Hematology & Medical Genetics & Family Medicine
Thalassémie | Clinique Omicron Québec
Thalassemias are a heterogeneous group of autosomal recessive inherited hemoglobinopathies caused by mutations in the genes for the globin chains (alpha or beta) making up normal adult hemoglobin (HbA = α₂β₂) - resulting in reduced or absent synthesis of one or more or several globin chains → imbalance between α and β chains → precipitation of excess chains → premature destruction of erythroblasts and erythrocytes (inefficient erythropoiesis + peripheral hemolysis) → chronic hypochromic microcytic anemia of variable intensity. With an estimated carrier prevalence of 5-7 % of the world's population - thalassemias are among the most frequent genetic diseases in the world - mainly affecting populations around the Mediterranean (Italy + Greece + Sicily + Sardinia + Near East + Turkey) + sub-Saharan Africa + the Indian subcontinent + and Southeast Asia + regions historically endemic to malaria (the thalassemic trait confers relative protection against Plasmodium falciparum - selective advantage explaining the high frequency of mutations in these populations). In Quebec, thalassemias mainly concern recent immigrant communities in these high-prevalence regions + and represent an important differential diagnosis of microcytic hypochromic anemia unresponsive to iron supplementation. The fundamental distinction is between mild forms (thalassemic trait - heterozygous - healthy carrier), which are asymptomatic or only slightly symptomatic but of major importance for premarital and prenatal genetic counseling + and severe homozygous or doubly heterozygous forms (thalassemia major or intermediate), which lead to transfusion dependence + progressive iron overload + and severe multisystemic complications requiring lifelong intensive specialized treatment.
Classification and clinical forms
| Shape | Genotype | Clinical presentation | Treatment |
|---|---|---|---|
| Beta-thalassemia minor (trait) | Heterozygous β+/β or β0/β - one normal allele | Asymptomatic + or mild microcytic anemia + often discovered on CBC (Hb 10-13 g/dL + VGM 60-75 fl + microcytosis + hypochromia + target erythrocytes) + normal or elevated ferritin + elevated HbA2 (3.5-8 % - key diagnostic marker) + DO NOT supplement with iron (worsens) | None + folic acid if pregnant + genetic counselling + DO NOT give iron unnecessarily |
| Beta-thalassemia intermedia | Homozygous or double heterozygous β+/β+ or β+/β0 - two mutated alleles but residual production | Chronic moderate to severe anemia (Hb 7-10 g/dL) + splenomegaly + bone deformities + extramedullary erythropoiesis + often little or no transfusion-dependent + iron overload due to intestinal hyperabsorption | Occasional transfusions + iron chelation + splenectomy if hypersplenism + lusupatercept (Reblozyl®) |
| Beta-thalassemia major (Cooley disease) | Homozygous β0/β0 - total absence of β chains | Severe anemia from 6-24 months of age (when HbF decreases) + Hb 2-7 g/dL + large splenomegaly + characteristic bone deformities (brush skull + mongoloid facies) + growth retardation + hepatomegaly + without transfusions = fatal in childhood. | Regular transfusions (every 2-4 weeks - pre-transfusion Hb target ≥ 9-10 g/dL) + intensive iron chelation + stem cell transplant (curative treatment) + gene therapy (betibeglogene - Zynteglo® approved FDA 2022) |
| Silent alpha-thalassemia (-α/αα) | 1 alpha gene deleted out of 4 | Totally asymptomatic + normal CBC or slightly low GMV + PCR diagnosis (deletion) + no specific biological signs | None + genetic counseling if partner is a carrier |
| Alpha-thalassemic trait (-α/-α or --/αα) | 2 alpha genes deleted out of 4 | Mild microcytic anemia (Hb 10-13 g/dL + VGM 70-80 fl) + NORMAL HbA2 (unlike beta-thalassemia) + undetectable HbH + smear: target red blood cells + microcytes + PCR diagnosis | None + genetic counseling + folic acid if pregnant |
| HbH disease (--/-α) | 3 alpha genes deleted out of 4 | Moderate to severe chronic hemolytic anemia + splenomegaly + Heinz bodies (excess β-chain precipitates) + HbH detected on electrophoresis (5-30 %) | Folic acid + avoid oxidizing agents (drugs) + transfusions if severe anemia + splenic monitoring |
| Hydrops fetalis (--/--) | 4 alpha genes deleted - total absence of alpha chains | Incompatible with life → immediate in utero or neonatal death + fetal hydrops + Bart's hemoglobin (γ₄) with no affinity for oxygen + pregnancy at maternal risk (preeclampsia + hemorrhage) → prenatal diagnosis imperative if parents homozygous carriers. | Medical termination of pregnancy + or exceptional in utero transfusions |
Biological diagnosis
- CBC + blood smear : hypochromic microcytic anemia + low GMV (often 50-75 fl) + normal MHCC (in contrast to martial deficiency where MHCC is low) + often high erythrocyte count (≥ 5.5 × 10¹²/L) for such a level of anemia + target red blood cells + elliptocytes + dacryocytes on smear
- Ferritin + serum iron + transferrin saturation : normal or elevated (thalassemia) vs. low (martial deficiency) → key to distinction + DO NOT prescribe iron if microcytosis with normal or elevated ferritin without full workup
- Hemoglobin electrophoresis (HPLC) : central diagnostic test for thalassemias and hemoglobinopathies + determination of HbA + HbA2 + HbF + HbS + HbC + etc. + beta-thalassemia minor: HbA2 ≥ 3.5 % (normal) <3.3 %) - reference diagnostic marker + beta-thalassemia major: very high HbF (30-100 %) + HbA absent or almost absent + alpha-thalassemia: HbA2 NORMAL → only PCR can confirm
- Genotyping PCR (alpha deletion) : essential for alpha-thalassemia (deletions are not detected by electrophoresis) → prenuptial or prenatal carrier test
- Distinguishing between martial deficiency and thalassemia minor (Mentzer formula): VGM/erythrocyte count → if <13 >13 = probable martial deficiency → indicative value + confirm with ferritin + electrophoresis
Management of beta-thalassemia major
- Regular transfusions : phenotypically compatible erythrocyte concentrates (ABO + Rh + Kell + at least) + pre-transfusion Hb target ≥ 9-10 g/dL + every 2-4 weeks + prevents bone deformations + extramedullary erythropoiesis + optimizes growth + major risk: progressive iron overload → hemosiderosis
- Iron chelation (essential for ferritin > 1,000 µg/L) : deferasirox (Exjade® + Jadenu®) per os 1×/d → agent of choice + or deferoxamine (Desferal®) SC 8-12 h/d × 5-7 d/week → older + very effective + but restrictive + or deferiprone (Ferriprox®) per os 3×/d → also active on cardiac iron + used in combination + ferritin target < 1 000 µg/L
- Luspatercept (Reblozyl®) : erythroid maturation agent (traps TGF-β ligands) → reduces ineffective erythropoiesis → reduced transfusion requirements by 33 % in trials (BELIEVE trial) + SC injection every 3 weeks + FDA + Health Canada approved
- Hematopoietic stem cell transplantation (HSCT) : only established curative treatment + success rate 85-95 % if intrafamilial HLA-compatible donor + procedure-related mortality 5-10 % + ideally before the onset of hemosiderosis and organ complications + optimal indication: child with an HLA-identical donor
- Gene therapy (betibeglogene - Zynteglo®) : lentiviral vector → insertion of a functional β-globin gene into autologous stem cells → FDA and EMA 2022 approval for transfusion-dependent beta-thalassemia → transfusion release in 89 % patients → very high cost + limited access
ℙ️
The classic clinical pitfall of thalassemia minor is the unnecessary prescription of iron in the presence of microcytosis - leading to iatrogenic iron overload. The rule is simple: in any hypochromic microcytic anemia, always measure ferritin BEFORE prescribing iron. If ferritin is normal or elevated with marked microcytosis → think thalassemia and request hemoglobin electrophoresis. The erythrocyte count is often high in thalassemia (≥ 5.5 × 10¹²/L) - unlike in martial deficiency, where it is low.
Medical consultation recommended
Consult a physician if persistent microcytic anemia does not respond to iron supplementation + or if hemoglobin electrophoresis shows elevated HbA2 + or if a couple is considering pregnancy and one or both partners are from a region with a high prevalence of thalassemia (Mediterranean + South Asia + Middle East + Africa) → genetic counseling before pregnancy. For a complete hematological workup (CBC + ferritin + hemoglobin electrophoresis + genetic counseling) and referral to hematology, Clinique Omicron offers consultations at its points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's specialized physicians and nurse practitioners (IPS) diagnose thalassemia minor in the presence of microcytosis with normal ferritin (hemoglobin electrophoresis + HbA2), and avoid unnecessary iron prescriptions in the absence of documented deficiency, provide premarital and prenatal genetic counseling for couples at risk, referral to hematology for intermediate and major forms + transfusion management + iron chelation + and evaluation for transplant or gene therapy. Consultations are available at several points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The contents of this page are provided for information purposes only and do not replace the advice of a physician or hematologist. Never prescribe iron for microcytic anemia without first measuring ferritin and ruling out thalassemia. Premarital genetic counseling is essential for couples in which both partners are thalassemia carriers - the risk of having a child with thalassemia major is 25 %.
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