Thalassemia

Thalassemia is not one disease but a heterogeneous group of inherited disorders of hemoglobin production — a genuinely different pathophysiology from sickle cell disease's single structural hemoglobin variant (HbS) that polymerizes and deforms red cells. In thalassemia, mutations reduce or abolish production of a normal-structure globin chain itself, leaving the other chain type in relative excess.^[1]

Alpha-thalassemia is caused by reduced or absent alpha-globin chain production; each person typically has four alpha-globin genes. Losing one gene (silent carrier) or two genes (alpha-thalassemia minor/trait) is usually clinically silent; losing three genes causes Hemoglobin H (HbH) disease — a form of non-transfusion-dependent thalassemia (NTDT) with moderate hemolytic anemia; losing all four genes causes Hb Barts hydrops fetalis, which is fatal in utero without aggressive intrauterine transfusion.^[1]

Beta-thalassemia is caused by reduced or absent beta-globin chain production; each person typically has two beta-globin genes, and the disease is inherited in an autosomal recessive pattern. The severity spectrum runs from beta-thalassemia trait/carrier (one mutated gene, mild asymptomatic microcytosis) through beta-thalassemia intermedia (NTDT) (compound heterozygous states for milder mutations, or variants such as HbE/beta-thalassemia or delta-beta-thalassemia, sometimes needing occasional transfusion) to beta-thalassemia major (transfusion-dependent thalassemia, TDT) — homozygous or compound heterozygous mutations that abolish beta-globin production, causing severe anemia that necessitates regular red cell transfusion beginning in infancy.^[1]

The unifying pathophysiology across every form is globin chain imbalance: the excess, unpaired chain precipitates within erythroid precursors, damaging red cell membranes and organelles and triggering both premature intramedullary destruction (ineffective erythropoiesis) and shortened peripheral red cell survival (hemolysis). The body's compensatory response — erythroid marrow hyperplasia — can reach 10-20 times normal in inadequately treated thalassemia major, and this compensatory marrow expansion is itself the direct cause of the disease's classic bony and facial deformities if regular transfusion does not adequately suppress it (see Recognize the Condition and Red Flags & Refer).^[2]

Thalassemia is genuinely relevant to Canadian practice: the Mediterranean, Middle East, North Africa, India, Southeast Asia, and China together account for roughly 95% of the world's thalassemia births, and ongoing migration to Canada from these regions means equitable access to comprehensive thalassemia care is an active, evolving challenge across the country.^[1]

• Autosomal recessive inheritance — both biological parents must carry at least one abnormal globin-gene allele for a child to be affected by a transfusion-dependent form; a child of two carriers has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither variant.^[3]
• Ethnic background from a high-risk region: North Africa, the Mediterranean, the Middle East, India, Southeast Asia, and China.^[3]
• A known carrier parent, or a first-degree relative with confirmed thalassemia — the specific, practical reason preconception and prenatal screening exist (see Assessment & Diagnosis).^[3]
• For the bony/facial complications of extramedullary hematopoiesis specifically: inadequate or delayed transfusion, lower baseline hemoglobin, and lower fetal hemoglobin (HbF) levels.^[2]
• For iron-overload complications: chronic transfusion in TDT; in NTDT, chronically decreased hepcidin driven by ineffective erythropoiesis and anemia, which increases intestinal iron absorption via ferroportin to roughly 2-4 times the normal rate even without any transfusion at all.^[4]
• For thromboembolic events (more common in NTDT than TDT): splenectomy, age over 35 years, serum ferritin over 1000 ng/mL, and hemoglobin under 90 g/L.^[4]
• For pulmonary hypertension: splenectomy, hydroxyurea-naive and chelation-naive status, transfusion-naive status, prior thromboembolic event, and hypoxia — again disproportionately an NTDT risk.^[4]

Classification

The clinical phenotype cannot always be accurately predicted from genotype alone — co-inheritance of alpha-thalassemia mutations and residual fetal hemoglobin production can meaningfully modify severity, so a newly diagnosed infant needs close clinical follow-up (at least monthly) until the phenotype is truly established, rather than a genotype-based label being treated as final on day one.^[7]

Diagnostic testing

• Complete blood count with red blood cell indices and a peripheral blood smear.
• Reticulocyte count — helps distinguish ineffective erythropoiesis from a primarily hemolytic picture, and is essential when an aplastic or hemolytic crisis is suspected.
• Serum ferritin — part of the initial screen; a normal ferritin alongside microcytic anemia is a genuine clue pointing away from iron deficiency and toward thalassemia.
• Hemoglobinopathy investigation — hemoglobin electrophoresis, high-performance liquid chromatography (HPLC), or capillary zone electrophoresis (CZE).
• Molecular genetic (genotype) analysis of both alpha- and beta-globin genes — the confirmatory test, and the only way to reliably distinguish some genotypes (e.g., beta-thalassemia from the more benign HbE/beta-thalassemia or HbEE, which show the same "FE" pattern on HPLC alone).^[3]
• Parents and siblings should be tested if not previously done, both to confirm the diagnosis and to begin family/genetic counseling.^[7]

Newborn, preconception, and prenatal screening

Several Canadian provinces and territories — Ontario, Quebec, British Columbia, PEI, Nova Scotia, New Brunswick, Yukon, and Nunavut — have newborn screening (by HPLC) that can detect significant thalassemia syndromes (beta-thalassemia major, HbH disease, HbE/beta-thalassemia) alongside other hemoglobinopathies; screening is not yet universal across the country, and Canada's ongoing immigration from high-risk regions means a first presentation can still be a previously undiagnosed infant, child, or adult. A newborn-screening finding of Hb F only, or Hb A2 under 1.5%, identifies most babies with beta-thalassemia major; Hb Bart's over 25% suggests HbH disease. Any positive screen needs prompt confirmatory molecular testing and referral to a pediatric hematology/genetics centre.^[3]

Per the Society of Obstetricians and Gynaecologists of Canada's guidance: prospective parents from high-risk regions should be screened before conception (CBC with indices, ferritin, hemoglobinopathy investigation); if both are found to be heterozygotes, genetic counseling is recommended, ideally before conception or as early as possible in pregnancy. Prenatal diagnosis (chorionic villus sampling or amniocentesis, with informed consent) should be offered to a couple at risk of an affected fetus; for those at risk of Hb Barts hydrops fetalis specifically, serial fetal ultrasound assessing the fetal cardiothoracic ratio (normal under 0.5) allows earlier identification of an affected fetus when invasive testing is declined or pregnancy presents after 20 weeks.^[3]

• In TDT: maintain a pre-transfusion hemoglobin of approximately 90-100 g/L to suppress erythroid marrow expansion and prevent growth retardation, extramedullary hematopoiesis, and the resulting bony/facial deformities.^[2]
• In NTDT: avoid basing the transfusion decision on hemoglobin level alone — individualize around growth, symptoms, and the specific complications below.^[2]
• Detect and treat iron overload before irreversible organ damage occurs — iron overload is the dominant cause of morbidity and mortality in inadequately chelated transfused patients, and is a real, if slower-developing, risk in NTDT as well from increased intestinal absorption alone.^[6][4]
• Prevent, screen for, and manage the major end-organ complications of chronic anemia and iron overload: cardiac, hepatic, endocrine, and skeletal.
• Prevent infection in a splenectomized or functionally asplenic patient.
• Support informed reproductive decisions through genetic counseling and complete first-degree relative/family cascade screening.
• Evaluate curative options (allogeneic stem cell transplant, and where appropriate gene therapy) at the right point in a patient's life — ideally discussed, and pursued if appropriate, before puberty to maximize the chance of preserving fertility.^[8]
• Provide culturally appropriate, language-accessible education and psychosocial support to the patient and family from the point of diagnosis onward.^[7]

Splenectomy — restrictive indications, not a routine intervention

Splenectomy can reduce transfusion requirements in TDT by roughly 30%, but it is not a routine or early intervention given its own real risks (infection, thromboembolism). It should be reserved for specific situations:^[2][4]

• Worsening anemia with poor growth/development where chronic transfusion or adequate iron chelation is not otherwise achievable.
• Hypersplenism with worsening cytopenias causing clinical problems such as bleeding or infection.
• Massive splenomegaly with risk of splenic rupture, significant left-upper-quadrant pain, or early satiety.
• In TDT, a total annual transfusion requirement exceeding roughly 200 mL/kg/year of pure red cells (about 5-6 units/month for a 70 kg adult) that cannot be reduced by adjusting the pre-transfusion hemoglobin target.^[2]

Pre- and post-splenectomy infection prevention

• Complete NACI-recommended vaccination before a planned splenectomy — the enhanced schedule against encapsulated organisms (pneumococcal, meningococcal, Hib) on top of the routine schedule.^[5]
• Provide explicit asplenia fever counseling: any fever after splenectomy is a genuine medical emergency requiring immediate assessment, never a wait-and-see approach.^[5]
• Based on expert opinion (evidence for routine post-splenectomy thromboprophylaxis is otherwise lacking), consider low-dose aspirin in a splenectomized NTDT patient with a platelet count over 500 x 10⁹/L.^[4]

Comprehensive, multidisciplinary care

• Care is best delivered through a comprehensive thalassemia program with prompt referral of any newly diagnosed infant/child to a pediatric hematologist, alongside access to endocrinology, hepatology, cardiology, a dietitian, and dental/orthodontic services as complications arise.^[7][5]
• Discuss diagnosis and management with the family in an open, sensitive, and culturally appropriate manner — with interpreter access if English or French is not the family's primary language — and provide a written summary of the diagnosis and treatment plan to the family and their primary care provider.^[7]
• Offer information on regional support groups; psychosocial support matters given the real, lifelong burden of a chronic transfusion/chelation regimen.^[7]

Nutrition and dentition

• Arrange regular multidisciplinary nutritional assessment, ideally including a dietitian — patients with TDT are known to have inadequate intake of fat-soluble vitamins (A, D, E, K) and low folate, B6, thiamine, calcium, magnesium, and zinc, several of which are directly tied to bone health.^[5]
• Offer regular dental and orthodontic assessment — craniofacial bone changes from inadequate/delayed/late-initiated transfusion can affect dentition and cause malocclusion.^[5]
• Encourage regular weight-bearing, low-impact exercise and smoking cessation specifically for bone health.^[9]

Genetic counseling and family screening

• Offer genetic counseling to patients and at-risk reproductive partners, ideally before conception; discuss prenatal diagnosis options (chorionic villus sampling or amniocentesis) for an at-risk pregnancy.^[3]
• Test parents and siblings of a newly diagnosed patient if not already done.^[7]
• A patient who has undergone stem cell transplant or gene therapy should still be counselled that they will pass a mutant thalassemia gene to each of their children — the corrected/donor cells address the patient's own blood production, not the germline.^[8][10]

Transfusion practice specifics

• Extended red cell phenotyping (or genotyping) before the first transfusion, with prophylactic matching for C, E, c, e, and K antigens — roughly 15-20% of thalassemia patients become alloimmunized to minor blood group antigens, with even higher rates in patients of Asian descent, and prophylactic matching meaningfully reduces this.^[2]
• Irradiation is reserved for specific at-risk recipients (intrauterine transfusion, a known blood relative as donor, stem cell transplant recipients, HLA-selected/homozygous platelet recipients) — asplenia in thalassemia is not by itself sufficient justification for irradiating blood products.^[2]
• CMV-seronegative products are not routinely needed for thalassemia transfusion, except in pregnancy, stem cell transplant candidacy, or intrauterine transfusion.^[2]

Iron chelation therapy

Bone health

NTDT-directed disease-modifying therapy

Pregnancy

NTDT patients may need occasional transfusion during pregnancy for an anticipated or acute hemoglobin drop; TDT patients continue their regular transfusion program with folic acid throughout. Pregnant patients with thalassemia are at increased risk of CMV and varicella infection, and CMV-seronegative blood products are indicated for transfusion during pregnancy.^[2][5] Hydroxyurea is contraindicated in pregnancy.^[4] Deferiprone is contraindicated in pregnancy and lactation; deferoxamine is contraindicated in the first trimester; chelation is generally deferred or individualized by the treating specialist for the remainder of pregnancy given limited safety data.^[6] If a patient's mother becomes pregnant with an affected sibling under consideration for future stem cell transplant, prenatal diagnosis (CVS or amniocentesis) can be discussed, and if the fetus does not have beta-thalassemia, cord blood can be harvested and stored for potential future transplant use.^[8]

Pediatrics

A newly diagnosed infant needs monthly assessment until the clinical phenotype is established, since genotype does not always accurately predict severity.^[7] Growth (height, weight, growth velocity) should be monitored and plotted on ethnicity-appropriate growth charts at every visit; bone mineral density screening (DEXA) begins at age 10-12; Tanner staging begins at age 10, with delayed puberty (no breast budding by 13 in girls, no testicular enlargement by 14 in boys) prompting an endocrine workup.^[9][4]

Curative options — allogeneic stem cell transplant

Allogeneic hematopoietic stem cell transplant (HSCT) is the only long-established cure for thalassemia major. With a fully HLA-matched donor (related or unrelated) and full-intensity conditioning, overall survival ranges from 91-98% and disease-free survival from 83-95%, largely independent of pre-transplant organ-complication risk class; outcomes are meaningfully better in children than in adults, and discussion should begin while the patient is young — ideally before puberty, to maximize the chance of preserving fertility.^[8] For patients without an HLA-matched donor, haploidentical-donor transplant with modern conditioning protocols has recently achieved outcomes (overall and event-free survival around 96% in children up to age 19) approaching those of matched-donor transplant. Sterility/gonadal deficiency occurs in roughly 60% of patients after full-conditioning HSCT, lower in those transplanted before puberty — fertility preservation (ovarian or testicular tissue banking in prepubertal children) should be part of pre-transplant planning. After HSCT, pre-existing iron overload should continue to be addressed by routine phlebotomy (with or without chelation), targeting a ferritin under 300 µg/L.^[8]

Curative options — gene therapy

Gene therapy corrects the patient's own hematopoietic stem cells (collected by apheresis) rather than replacing them with a donor's, avoiding the need for an HLA-matched donor and its graft-versus-host-disease risk — but it still requires high-dose conditioning chemotherapy to clear the native bone marrow before the corrected cells are infused, carrying the same fertility and (theoretical, not yet observed in thalassemia gene therapy) secondary-malignancy considerations as HSCT.^[10] Exagamglogene autotemcel (Casgevy), a CRISPR/Cas9 gene-edited autologous cell therapy that reactivates fetal hemoglobin production, is Health Canada-approved for transfusion-dependent beta-thalassemia in patients 12 years of age and older — a genuine, currently accessible (though highly specialized, limited-centre) Canadian option, distinct from the older lentiviral gene-addition approach.^[11] Betibeglogene autotemcel (Zynteglo), a lentiviral vector-based gene-addition therapy, holds FDA approval (2022) and previously held an EU conditional marketing authorization that its manufacturer voluntarily withdrew from the EU market in 2021 for commercial reasons — no Health Canada approval has been identified, so it should not be presented to a Canadian patient as a currently accessible option. Regardless of technique, patients undergoing gene therapy must be counselled that the correction applies only to their blood-forming cells, not their egg or sperm cells — they will still pass a mutant thalassemia gene to each of their children.^[10]

Transfusion-dependent thalassemia (TDT)

• Serial hemoglobin around each transfusion; serum ferritin every 3 months.^[6]
• Liver iron concentration (LIC) by validated MRI after approximately 10-20 transfusions and before starting chelation, then every 6-24 months as clinically indicated.^[6]
• Cardiac MRI T2* starting at age 6 (or earlier, with sedation/anesthesia if needed, since cardiac iron can accumulate by this age in chronically transfused patients), repeated every 6-24 months — myocardial T2* under 25 ms (normal is over 42 ms) predicts progressive decline in left ventricular ejection fraction, and there is no adequate non-MRI surrogate; every thalassemia patient in Canada should have access to cardiac MRI iron assessment.^[6]
• Chelator-specific toxicity monitoring — see Drug Tables for the full detail by agent (deferoxamine: annual audiometry/ophthalmology, biannual growth assessment in children, baseline and periodic screening x-rays; deferasirox: baseline then monthly renal function/urinalysis/liver enzymes/CBC, then every 1-3 months once stable, annual audiometry/ophthalmology; deferiprone: weekly CBC with differential, monthly ALT for 3-6 months then every 3 months).^[6]
• Annual hepatitis B and C serology in transfused patients.^[5]

Non-transfusion-dependent thalassemia (NTDT)

• Iron burden screening by MRI (e.g., T2*) beginning by age 10 — this can be delayed to age 15 in deletional HbH disease, which accumulates iron more slowly.^[4]
• Once chelation is started: imaging yearly, serum ferritin every 3 months; discontinue chelation once LIC falls under 3 mg Fe/g dry weight, or ferritin under 300 µg/L if MRI is unavailable.^[4]
• Annual echocardiogram (tricuspid regurgitant jet velocity) for pulmonary hypertension screening.^[4]
• Liver enzymes/function every 6 months from age 10; consider transient elastography for fibrosis if LIC ≥5 mg Fe/g dry weight or ferritin ≥800 ng/mL.^[4]

Applies to both TDT and NTDT

• Growth parameters (height, weight, growth velocity) at every visit in children, plotted on ethnicity-appropriate charts.^[9]
• Bone mineral density by DEXA (spine and hip; radius/ulna in NTDT) starting at age 10-12.^[9][4]
• Annual Tanner staging from age 10, with an endocrine panel (free T4, TSH, calcium, phosphate, vitamin D, fasting glucose) checked annually from age 10.^[4]
• Annual abdominal ultrasound to screen for gallstones.^[4]
• Post-HSCT: close monitoring for at least the first 2 years, including management of pre-existing iron overload by phlebotomy targeting ferritin under 300 µg/L.^[8]

1. Ferritin or LIC not improving on single-agent chelation at the maximum tolerated dose: check adherence first, then escalate — for LIC over 15 mg Fe/g dry weight, cardiac T2* under 10 ms, or abnormal cardiac function/rhythm, move to aggressive chelation: continuous-infusion deferoxamine over 50 mg/kg/day (maximum 6 g/24 hours), or combination therapy with deferiprone or deferasirox.^[6]
2. Mild-to-moderate cardiac iron loading (T2* 8-20 ms): combination deferoxamine plus deferiprone reduces myocardial iron, lowers ferritin, and improves LVEF more than either agent alone.^[6]
3. NTDT patient started on routine transfusion with no benefit at the 6-month re-evaluation (no improvement in symptoms or objective organ-dysfunction measures): discontinuation is reasonable, preferably with a tapering schedule to allow recovery from erythropoietic suppression.^[4]
4. Deferiprone-associated arthropathy: manage with dose reduction or cessation, plus NSAIDs as needed.^[9]
5. Excessive TDT transfusion requirement (over ~200 mL/kg/year pure red cells) that cannot be reduced by adjusting the pre-transfusion target: consider splenectomy per its restrictive indications, or — particularly once epiphyseal growth plates have fused — a slightly lower pre-transfusion hemoglobin target (80-90 g/L) with close monitoring for signs of under-transfusion (bony pain, progressive hepatosplenomegaly, pulmonary hypertension).^[2]
6. No HLA-matched donor available for HSCT: consider a haploidentical-donor transplant with a modern conditioning protocol (now approaching matched-donor outcomes), or refer for evaluation of gene-therapy eligibility, including exagamglogene autotemcel for an eligible patient 12 years or older with TDT.^[8][11]

• Diagnosing or excluding iron overload from serum ferritin alone rather than MRI-based LIC and cardiac T2* — ferritin correlates poorly with myocardial iron, and in NTDT specifically it systematically underestimates true liver iron burden.^[6][4]
• Basing the NTDT transfusion decision purely on hemoglobin level rather than the full clinical and complication picture — patients with HbE/beta-thalassemia in particular can tolerate severe-looking anemia well due to a right-shifted oxygen dissociation curve.^[2]
• Routinely "supertransfusing" a TDT patient above a pre-transfusion hemoglobin of 100 g/L — this only accelerates iron loading and should be reserved for short-term pseudotumour-shrinkage protocols.^[2]
• Treating microcytic anemia with normal ferritin/iron studies as iron-deficiency anemia and giving empiric iron — patients with thalassemia are not iron deficient, and inappropriate supplementation on top of chronic hemolysis (and, in transfused patients, transfusional loading) risks worsening iron overload.
• Performing splenectomy as an early or routine intervention rather than reserving it for the specific, restrictive indications — and failing to complete pre-splenectomy vaccination or post-splenectomy fever counseling.^[4][5]
• Using high-dose deferoxamine when ferritin is already low — keep the therapeutic index (mean daily dose ÷ ferritin) under 0.025 to limit ototoxicity/retinal toxicity risk.^[6]
• Missing deferiprone-associated agranulocytosis by skipping weekly CBC with differential, particularly in the first 6 months of therapy.^[6]
• Assuming a "milder" phenotype can never need urgent attention — deletional HbH disease patients can still decompensate acutely with infection, oxidative stress, surgery, or pregnancy, and NTDT patients accumulate real iron overload and develop genuine complications even without ever being transfused.^[2][4]
• Overlooking genetic counseling and first-degree relative/reproductive-partner testing once a diagnosis is confirmed.^[3]
• Presenting a newer disease-modifying option (luspatercept, exagamglogene autotemcel) as available or appropriate for every patient without confirming current Health Canada approval status and the specific eligibility criteria (age, genotype, transfusion status) that actually apply.^[11][12]

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Iron chelation therapy

Doses are adult doses unless stated and require patient-specific confirmation, including renal/hepatic adjustment. NTDT dosing differs meaningfully from TDT dosing — see the NTDT-specific note in each row.

Adjunct and disease-modifying therapy

Bone health

Vitamin D and calcium supplementation is reasonable for essentially every thalassemia patient; bisphosphonates are reserved for confirmed low bone density not responding to lifestyle/dietary optimization alone, and require endocrinology referral.

Evidence note: Drug inventory, dosing, monitoring, and comments reflect current Canadian practice, drawn primarily from the CanHaem Consensus Statement of Clinical Care of Patients with Thalassemia in Canada (2024 revision), cross-checked for current Health Canada regulatory status against CDA-AMC reimbursement reviews for exagamglogene autotemcel and luspatercept.