophilic stippling, teardrop cells, nucleated RBCs, Howell-Jolly bodies (if asplenic), HbH inclusions on supravital stain with brilliant cresyl blue
— Ferritin normal or elevated, transferrin saturation normal/high
— Rules out iron deficiency and prevents inappropriate iron supplementation
— In transfused patients, ferritin reflects iron overload (target <1000 ng/mL)
— ↑ Indirect bilirubin, ↑ LDH, ↓ haptoglobin, ↑ reticulocyte count
— Reticulocyte index often inappropriately low in β-thal major due to ineffective erythropoiesis despite hyperplastic marrow
— High in HbH disease (peripheral hemolysis)
— Disproportionately low in β-thal major (intramedullary destruction)
— <13 → thalassemia likely
— >13 → iron deficiency likely
— Useful screening in primary care
— Reticulocyte count, bilirubin fractionation
— G6PD screen if hemolytic crisis suspected in HbH
— LFTs and HIV/HCV serologies if transfusion history
Key distinction: Iron deficiency = low RBC, high RDW, low ferritin, low retics. Thalassemia trait = normal/high RBC, normal RDW, normal/high ferritin. Mixing them up is the most common Step 3 trap in microcytic anemia stems.
Board pearl: Order ferritin BEFORE hemoglobin electrophoresis — coexisting iron deficiency can falsely lower HbA2 and mask β-thalassemia minor on electrophoresis.
— β-thalassemia minor: HbA2 elevated (>3.5%), HbF often slightly elevated (1–5%)
— β-thalassemia major: HbF dramatically elevated (>90%), HbA2 variable, HbA absent or very low
— β-thalassemia intermedia: Intermediate pattern
— Alpha thalassemia: Electrophoresis is normal in adults with α-trait — diagnosis requires DNA analysis
— HbH disease: HbH band (β4 tetramer, 5–30%); fast-moving band on electrophoresis
— Hb Bart's: γ4 tetramers seen on newborn screen
— Required for α-thalassemia diagnosis (gene deletion analysis via PCR/MLPA)
— Confirms β-thal mutations for prenatal counseling and prognosis
— Identifies cis vs trans deletions in α-thal — critical for genetic counseling (cis = both deletions on same chromosome → risk for offspring Hb Bart's)
— Demonstrates HbH inclusions ("golf ball" RBCs) — diagnostic for HbH disease
— Serum ferritin every 3 months (trend matters; goal <1000)
— Cardiac T2* MRI: <20 ms = iron loading; <10 ms = severe, high arrhythmia risk
— Liver iron concentration (LIC) by MRI R2/T2*: >7 mg/g dry weight = elevated; >15 = severe
— Liver biopsy now rarely needed given MRI accuracy
— Detects Bart's (α-thal) and absent HbA (β-thal major) — actionable for early referral
Step 3 management: In a couple where both partners have microcytosis with normal iron studies and non-diagnostic electrophoresis, order α-globin gene deletion analysis — they may both be silent carriers at risk for a hydrops fetalis pregnancy.
Board pearl: HbA2 >3.5% with microcytosis is essentially pathognomonic for β-thalassemia minor, even before genetic testing.
— Transfusion-Dependent Thalassemia (TDT): β-thal major, severe HbH, some β-thal intermedia → requires regular transfusions for survival and growth
— Non-Transfusion-Dependent Thalassemia (NTDT): β-thal intermedia, HbH disease, β-thal minor → intermittent or no transfusions, but still risk iron overload from increased GI absorption
— Baseline Hb (<7 → likely TDT)
— Growth/development trajectory in children
— Splenomegaly and hypersplenism (worsening cytopenias)
— Extramedullary hematopoiesis on imaging
— Pulmonary hypertension on echo
— Iron overload markers: ferritin, cardiac T2*, LIC
— Maintain pre-transfusion Hb 9–10.5 g/dL in TDT (suppresses ineffective erythropoiesis, prevents bone changes, allows normal growth)
— Prevent and treat iron overload with chelation
— Preserve fertility, endocrine function, cardiac function
— Screen for comorbidities of chronic transfusion: viral hepatitis, alloimmunization, endocrinopathies
— Hematology (primary), cardiology, endocrinology, hepatology
— Genetics for family screening and reproductive counseling
— Social work and mental health (chronic illness burden)
— Comprehensive thalassemia center referral when available
— Allogeneic HSCT: curative, best in children with matched sibling donor before iron overload develops
— Gene therapy (betibeglogene autotemcel, exa-cel): emerging curative options for TDT
— Luspatercept: reduces transfusion burden in adults with β-thal
Step 3 management: A pediatric β-thal major patient with a matched sibling donor should be referred for HSCT evaluation early — outcomes are best before significant iron overload (ideally before age 14, ferritin <2500).
Board pearl: Iron overload in NTDT comes from enhanced GI absorption, not transfusions — these patients still need chelation when LIC ≥5 mg/g.
— Ferritin >1000 ng/mL on serial measurements, OR
— ≥10–20 transfusions received, OR
— LIC ≥3 mg/g dry weight (NTDT) or ≥5 mg/g (TDT)
— Cardiac T2* <20 ms
— Subcutaneous infusion over 8–12 hours, 5–7 nights/week
— Dose: 20–60 mg/kg/day
— Adverse: ototoxicity (high-frequency hearing loss), retinopathy, growth retardation in young children (limit dose), local injection reactions, Yersinia infection risk
— Monitor: annual audiology and ophthalmology
— Pregnancy: safest chelator (limited data, used after first trimester)
— Oral once-daily, first-line in most adults and children ≥2
— Dose: 14–28 mg/kg (Jadenu film-coated)
— Adverse: renal dysfunction (rising creatinine), hepatotoxicity, GI upset, rash, cytopenias, rare fatal hepatic/renal failure
— Monitor: monthly Cr, LFTs, urinalysis for proteinuria
— Hold if Cr rises >33% above baseline
— Oral TID; uniquely effective at removing cardiac iron
— Adverse: agranulocytosis (0.5–1%) and neutropenia — weekly CBC required, arthralgia, GI upset, elevated LFTs, zinc deficiency
— Often used in combination with DFO for severe cardiac siderosis
— Hydroxyurea: increases HbF, reduces transfusion need in some β-thal intermedia
— Luspatercept: erythroid maturation agent, SQ every 3 weeks; reduces transfusion burden ~30% in adults with TDT β-thal
— Folic acid 1 mg daily in all chronic hemolysis to support erythropoiesis
Step 3 management: Patient on deferasirox develops Cr 1.4 (baseline 1.0). Hold deferasirox, recheck in 1 week, reduce dose by 10 mg/kg if persistent, evaluate for volume depletion or nephrotoxin co-exposure.
Board pearl: Deferiprone is the chelator of choice for cardiac iron overload (cardiac T2* <10 ms), often combined with deferoxamine for synergy.
— Goal pre-transfusion Hb 9.5–10.5 g/dL, post-transfusion ≤14
— Typically every 2–5 weeks, 10–15 mL/kg leukoreduced PRBCs
— Extended phenotype matching (Rh, Kell at minimum; full extended panel preferred) to prevent alloimmunization
— Use leukoreduced units to reduce febrile reactions, HLA alloimmunization, CMV transmission
— Type, screen, antibody panel before each transfusion
— Baseline extended RBC phenotype before first transfusion (becomes impossible to obtain later)
— Hepatitis B vaccination prior to chronic transfusion if non-immune
— Document allergies, prior reactions
— Acute hemolytic (ABO incompatibility): fever, back pain, hemoglobinuria — stop transfusion, supportive care, send DAT
— Delayed hemolytic (5–14 days post): unexplained drop in Hb, jaundice — common with alloantibodies
— Febrile non-hemolytic: prevent with leukoreduction; treat with antipyretics
— TRALI, TACO, anaphylaxis: standard management
— Indicated for hypersplenism increasing transfusion requirement >50% above baseline
— Defer until age ≥5 to reduce post-splenectomy sepsis risk
— Pre-op: pneumococcal, meningococcal, Hib vaccines; lifelong penicillin prophylaxis in children
— Post-splenectomy: increased thrombosis risk, pulmonary hypertension — consider antiplatelet therapy in NTDT
— Allogeneic HSCT from matched sibling donor: 80–90% disease-free survival in low-risk children
— Gene therapy: betibeglogene autotemcel (lentiviral β-globin), exagamglogene autotemcel (CRISPR BCL11A editing reactivating HbF) — approved for TDT β-thal
— Lifelong follow-up for late HSCT/gene therapy effects
CCS pearl: Order type and crossmatch, extended RBC phenotype, hepatitis serologies, and folate before initiating chronic transfusion in a newly diagnosed TDT patient.
Board pearl: Splenectomized thalassemia patients have markedly elevated pulmonary hypertension and VTE risk — screen with annual echo.
— Often diagnosed late in life when persistent microcytosis is investigated
— Coexisting comorbidities (CKD, GI bleeding, malignancy) can complicate the picture
— Do not attribute new anemia to thalassemia trait alone — workup for occult blood loss, B12/folate deficiency, MDS, and renal anemia
— Mild baseline anemia (Hb 10–13) is expected; new drop warrants full workup
— First generation of survivors now living into 40s–60s due to improved chelation
— Multi-organ iron overload: cardiomyopathy, cirrhosis, diabetes, hypogonadism, hypothyroidism, hypoparathyroidism, osteoporosis
— High burden of HCV from pre-1992 transfusions — screen and treat with DAAs
— HCC surveillance with q6mo ultrasound + AFP if cirrhosis or HCV
— Polypharmacy concerns with chelators
— Deferasirox contraindicated if CrCl <40 mL/min or rapidly declining renal function
— Adjust dose if Cr rises persistently >33% above baseline
— Monitor monthly urinalysis for proteinuria — Fanconi-like syndrome possible
— Deferoxamine and deferiprone preferred in significant CKD
— Avoid nephrotoxins (NSAIDs, IV contrast when possible) given baseline renal stress from chelation
— Liver iron deposition + viral hepatitis = high cirrhosis/HCC risk
— Deferasirox: monitor LFTs monthly; black-box warning for hepatic failure
— Hold chelator if transaminases >5× ULN; restart at reduced dose after recovery
— Deferiprone preferred when significant transaminitis on deferasirox
— Treat HCV with sofosbuvir-based DAA regimens — high cure rates regardless of iron status
Step 3 management: In a 55-year-old TDT patient with rising Cr from 1.0→1.5 on deferasirox, hold the drug, rule out volume depletion/NSAIDs/contrast, recheck in 1 week, and switch to deferoxamine if Cr remains elevated.
Board pearl: Always screen aging TDT patients for endocrinopathies annually: fasting glucose/A1c, TSH, free T4, LH/FSH, testosterone or estradiol, IGF-1, vitamin D, DEXA.
— All couples of at-risk ancestry (Mediterranean, SE Asian, African, Middle Eastern) → screen with CBC and hemoglobin electrophoresis
— If both partners are carriers: refer for genetic counseling and prenatal diagnosis (CVS at 10–13 weeks or amniocentesis at 15–20 weeks)
— Discuss reproductive options: PGT-IVF, donor gametes, prenatal diagnosis with termination option, adoption
— Mild anemia expected, often worsens in second trimester
— Folate 1–5 mg daily (higher than standard 0.4 mg)
— Avoid empiric iron unless iron deficiency documented — risk of overload
— Routine OB care otherwise
— High-risk pregnancy; preconception cardiac T2* MRI and intensive chelation to reduce iron stores
— Stop deferasirox and deferiprone before conception (teratogenic in animals)
— Deferoxamine may be cautiously continued after first trimester if needed
— Transfuse aggressively to maintain Hb >10
— Cardiology co-management; cesarean for obstetric indications only
— Postpartum: resume oral chelation; safe to breastfeed on deferoxamine; deferasirox/deferiprone generally avoided
— Universal newborn screening identifies β-thal major and Hb Bart's
— Start transfusions when Hb persistently <7 or symptomatic
— Iron chelation typically starts after age 2 and ≥10–20 transfusions
— Deferasirox approved ≥2 years; deferoxamine dosing limited in young children due to growth/bone toxicity
— Monitor growth, puberty, bone age annually
— HSCT evaluation early when matched sibling available
— Historically fatal; now intrauterine transfusion + postnatal chronic transfusion ± HSCT can permit survival
— Maternal risks: severe preeclampsia, hemorrhage
Step 3 management: A Southeast Asian couple, both with MCV 68 and normal iron studies, plan pregnancy → order α-globin gene deletion analysis on both before conception.
Board pearl: Discontinue deferasirox and deferiprone preconception; deferoxamine is the only chelator with a reasonable pregnancy safety profile.
— Cardiac: restrictive then dilated cardiomyopathy, arrhythmias (AF, VT), heart failure — historically #1 cause of death in TDT
— Hepatic: fibrosis, cirrhosis, hepatocellular carcinoma (especially with HCV co-infection)
— Endocrine: hypogonadotropic hypogonadism (earliest), growth hormone deficiency, hypothyroidism, hypoparathyroidism, iron-induced diabetes mellitus (combined β-cell toxicity and insulin resistance), adrenal insufficiency
— Skin: bronze hyperpigmentation
— Pigmented gallstones → cholecystitis, choledocholithiasis
— Aplastic crisis with parvovirus B19 infection (especially in HbH)
— Megaloblastic crisis if folate deficient
— Alloimmunization (16–25% of chronically transfused) — extended phenotype matching reduces risk
— Osteoporosis and osteopenia — multifactorial (marrow expansion, hypogonadism, chelator effects, vit D deficiency)
— Pathologic fractures, vertebral compression, kyphoscoliosis
— Extramedullary hematopoiesis masses → spinal cord compression (β-thal intermedia)
— Hypercoagulable state in NTDT, especially post-splenectomy
— Pulmonary hypertension — screen annually with echo
— DVT/PE, cerebrovascular events (silent infarcts on MRI)
— Leg ulcers
— Yersinia enterocolitica with deferoxamine (iron-loving organism)
— Encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis) post-splenectomy
— Transfusion-transmitted infections (HBV, HCV, HIV — much lower now with screening)
— DFO: ototoxicity, retinopathy, growth retardation
— DFX: nephrotoxicity, hepatotoxicity, GI bleeding
— DFP: agranulocytosis (weekly CBC mandatory)
Board pearl: A TDT patient on deferoxamine with fever and bloody diarrhea → think Yersinia enterocolitica; treat empirically with TMP-SMX or fluoroquinolone and hold deferoxamine during infection.
Step 3 management: Annual surveillance bundle: echo + cardiac T2* MRI, liver MRI, HbA1c, TSH, gonadal hormones, vitamin D, DEXA, audiology, ophthalmology.
— Decompensated heart failure from iron cardiomyopathy: pulmonary edema, hypotension, malignant arrhythmias
— Acute MI-mimic or new arrhythmia in TDT patient → likely cardiac siderosis; admit for telemetry, urgent cardiac MRI, intensified IV deferoxamine + oral deferiprone combination
— Severe symptomatic anemia (Hb <5 or angina, syncope, heart failure)
— Aplastic crisis from parvovirus B19 — transfusion support, isolation, IVIG if persistent
— Acute hemolytic transfusion reaction: stop transfusion, fluids, monitor renal function, ICU if hemodynamically unstable
— Sepsis in asplenic patient — full sepsis bundle, broad-spectrum antibiotics including coverage for encapsulated organisms
— Yersinia infection suspicion in deferoxamine patient — admit if systemic illness
— Spinal cord compression from extramedullary hematopoiesis — emergent MRI, neurosurgery/radiation oncology consult, transfuse to suppress erythropoiesis
— Acute cholangitis or pancreatitis from pigmented gallstones — surgery/GI consult
— VTE in post-splenectomy patient — anticoagulation
— Agranulocytosis on deferiprone (ANC <500) — stop drug, broad-spectrum antibiotics if febrile, G-CSF, hematology consult
— Hematology: all new diagnoses and chronic management
— Cardiology: cardiac T2* <20 ms or any cardiac symptoms
— Hepatology: cirrhosis, HCC surveillance, HCV treatment
— Endocrinology: any abnormal screening hormone
— Genetics: preconception, prenatal diagnosis
— HSCT center: pediatric TDT with sibling donor, or eligible adults for gene therapy
— Fever (especially if asplenic or on deferiprone) → ED
— Chest pain, palpitations, syncope → ED
— Acute back pain or neurologic symptoms → ED for cord compression
— Bloody diarrhea on deferoxamine → urgent care
CCS pearl: In a TDT patient admitted with new heart failure, simultaneously order cardiac T2* MRI, echo, BNP, troponin, and consult hematology for intensified chelation — don't just diurese and discharge.
Board pearl: New AF or VT in a young TDT adult = cardiac siderosis until proven otherwise.
— Low ferritin, low transferrin saturation, high TIBC
— Low RBC count, high RDW, low retics
— Smear: anisopoikilocytosis, pencil cells (no target cells, no basophilic stippling)
— Mentzer index >13
— Responds to iron supplementation
— Usually normocytic; ~25% microcytic
— Elevated ferritin, low TIBC, low transferrin saturation, elevated hepcidin
— Clinical context: chronic infection, autoimmune disease, malignancy, CKD
— No target cells, no elevated HbA2
— High ferritin and transferrin saturation (iron-loaded marrow)
— Smear: dimorphic RBCs, basophilic stippling, Pappenheimer bodies
— Marrow: ringed sideroblasts on Prussian blue stain
— Causes: hereditary (X-linked ALAS2), MDS, alcohol, lead, isoniazid, copper deficiency, zinc toxicity
— Lead poisoning: occupational/environmental exposure, abdominal pain, neurocognitive symptoms, basophilic stippling
— Microcytic anemia, basophilic stippling, elevated blood lead level
— Treat with chelation (succimer, EDTA, dimercaprol)
— SE Asian populations
— HbE detected on electrophoresis; HbE/β-thal can mimic β-thal major
— Ferritin low → IDA
— Ferritin high + low TSAT + low TIBC → ACD
— Ferritin high + high TSAT + ringed sideroblasts → sideroblastic
— Ferritin normal/high + target cells + elevated HbA2 or HbH → thalassemia
Key distinction: A child with PICA, abdominal pain, developmental regression, microcytic anemia + basophilic stippling → lead poisoning (check blood lead level), not thalassemia.
Board pearl: Coexisting IDA can mask β-thal trait by lowering HbA2 — always treat iron deficiency first, then repeat electrophoresis if microcytosis persists.
— Hereditary spherocytosis: spherocytes, increased MCHC, positive osmotic fragility/EMA binding, splenomegaly — normocytic, not microcytic
— G6PD deficiency: episodic hemolysis after oxidant stress, bite cells, Heinz bodies — normal MCV between episodes
— Sickle cell disease/trait: Hb electrophoresis with HbS; sickle cells on smear
— Pyruvate kinase deficiency: chronic hemolytic anemia, normal-to-elevated MCV, splenomegaly
— HbS/β-thal: combines sickling with microcytosis; common in African and Mediterranean populations; can be severe (S/β⁰) or mild (S/β⁺)
— HbC disease: target cells, mild hemolysis — distinguished on electrophoresis
— HbE/β-thal: SE Asian; can be severe
— MDS in older adults: macrocytic > microcytic typically, but ring sideroblast subtype can be microcytic; dysplastic features on smear and marrow
— Autoimmune hemolytic anemia: positive DAT (Coombs), spherocytes — normocytic/macrocytic
— Microangiopathic hemolytic anemia (TTP, HUS, DIC): schistocytes, thrombocytopenia — normocytic
— Cold agglutinin disease: RBC clumping on smear, agglutination in cold
— Infectious: EBV, malaria, leishmaniasis, endocarditis
— Hematologic: CML, myelofibrosis, lymphoma, hairy cell leukemia
— Storage diseases: Gaucher, Niemann-Pick
— Portal hypertension/cirrhosis
— Transient erythroblastopenia of childhood, Diamond-Blackfan anemia, congenital dyserythropoietic anemia — distinguished by clinical context and marrow findings
Key distinction: Spherocytes + negative DAT = hereditary spherocytosis; spherocytes + positive DAT = autoimmune hemolytic anemia. Neither is typically microcytic.
Board pearl: In a Mediterranean adult with mild microcytic anemia, gallstones, and splenomegaly, the differential is β-thal trait + cholelithiasis vs HbH disease vs hereditary spherocytosis — Hb electrophoresis + DAT + osmotic fragility differentiate.
— Iron chelator: deferasirox 14–28 mg/kg PO daily (most common); deferoxamine SQ 5–7 nights/week; deferiprone if cardiac iron or DFX intolerance
— Folic acid 1 mg PO daily lifelong
— Vitamin D 1000–2000 IU daily with calcium for bone health
— Hepatitis B vaccine series if non-immune; consider HAV vaccine if liver disease
— Bisphosphonates for osteoporosis when DEXA T-score ≤ −2.5 or fragility fracture
— Hormone replacement for documented endocrine deficiencies (testosterone, estrogen, levothyroxine, GH per peds endocrine)
— Insulin or oral hypoglycemics for iron-induced DM
— Luspatercept SQ q3 weeks in eligible adults with TDT β-thal to reduce transfusion burden
— Lifelong penicillin VK 250 mg BID (or amoxicillin) in children; consider in adults x 3–5 years
— Pneumococcal (PCV20 then PPSV23), meningococcal (MenACWY + MenB), Hib vaccines — re-dose per schedule
— Annual influenza, COVID-19 vaccines
— Carry medical alert; emergency antibiotic supply
— Consider aspirin 81 mg if NTDT + post-splenectomy given thrombosis risk
— Avoid iron supplements unless documented deficiency
— Limit alcohol (additive hepatotoxicity with iron overload)
— Avoid raw shellfish (Vibrio risk if cirrhotic, Yersinia in deferoxamine)
— Encourage exercise (counters osteoporosis)
— Screen at diagnosis and periodically
— Treat HCV with DAAs regardless of fibrosis stage
— HBV antivirals if chronic active infection
— HCC surveillance: abdominal US + AFP every 6 months if cirrhosis or HCV
— Standard age-appropriate cancer screening
Step 3 management: On discharge after first transfusion-related admission, schedule hematology follow-up in 2–4 weeks, set up monthly labs (CBC, CMP, ferritin), arrange annual cardiac T2* and liver MRI, and refer to genetic counseling for family.
Board pearl: Update all post-splenectomy vaccinations 2 weeks before elective splenectomy, or as soon as possible after emergent splenectomy.
— Pre-transfusion CBC every 2–5 weeks
— Ferritin every 3 months (trend > single value)
— CMP and LFTs monthly if on deferasirox or deferiprone
— Urinalysis monthly on deferasirox (proteinuria)
— Weekly CBC on deferiprone (agranulocytosis surveillance) — non-negotiable
— Cardiac T2* MRI annually (more often if <20 ms)
— Liver MRI (R2/T2*) annually
— Echocardiogram annually (LV function, pulmonary hypertension)
— Annual audiometry and ophthalmologic exam (DFO toxicity, retinopathy)
— Annual endocrine panel: HbA1c, TSH, free T4, LH/FSH, testosterone/estradiol, IGF-1, cortisol, calcium, PTH, vit D
— DEXA every 2 years
— HCV/HBV/HIV at baseline and periodically
— Annual CBC for trait
— NTDT: ferritin and LIC by MRI every 1–2 years; echo for pulmonary hypertension; monitor for extramedullary hematopoiesis
— Growth parameters and Tanner staging every 3–6 months
— Bone age annually
— Developmental milestones
— School support and psychosocial assessment
— Adherence to chelation (single biggest determinant of survival)
— Symptoms warranting urgent care (fever, chest pain, neurologic changes)
— Reproductive planning, contraception, partner screening
— Mental health screening — depression and anxiety common in chronic illness
— Transition from pediatric to adult care (formal program around age 18–21)
— Fertility preservation discussion before HSCT or gene therapy
— Time-in-target pre-transfusion Hb
— Ferritin trend and chelation adherence
— Vaccination completeness
— Annual MRI completion
CCS pearl: Schedule hematology follow-up every 4 weeks for active TDT and every 3–6 months for NTDT; obtain annual cardiac and liver MRI as a standing order.
Board pearl: Chelation adherence is the single strongest predictor of survival in TDT — address barriers (cost, GI side effects, injection burden) at every visit.
— Carrier couples must receive non-directive counseling about reproductive options (natural conception with prenatal diagnosis, PGT-IVF, donor gametes, adoption, not having biological children)
— Respect cultural and religious values around prenatal diagnosis and termination
— Confidentiality of carrier status — implications for siblings and extended family; encourage but do not coerce family disclosure
— HSCT and gene therapy: discuss infertility risk from conditioning, treatment-related mortality (~5%), potential for graft failure, and the alternative of lifelong transfusion/chelation. Offer fertility preservation (sperm banking, oocyte/embryo cryopreservation) before initiation
— Pediatric assent: developmentally appropriate discussion in addition to parental consent for HSCT/gene therapy
— Chronic transfusion in Jehovah's Witness families: explore alternatives (luspatercept, hydroxyurea, HSCT), document goals-of-care discussions, involve ethics consult; in life-threatening pediatric anemia, court order may be sought
— Pediatric-to-adult hematology transition is a vulnerable period with documented increases in missed transfusions, chelation non-adherence, and ED visits
— Use a structured transition program starting at age 14–16 with formal handoff by 21
— Reconcile chelation regimens at every transition (hospital→outpatient, peds→adult)
— Two-patient identifier verification at bedside before transfusion
— Extended RBC phenotyping before first transfusion prevents alloimmunization-related delays in future emergencies
— Vigilance for transfusion reactions — bedside RN observation first 15 minutes
— Hemovigilance reporting of reactions per institutional policy
— Newborn screen results must be communicated to families with linkage to comprehensive care center
— Report transfusion-transmitted infections per state requirements
— Some states track hemoglobinopathy registries — typically consent-based
— Chelators are expensive ($30,000–60,000/year); ensure prior authorization and patient assistance programs
— Gene therapy costs >$2 million — navigate payer approval, single-case agreements
Step 3 management: Before referring a 14-year-old for HSCT, ensure age-appropriate assent, fertility preservation counseling, and a written transition plan are documented.
Board pearl: Failed transition from pediatric to adult care is the most preventable cause of late morbidity in TDT — protocolize it.
— α-globin gene cluster: chromosome 16, 4 genes total
— β-globin gene cluster: chromosome 11, with γ, δ, ε, β
— Cis deletion (α α/− −): seen in SE Asians → risk for Bart's
— Trans deletion (α −/α −): seen in Africans → no Bart's risk
— Inheritance: autosomal recessive
— HbA (α2β2): 97% in adults
— HbA2 (α2δ2): 2–3.5% normally; >3.5% diagnostic of β-thal trait
— HbF (α2γ2): dominant fetal Hb; elevated in β-thal major and HbS conditions
— HbH (β4): pathologic; 3-gene α deletion
— Hb Bart's (γ4): pathologic; 4-gene α deletion
— Target cells (codocytes): thalassemia, HbC, liver disease, post-splenectomy, IDA
— Basophilic stippling: thalassemia, lead poisoning, sideroblastic anemia
— Howell-Jolly bodies: post-splenectomy
— Heinz bodies: G6PD deficiency, HbH disease (with supravital stain)
— Mediterranean child with chipmunk facies and hepatosplenomegaly → β-thal major
— SE Asian adult with chronic hemolysis, gallstones, HbH on electrophoresis → HbH disease
— Asymptomatic adult with MCV 65, RBC 5.8, normal ferritin → β-thal trait
— Hydropic fetus, SE Asian parents → Hb Bart's
— TDT patient with new AF → cardiac siderosis
— Deferoxamine: ototoxicity, retinopathy, Yersinia
— Deferasirox: nephrotoxicity, hepatotoxicity, GI bleed
— Deferiprone: agranulocytosis, best for cardiac iron
— Hydroxyurea: increases HbF
— Luspatercept: reduces transfusion burden in β-thal
— Cardiac T2* <20 ms = iron loading; <10 ms = severe
— LIC ≥7 mg/g = elevated; ≥15 mg/g = severe
— Ferritin >1000 → start chelation
— Mentzer <13 → thalassemia
Board pearl: "Target cells + basophilic stippling + normal iron studies + Mediterranean ancestry" is the canonical Step 3 thalassemia trifecta.
Key distinction: β-thal = elevated HbA2; α-thal = normal electrophoresis (need DNA testing).
"22-year-old Greek man, asymptomatic, MCV 67, Hb 11.8, RBC 6.1, ferritin 95, RDW 14. Next step?"
→ Hemoglobin electrophoresis (looking for elevated HbA2 → β-thal trait). Avoid empiric iron.
"30-year-old woman, microcytic anemia, ferritin normal, given iron x 3 months with no response. Most likely diagnosis?"
→ Thalassemia trait. Order electrophoresis ± α-globin gene analysis.
"Both partners (SE Asian) have microcytosis with normal iron studies. Best next step?"
→ α-globin gene deletion analysis on both before pregnancy; refer to genetic counseling.
"25-year-old with β-thal major, palpitations, new AF, EF 35%, ferritin 4500. Best next test?"
→ Cardiac T2* MRI. Management: intensify chelation (DFO + deferiprone combination).
"TDT patient on deferasirox develops Cr rise 1.0→1.5, persistent. Best next step?"
→ Hold deferasirox, evaluate for reversible causes, switch to deferoxamine if persistent.
"Patient on deferiprone with fever and sore throat. ANC 300. Next step?"
→ Stop deferiprone, blood cultures, broad-spectrum antibiotics, G-CSF, hematology.
"Fetus with anasarca, pleural effusions, severe anemia, SE Asian parents both with microcytosis. Diagnosis?"
→ Hb Bart's hydrops fetalis (4-gene α deletion).
"TDT patient on deferoxamine, fever, bloody diarrhea. Likely organism?"
→ Yersinia enterocolitica. Treat with TMP-SMX or fluoroquinolone, hold DFO.
"Thalassemia intermedia patient s/p splenectomy, now dyspneic, RV strain on echo. Diagnosis?"
→ Pulmonary hypertension ± PE.
"TDT woman on deferasirox plans pregnancy. Best advice?"
→ Stop deferasirox, optimize iron stores preconception, switch to deferoxamine if needed after first trimester.
"5-year-old with β-thal major, HLA-matched sibling. Best long-term option?"
→ Allogeneic HSCT — curative with best outcomes in young, low-iron patients.
Board pearl: When a stem mentions "Mediterranean/SE Asian ancestry + microcytosis + normal iron", the answer involves electrophoresis or genetic testing, never empiric iron.
Thalassemia is an inherited globin-chain synthesis disorder producing microcytic anemia where management hinges on accurately distinguishing trait from transfusion-dependent disease, supporting transfusion to suppress ineffective erythropoiesis, and aggressively chelating the inevitable iron overload to prevent cardiac, hepatic, and endocrine death.
Board pearl: The Step 3 thalassemia patient is rarely the child with chipmunk facies — they're the adult with persistent microcytosis after a failed iron trial, the pregnant carrier needing partner screening, or the long-surviving TDT adult with new AF from cardiac siderosis.
Step 3 management: Build the longitudinal care plan around adherence to chelation — it is the single greatest determinant of survival.