OVERVIEW

What is thalassemia?

Thalassemia, also known as hemoglobinopathy or Mediterranean anemia, is a group of anemias caused by genetic defects. Abnormal globin genes disrupt the production ratio of globin peptide chains, damage red blood cells in the bone marrow and circulation, and ultimately lead to anemia^[1,2].

Thalassemia is prevalent in populations along the Mediterranean coast, Southeast Asia, and regions of China such as Guangdong, Guangxi, Sichuan, Chongqing, Hunan, Hubei, and Hainan, where the incidence is relatively high^[1,3].

Mild thalassemia requires no special treatment, while moderate and severe cases may be treated with blood transfusions, iron chelation, splenectomy, bone marrow transplantation, or gene activation therapy^[1].

What is anemia?

Anemia is typically diagnosed through routine blood tests. For adult males, hemoglobin < 120 g/L; for non-pregnant adult females, hemoglobin < 110 g/L; and for pregnant women, hemoglobin < 100 g/L indicates anemia.

The severity classifications are: mild anemia (hemoglobin > 90 g/L), moderate anemia (hemoglobin 60–90 g/L), severe anemia (hemoglobin 30–60 g/L), and extremely severe anemia (hemoglobin < 30 g/L)^[1].

Is thalassemia highly prevalent?

Thalassemia has a relatively high incidence among pediatric blood disorders, though authoritative data on exact rates are lacking. Current references are based on the prevalence of thalassemia gene defects in certain regions of China.

In 2008, the gene defect rate for thalassemia in southern China ranged from 2.5% to 20% (25–200 per 1,000 people). Guangdong and Guangxi had particularly high rates of 10% and 20%, respectively, with α-thalassemia occurring about 1–1.5 times more frequently than β-thalassemia^[3].

SYMPTOMS

What are the symptoms of thalassemia?

The main symptom of this disease is anemia, generally manifested as pale complexion, hepatosplenomegaly, etc. However, the specific symptoms vary depending on the type of anemia. Refer to the detailed descriptions of different types below.

What are the classifications of thalassemia?

Based on the different globin peptide chains, it is clinically classified into α-thalassemia and β-thalassemia, with varying clinical manifestations depending on the type^[1,2].

1. α-thalassemia: Normal individuals have four α-globin genes. Abnormalities (deletion or mutation) in one or more of these genes cause α-thalassemia. It is further divided into:
   • Silent carrier (1 abnormal α gene): Generally asymptomatic and requires no treatment.
   • Standard type (2 abnormal α genes): Asymptomatic or mild anemia, usually no treatment needed.
   • HbH disease (3 abnormal α genes): Mild to moderate anemia (pale complexion, hepatosplenomegaly, etc.). Severe cases may require splenectomy or blood transfusion, with generally long-term survival.
   • Bart's hydrops fetalis syndrome (4 abnormal α genes): Most cases result in stillbirth or death shortly after birth. No treatment is currently available, and prevention is key.
2. β-thalassemia: Normal individuals have two β-globin genes. Mutations in one or both genes cause β-thalassemia. Based on β-globin synthesis, it is classified into:
   • Minor (mild): Asymptomatic or mild anemia, usually no treatment needed.
   • Intermediate: Pale complexion, slightly enlarged spleen, normal growth and development. Regular transfusions are usually unnecessary, but adults may become transfusion-dependent.
   • Major (severe): Early symptoms include poor appetite and developmental delays, progressing to pallor and progressive hepatosplenomegaly. Death often occurs due to recurrent infections. Treatment includes blood transfusions, splenectomy, hematopoietic stem cell transplantation, or gene therapy^[1,2].

What is Bart's hydrops fetalis syndrome?

It is a form of thalassemia caused by abnormalities in all four α genes. Most cases result in stillbirth or miscarriage between 30–40 weeks of gestation, with nearly all fetuses dying in utero or within half an hour after birth. Affected fetuses exhibit severe anemia, pallor, generalized edema, and developmental abnormalities, with ascites, pericardial effusion, jaundice, skin hemorrhages, marked hepatosplenomegaly, a large and fragile placenta, and umbilical cord edema^[1].

What is HbH disease?

It is a form of thalassemia caused by abnormalities in three α genes. Infants are born normally and mostly show no anemia symptoms before age one. However, mild to moderate chronic anemia (dizziness, pallor), hepatosplenomegaly (palpable abdominal mass), and intermittent mild jaundice (yellowing of eyes/skin) develop with age. Despite this, growth and development are normal, and long-term survival is possible.

What is standard α-thalassemia?

It is a form of thalassemia caused by abnormalities in two α genes. Clinically, it is asymptomatic or presents with mild anemia, no hepatosplenomegaly, and laboratory tests show abnormal hemoglobin at birth that disappears within months. Red blood cells exhibit only mild morphological changes, such as target cells (resembling bullseyes), slightly reduced or normal hemoglobin, and positive red cell fragility tests. One or both parents have α-thalassemia^[4].

What is silent α-thalassemia?

It is a form of thalassemia caused by an abnormality in one α gene. Affected individuals have abnormal hemoglobin at birth, which disappears quickly. Clinically, there is no anemia, hemoglobin electrophoresis is normal, red blood cell morphology is usually normal, and red cell fragility tests are occasionally positive. At least one parent has α-thalassemia^[4].

What is β-thalassemia?

β-thalassemia is a hemolytic anemia caused by mutations in the β-globin gene, leading to insufficient β-globin chain synthesis. It is the most severe hemoglobinopathy and one of the most common genetic disorders worldwide.

In China, high-prevalence regions include Guangdong, Guangxi, Sichuan, Hong Kong, northern Taiwan, Yunnan, Guizhou, Hainan, Fujian, Hunan, and Hubei. Based on severity, it is classified into minor (mild), intermediate, and major (severe) types, with the major type being the most harmful^[1].

What are the manifestations of major β-thalassemia?

Major β-thalassemia, also called Cooley’s anemia, involves complete suppression of β-globin chain synthesis.

Infants appear normal at birth but develop symptoms between 3–12 months, including poor appetite, feeding difficulties, diarrhea, irritability, developmental delays, and failure to thrive. Later, pallor and progressive hepatosplenomegaly (abdominal distension) appear^[2].

They then develop the classic "thalassemia facies." Hemoglobin levels often drop below 60 g/L, requiring lifelong transfusions. Massive splenomegaly leads to hypersplenism, increasing infection and bleeding risks. Most patients die from recurrent infections or myocardial damage^[4].

What is thalassemia facies?

Chronic anemia causes prolonged bone marrow hyperplasia, leading to osteoporosis and skeletal deformities. Affected children exhibit short stature, muscle weakness, bone deformities, frontal/occipital/parietal bossing, protruding cheekbones, a flattened nasal bridge, and maxillary/dental protrusion—collectively termed thalassemia facies^[4].

Why does major β-thalassemia cause skeletal changes?

Chronic compensatory bone marrow hyperplasia widens the marrow cavity and thins the bone cortex. X-rays show vertical striations between cortices, resembling a "hair-on-end" appearance^[4].

What are the manifestations of intermediate β-thalassemia?

Intermediate and major types differ in genetic mutations—major involves complete β-globin synthesis failure, while intermediate allows partial synthesis.

Symptoms typically appear at 2–4 years, with hemoglobin levels between 60–90 g/L. Patients show mild pallor and slight splenomegaly but otherwise normal growth and development, usually without regular transfusions^[2].

However, many become transfusion-dependent by age 20–40 or require transfusions during infections, medication errors, or pregnancy^[2].

What are the manifestations of minor β-thalassemia?

These patients are carriers of β-thalassemia genes with only mild hemoglobin production issues. They may be asymptomatic or have mild anemia and occasional slight splenomegaly^[2].

CAUSES

Why do globin abnormalities cause hemolytic anemia?

Globin is the main component of hemoglobin. Abnormalities in globin genes can lead to reduced or absent synthesis of globin chains in hemoglobin, resulting in abnormal hemoglobin structure.

Reduced or absent globin chains can damage red blood cells in circulation, shortening their lifespan. When the destruction rate of red blood cells exceeds the bone marrow's ability to produce new ones, hemolytic anemia occurs^[2].

How is thalassemia inherited?

Normal individuals have four functional α-globin genes (αα/αα) and two functional β-globin genes (β/β), inherited from both parents. If either or both parents are carriers/patients with defective globin genes, their children may inherit the abnormal genes^[1].

For example, when both parents are silent α-thalassemia carriers [father (-α/αα), mother (-α/αα)], their child may:

1. Have a 1/4 chance of inheriting thalassemia genes from both parents, developing standard thalassemia [(--/αα) or (α-/α-)];
2. Have a 1/2 chance of inheriting one normal and one abnormal gene, becoming a carrier like the parents (-α/αα);
3. Have a 1/4 chance of inheriting two normal genes, completely avoiding the disease or carrier status (αα/αα).

DIAGNOSIS

What tests are needed to diagnose alpha thalassemia?

1. Complete blood count (CBC): Used to assess hemoglobin concentration and red blood cell size, helping doctors preliminarily determine the severity of anemia. The anemia is typically microcytic and hypochromic, with mean corpuscular volume (MCV) < 80 fl, mean corpuscular hemoglobin (MCH) < 28 pg, and mean corpuscular hemoglobin concentration (MCHC) < 32%. Reticulocyte count may be normal or elevated^[5].

   Silent carriers have normal hemoglobin levels, while standard alpha-thalassemia patients may have normal or mildly reduced hemoglobin. HbH disease patients typically have hemoglobin levels between 70–100 g/L, with severe cases dropping below 30 g/L. Hb Bart's hydrops fetalis syndrome shows hemoglobin levels between 30–100 g/L^[4].

2. Peripheral blood smear (finger or earlobe prick test): Helps classify different types of thalassemia. HbH patients may show HbH inclusions, while Hb Bart's hydrops fetalis syndrome may reveal anisocytosis, poikilocytosis, target cells, nucleated red blood cells, and increased reticulocytes^[6].

3. Bone marrow aspiration (using a thick needle to extract hematopoietic marrow from specific bone sites): Due to anemia, the marrow compensates by producing more red blood cells. Bone marrow findings show significant erythroid hyperplasia, with HbH disease patients exhibiting HbH inclusions in nucleated red blood cells^[4].

4. Hemoglobin electrophoresis: Detects abnormal hemoglobin and its proportions, crucial for confirming thalassemia and its type. Silent carriers and standard alpha-thalassemia patients may show normal results, while HbH disease and Hb Bart's hydrops fetalis syndrome patients exhibit abnormal hemoglobin patterns^[5].

5. Genetic testing: The most accurate diagnostic method, identifying abnormal genes^[5].

How is alpha thalassemia diagnosed?

Diagnosis is based on symptoms like pallor, jaundice, fatigue, and generalized edema, combined with CBC showing reduced hemoglobin, hemoglobin electrophoresis detecting abnormal hemoglobin proportions, and bone marrow/peripheral blood smear revealing red blood cell inclusions. HbH disease and Hb Bart's hydrops fetalis syndrome can be diagnosed this way, while genetic testing is required for definitive typing.

Silent carriers and alpha-thalassemia trait cases, lacking typical clinical or lab features, require genetic testing for confirmation^[4,5].

What tests are needed to diagnose beta thalassemia?

1. Complete blood count (CBC): Helps classify disease severity. Mild beta-thalassemia shows hemoglobin > 100 g/L, severe cases < 60 g/L, and intermediate cases between 60–70 g/L, with elevated reticulocyte count^[4].
2. Hemoglobin electrophoresis: Identifies abnormal hemoglobin and proportions, critical for diagnosis. Mild cases show slightly elevated HbA2, while severe cases exhibit significantly increased HbF^[7].
3. X-ray: Severe cases may show skeletal changes, such as widened skull with "hair-on-end" trabecular striations^[4].
4. Genetic testing: The most accurate method to detect abnormal genes^[6,7].
5. Other tests: Doctors may order osmotic fragility tests, blood smears, or bone marrow aspiration for辅助诊断^[6].

What are common screening methods for thalassemia?

As thalassemia is inherited, screening couples before marriage or pregnancy helps reduce affected births. China uses a "two-step" approach: first, CBC and osmotic fragility tests; if positive, hemoglobin electrophoresis follows to measure HbA, HbA2, and HbF levels^[6].

For those with lifelong anemia worsening with age, jaundice, or yellowing eyes/skin, CBC and red blood cell morphology should be checked. Target cells suggest thalassemia, warranting osmotic fragility tests and hemoglobin electrophoresis. Genetic testing may be needed^[6].

When is prenatal diagnosis for thalassemia performed?

1. 9–11 weeks after last menstrual period (LMP): Chorionic villus sampling (CVS) for DNA analysis.
2. 18–30 weeks after LMP: Amniocentesis for DNA analysis.
3. If missed, fetal cord blood (2 mL) and parental peripheral blood (2 mL each) are collected for genetic testing^[8].

TREATMENT

Can thalassemia be cured?

It is difficult to cure. Thalassemia is a disease that is easier to prevent than to treat. Mild cases without symptoms may not require treatment, only regular follow-up observation. Severe thalassemia requires treatments such as blood transfusions, hematopoietic stem cell transplantation, and splenectomy^[9,10].

Patients who do not undergo hematopoietic stem cell transplantation can only rely on blood transfusions. Long-term transfusions can lead to iron deposition in organs such as the liver and spleen, causing organ failure. Therefore, regular use of iron chelators for iron removal therapy is necessary (see "What are the risks of not using iron chelators?" below), along with periodic blood tests for serum ferritin to delay iron deposition as much as possible^[9].

How is α-thalassemia treated?

Silent carriers and standard-type patients do not require treatment^[10].

HbH disease patients do not need treatment if anemia is not severe. For severe anemia, frequent infections, aggravated hemolysis, or splenomegaly, treatments such as splenectomy, splenic artery embolization, or blood transfusion may be considered^[9].

Hb Bart's hydrops fetalis syndrome often results in death before or shortly after birth. Currently, there is no treatment, and prevention is the main focus^[9].

How is β-thalassemia treated?

Mild cases do not require treatment. Intermediate and severe cases may be treated with blood transfusions, splenectomy, splenic artery embolization, hematopoietic stem cell transplantation, or gene therapy^[9].

What is the purpose and method of blood transfusion therapy for β-thalassemia?

The goal of transfusion is to maintain hemoglobin levels and alleviate symptoms. Severe cases require regular long-term transfusions every 3–4 weeks to maintain hemoglobin at 100–120 g/L. Intermediate cases can typically maintain hemoglobin above 60 g/L without relying on transfusions, but transfusions may be needed during pregnancy or infections^[9].

What are the risks of not using iron chelators for thalassemia patients with frequent transfusions?

Long-term repeated transfusions, excessive production of non-functional blood by the bone marrow, and increased intestinal iron absorption can lead to iron overload in the body.

Without iron chelators, excess iron can deposit in organs such as the heart, liver, pancreas, and brain, causing hemochromatosis—manifested as a grayish complexion, heart failure, liver cirrhosis, diabetes, and growth retardation (especially skeletal development) in children. Heart failure is the leading cause of death in these patients, making timely iron chelation therapy essential.

What is iron chelation therapy?

Iron chelation therapy involves using iron chelators (such as deferoxamine, deferiprone, or deferasirox, often in combination) during transfusions to promote iron excretion through urine and feces, reducing the suffering caused by long-term transfusions and improving patients' quality of life^[9]. It is generally suitable for patients who rely on long-term transfusions.

What are the indications for splenectomy in β-thalassemia?

1. Severe jaundice and significant splenomegaly;
2. Growth retardation;
3. Patients requiring frequent transfusions or in areas with limited blood supply;
4. Poor compliance with transfusions or iron chelation, or intolerance to treatment drugs^[11].

What is hematopoietic stem cell transplantation for β-thalassemia?

Hematopoietic stem cell transplantation includes peripheral blood stem cell transplantation, bone marrow transplantation, and autologous or allogeneic umbilical cord blood transplantation. It is a key treatment for severe β-thalassemia^[9].

Transplantation is the preferred treatment for severe cases. Its success depends on factors such as the patient's age, physical condition, pretreatment regimen, donor source, HLA compatibility, and management of complications.

What is gene therapy for thalassemia?

Gene therapy involves using genetic engineering to transplant healthy genes into a patient's cells to replace or correct defective genes, aiming for a cure. However, current research is limited, and further clinical trials are needed to confirm its efficacy and safety^[10].

Which department should thalassemia patients visit?

Hematology.

DIET & LIFESTYLE

What should thalassemia patients pay attention to in daily life and diet?

1. Eat light, easily digestible foods rich in vitamins and protein, such as fresh vegetables, fruits, milk, eggs, etc.
2. Long-term blood transfusions can lead to excess iron in the body, so such patients can consume foods that affect iron absorption, such as strong tea or coffee^[12].
3. Avoid strenuous activities and opt for mild exercises like walking, jogging, tai chi, or yoga. Vigorous exercise may cause symptoms like dizziness in anemic patients.

Can pregnant women with thalassemia continue their pregnancy?

For pregnant women with severe thalassemia, if tests confirm the fetus has severe β-thalassemia, Bart's hydrops fetalis syndrome, or HbH disease, artificial abortion is recommended to terminate the pregnancy.

If test results show the fetus has normal genes or mild thalassemia, the pregnancy can continue^[8].

PREVENTION

How to prevent thalassemia?

Thalassemia is a genetic disorder. Prenatal or pre-pregnancy screening can reduce its incidence.

1. Genetic counseling: Both partners should undergo thalassemia screening and genetic counseling at a professional medical institution before marriage or pregnancy to assess the probability of their offspring inheriting the disease.
2. Prenatal testing: If screening was not done before pregnancy, fetal genetic testing should be performed during pregnancy as advised by a doctor. Based on the results and medical recommendations, a decision can be made regarding whether to terminate the pregnancy.

How to prevent Bart's hydrops fetalis syndrome?

It is mainly identified through prenatal diagnosis to avoid the birth of an affected fetus.

Bart's hydrops fetalis syndrome often leads to stillbirth or miscarriage between 30–40 weeks of gestation. The fetus usually dies in the womb or within half an hour after delivery.

Therefore, women with a history of stillbirth or previous Bart's hydrops fetalis syndrome should undergo prenatal testing in subsequent pregnancies, including genetic diagnosis using fetal chorionic villi, amniotic fluid, or umbilical cord blood to determine whether the fetus has the condition^[5].

How to prevent severe β-thalassemia?

Severe β-thalassemia is highly detrimental, with most affected children dying before school age due to infections or heart failure. Thus, couples who have previously had a child with severe thalassemia or are both carriers of β-thalassemia should undergo prenatal diagnosis to analyze whether the fetus carries thalassemia gene mutations^[6].