What is Thalassemia
Thalassemia is a group of inherited autosomal recessive blood disorders characterized by decreased or absent production of specific globin chains (alpha or beta) that make up hemoglobin, resulting in ineffective red blood cell production, premature red cell destruction, and varying degrees of anemia. 1, 2
Basic Pathophysiology
The fundamental defect involves an imbalance in globin chain production - in beta-thalassemia, there is reduced or absent beta-globin chain synthesis, while in alpha-thalassemia, alpha-globin chain production is impaired 1, 2
This imbalance leads to excess unpaired globin chains that cause oxidative damage to red blood cell precursors, resulting in their premature death in the bone marrow (ineffective erythropoiesis) and shortened survival of mature red cells (hemolytic anemia) 2, 3
The body attempts to compensate through bone marrow expansion and extramedullary hematopoiesis (blood cell production outside the bone marrow), which can cause skeletal deformities and organ enlargement 2
Clinical Spectrum
Beta-Thalassemia Forms
Thalassemia Major (Transfusion-Dependent): The most severe form, characterized by profound anemia that becomes life-threatening by 1-2 years of age when fetal hemoglobin levels decline 1, 4
Thalassemia Intermedia: A moderate form where patients produce enough hemoglobin to survive without regular transfusions initially 1
Thalassemia Minor/Trait: Carriers are generally asymptomatic with mild microcytic anemia 2
Alpha-Thalassemia Forms
Silent Carrier (1 gene deletion): Asymptomatic with normal blood counts 2
Alpha-Thalassemia Trait (2 gene deletions): Mild microcytic anemia, generally asymptomatic 2
Hemoglobin H Disease (3 gene deletions): Variable anemia requiring monitoring and sometimes transfusions 5, 2
Alpha-Thalassemia Major/Hemoglobin Bart's Hydrops Fetalis (4 gene deletions): Results in severe intrauterine hypoxia, hydrops fetalis, and is typically fatal at birth 1, 5, 2
Geographic Distribution
Thalassemia is most prevalent in regions with historic malaria exposure - Asia, the Middle East, Mediterranean Europe, and Africa - because heterozygosity (carrier state) offers protection against malaria 1, 6
Alpha-thalassemia is particularly common in Southeast Asian populations, accounting for 28-55% of non-immune hydrops fetalis cases in these populations 5
Diagnostic Clues
Suspect thalassemia in patients with microcytic anemia (low MCV) and normal or elevated ferritin levels - this distinguishes it from iron deficiency anemia where ferritin is low 2
Mean corpuscular volume (MCV) less than 80 fL in parents suggests possible carrier status and warrants further evaluation 5
Hemoglobin electrophoresis reveals characteristic patterns for different thalassemia subtypes, but genetic testing (DNA analysis for deletions or mutations) is required for definitive diagnosis 2
Major Complications
Iron Overload - The Dominant Clinical Problem
Each unit of transfused blood contains approximately 200-250 mg of elemental iron, and the human body has no physiological mechanism to excrete excess iron 7
Iron accumulates from two sources: regular blood transfusions and increased gastrointestinal iron absorption due to ineffective erythropoiesis and hepcidin suppression 1, 7
When iron exceeds transferrin binding capacity, non-transferrin bound iron enters tissues through L-type calcium channels, causing organ damage 7
Cardiac iron loading is the leading cause of death, accounting for approximately 70% of mortality in transfusion-dependent patients 1, 4, 7
Other organs affected by iron deposition include the liver, endocrine organs (causing diabetes, hypogonadism, hypothyroidism), and skeletal system 2, 8
Cardiovascular Complications
Heart failure was the predominant cause of death before modern chelation therapy 1
Chronic anemia causes increased cardiac output and blood volume expansion, placing additional stress on the cardiovascular system 1
Treatment Approaches
Regular blood transfusions maintain pre-transfusion hemoglobin at 9-10 g/dL and post-transfusion at 13-14 g/dL to suppress ineffective erythropoiesis while minimizing iron loading 1
Lifelong iron chelation therapy is mandatory using deferoxamine, deferiprone, or deferasirox to prevent or reverse iron-related organ damage 1, 4, 7
Hematopoietic stem cell transplantation remains the only curative option, with current disease-free survival around 80% and overall survival over 90% 4
Supportive treatments include folic acid supplementation, splenectomy in selected cases, hydroxyurea to increase fetal hemoglobin production, and newer agents like luspatercept 2, 8
Prognosis Evolution
Life expectancy has improved dramatically over the past 50 years with the introduction of regular transfusions and iron chelation therapy 2
In the UK, median age at death improved from 10 years (unchelated) to 35 years by 2000 with deferoxamine treatment, and continues to improve with newer chelation agents 1, 4
Prevention and Screening
Newborn screening programs exist in all 50 US states and can make a definitive diagnosis at birth 1
Genetic counseling and carrier screening in high-risk populations (based on ethnicity) can assist in reducing disease prevalence 5, 2
Prenatal diagnosis using amniocentesis or chorionic villus sampling is recommended when both parents are carriers to detect severe forms 1, 5