What is Beta Thalassemia Major (Cooley Anemia)?

Thalassemia and sickle cell disease are two of the most common genetic blood disorders that people can inherit worldwide. Unlike sickle cell disease, which is caused by the production of abnormal hemoglobin, thalassemia arises from not having enough of one or more types of hemoglobin, leading to a condition called hypochromic microcytic anemia (a type of anemia resulting in smaller and paler red blood cells).

Thalassemia was first reported in Detroit by a doctor named Cooley, and because of this, it’s sometimes referred to as Cooley anemia. It often affects people of Mediterranean, Middle Eastern, and Asian descent. While it’s believed that thalassemia first appeared in the United States, it was overlooked initially due to its symptoms being similar to malaria.

On the other hand, sickle cell disease is thought to have originated in Central Africa. Nowadays, due to changes in population demographics, both of these conditions have turned into significant health concerns globally.

Genetic variations and mutations have led to different forms and severities of thalassemia. Based on medical and lab findings, doctors classify it into three main types: minor, intermedia, and major (a condition resulting from inheritance from both parents). Furthermore, severe forms of thalassemia, depending on whether they require regular blood transfusions, are classified as transfusion-dependent and non-transfusion-dependent respectively. These severe forms can cause a range of problems, from mild to severe anemia, along with other issues like significant destruction of red blood cells (hemolytic anemia), bone abnormalities, and an enlarged liver and spleen (hepatosplenomegaly).

What Causes Beta Thalassemia Major (Cooley Anemia)?

Beta-thalassemia is a genetic disorder caused by over 200 mutations or changes in a specific gene. This gene, known as the beta-globin gene, plays an important role in the creation of a part of our red blood cells. When the gene is altered, it causes fewer or no beta-globin chains to be made, affecting the formation of hemoglobin. Hemoglobin is a protein in our red blood cells which carries oxygen throughout the body.

Sometimes, the hemoglobin-carrying gene can be completely deleted from the 11th chromosome, contributing to the condition. Most of the changes in the gene cause a shift in the DNA sequence due to deletion, replacement, or addition of a single DNA building block.

The severity of the disorder heavily depends on whether a person has inherited two copies of the gene, one from each parent. If a person inherits a mutated gene that causes decreased beta-globin production (beta+), or one that causes absent beta-globin production (beta 0), it can influence the effects of the condition.

Beta-thalassemia exists in varying levels of severity, ranging from minor, intermediate, to major, and this is closely linked to the kind of mutated beta-globin gene a person inherits and whether they have one or two copies of the mutated gene.

Risk Factors and Frequency for Beta Thalassemia Major (Cooley Anemia)

Beta-thalassemia is a disease that affects people all around the world, but it is more common in some areas. Every year, about 68,000 children around the globe are born with a severe form of this disease, known as beta-thalassemia major. While it is hard to know exactly how prevalent this disease is in the United States, it is thought that the number is increasing due to immigration. In some parts of Iran and India, this disease is especially common. It’s also worth noting that there has been a major reduction in newborns with the disease in India since a pre-marital screening test was introduced. Some research suggests that this disease might be more common in areas where malaria is common, as having beta-thalassemia might provide some protection against this disease.

  • Beta-thalassemia is a disease that’s found all over the world.
  • This disease is most commonly seen in the Mediterranean, Middle East, Southeast and South Asia, and southern China.
  • About 68,000 children are born with the severe form of this disease each year.
  • While it’s hard to say exactly how many people have this disease in the United States, the number is thought to be increasing due to immigration.
  • The disease is especially common in certain parts of Iran and India.
  • In India, the introduction of a pre-marital screening test has greatly reduced the number of newborns with this disease.
  • Some regions have more cases of this disease possibly because it provides some protection against malaria.

Signs and Symptoms of Beta Thalassemia Major (Cooley Anemia)

Thalassemia is a genetic blood disorder, and its severity can vary between individuals. Those with thalassemia minor or trait usually don’t show symptoms or might just have mild anemia. However, cases of thalassemia intermedia can show a range of physical signs such as:

  • Pale skin (pallor)
  • Failure to grow or develop properly (Failure to Thrive or FTT)
  • Tiredness or lack of energy (lethargy and fatigue)

Usually these individuals don’t need regular blood transfusions. On the other hand, patients with beta thalassemia major, also known as Cooley anemia, often start showing symptoms from six months of age. They exhibit more severe symptoms than those with thalassemia minor, and they include:

  • Pale skin
  • Shortness of breath
  • Irritability
  • Failure to grow or develop properly
  • Enlarged liver and spleen (hepatosplenomegaly)
  • Frequent fevers
  • Difficulty with feeding
  • Bloating of the abdomen

This is due to the blood disorder starting to affect the levels of adult hemoglobin (HbA) as infant hemoglobin (HbF) levels fall. If left untreated or poorly managed, especially in areas where comprehensive treatment is unavailable, patients could experience:

  • Stunted growth
  • Skin discoloration to a brown shade
  • Yellowing of the skin and eyes (jaundice)
  • Sores on the legs (leg ulcers)
  • Knee deformity (genu valgum or knock knee)

This condition can also cause deformities in the long bones and face, such as an enlarged forehead (frontal bossing), high cheekbones, a sunken nasal bridge, and an excessively large upper jaw. These changes give the face a distinctive chipmunk-like appearance. Additionally, due to the ongoing damage to red blood cells (chronic hemolysis), these patients also often develop gallstones.

Testing for Beta Thalassemia Major (Cooley Anemia)

Cooley anemia, also known as beta thalassemia major, is a condition that can be suspected in infants and children under 2 years old who show signs of a pale or yellowish skin (jaundice), severe form of anemia causing smaller than usual red blood cells (hypochromic microcytic anemia), and liver or spleen enlargement (HSM).

In the laboratory, a complete blood count (CBC) would show smaller than normal red blood cells (microcytic anemia) with a low level of hemoglobin (Hb), the protein in red blood cells that carries oxygen. The mean corpuscular volume (MCV), average volume of red blood cells, can be between 50 to 70 fl, and mean corpuscular hemoglobin (MCH), average amount of hemoglobin in red blood cells, between 12 to 20pg.

The shapes and sizes of red blood cells can also change, and a variety of abnormal types of cells including microcytes, hypochrome cells, misshapen cells (poikilocytes), varying-sized cells (anisocytes), and precursors to red blood cells (nucleated RBCs) can be seen in a blood smear. Other cells including target cells, teardrop cells, and basophilic stippling can also be seen.

To confirm the diagnosis, it’s necessary to carry out tests like hemoglobin electrophoresis or high-performance liquid chromatography (HPLC), which analyze the types and amounts of hemoglobin in the blood. In cases of beta thalassemia major, there’s usually no production of beta-globin chain, which means that fetal hemoglobin (HbF) is 92% to 95%, HbA2 is 5% to 8% and the adult form of hemoglobin (HbA) is 0%.

Sometimes, increased HbA2 can also occur in cases of hyperthyroidism, vitamin B12 and folic acid deficiency, and anti-retroviral therapy. Prenatal screening and genetic counselling can also be useful for the early detection and prevention of inherited conditions like beta thalassemia.

Radiographic images can provide additional information about the condition. For example, due to increased production of red blood cells in the bone marrow, a distinct “chicken wire” pattern can be seen in the facial bones X-ray. In the long bones, low bone density (osteopenia) and thinning of the hard, outer layer of bone (cortical thinning) due to enlarged bone marrow spaces can often be seen, which can lead to fractures. A “hair on end” appearance may also be visible in the skull X-rays, and the bones of the spine can have a ground-glass appearance. MRI of the brain, heart, and liver can also be used to check for iron deposits in these organs in cases where too much iron is suspected.

Treatment Options for Beta Thalassemia Major (Cooley Anemia)

Beta-thalassemia major, also known as Cooley anemia, is primarily treated through regular blood transfusions. Without treatment, patients typically do not survive past adolescence. These transfusions provide healthy red blood cells that can temporarily compensate for the ones the patient’s body cannot produce. This slows down the body’s own ineffective blood production, reduces oxidative stress, and helps symptoms like bone deformities. More importantly, it can help patients live longer.

Organizations like the Thalassemia International Federation and national guidelines from the UK and the US mostly agree on this treatment approach. However, they have slight differences when it comes to managing iron overload and iron chelation therapy strategies – both of which are known side effects of regular blood transfusions.

When deciding how often blood transfusions are needed, medical professionals consider the severity of the patient’s anemia and other clinical findings. They typically aim to raise the patient’s pre-transfusion hemoglobin (Hb) level to 9-10g/dL to improve symptoms and promote growth. This target increases to 10-12g/dL if the patient exhibits complications like extramedullary hematopoiesis or cardiac abnormalities. But, care must be taken when administrating regular blood transfusions due to the risk of complications like iron overload, infections, transfusion reactions, and antibodies formation.

Iron overload, which can happen from regular transfusions, is monitored using clinical features and serum ferritin levels. Iron chelation therapy is a common treatment for iron overload. The first treatment used was deferoxamine, which was administered through the skin or intravenously, but patients found it hard to follow the regimen. Now, oral iron chelation therapy is more common and generally well-tolerated. It’s important to remember that patients may also need supplementation for other nutritional deficiencies, such as folate/vitamin B12, and calcium.

While hydroxyurea has not been found to be beneficial for patients achieving desired pretransfusion goals, the only definite treatment currently is allogeneic hematopoietic stem cell transplant. This method has a success rate of over 90% if performed before damage from iron overload occurs.

A new treatment, luspatercept, has been approved for treating anemia in adult beta-thalassemia patients. Early studies show promising results, such as reduced dependency on blood transfusions.

Another potential cure on the horizon is gene therapy. While several clinical trials are underway, initial results have been promising. However, more data is needed to confirm the efficacy and safety of these treatments.

Surgical treatment may be necessary in cases where thalassemia patients develop hypersplenism and excessive enlargement of the spleen. Post-surgery, patients also require vaccinations against certain bacteria due to an increased risk of infection.

Prevention strategies are also needed, particularly in developing countries where access to standard treatments is limited. Genetic counseling, molecular diagnostics, carrier detection, and prenatal screening are key tools in this strategy.

When it comes to identifying beta-thalassemia, a type of blood disorder, doctors often need to check for similar conditions. These can include sideroblastic anemia, iron-deficiency anemia (IDA), anemia of chronic disease (ACD), and other forms of disorders related to hemoglobin (the protein in red blood cells that carries oxygen).

Sideroblastic anemia, for instance, can be recognized by unique iron deposits and increased levels of a substance called erythrocyte protoporphyrin in the red blood cells.

To rule out iron-deficiency anemia, doctors can carry out iron studies such as checking the level of iron in the blood, the total capacity of the blood to bind iron, the level of serum ferritin (a protein that stores iron inside the cells), and the level of transferrin saturation. In cases of IDA, serum ferritin levels and transferrin saturation tend to be low. Furthermore, the red blood cells in IDA tend to have less color and be smaller than those seen in beta-thalassemia.

Lastly, to exclude other blood disorders related to hemoglobin, doctors can use techniques like HPLC (High Performance Liquid Chromatography) or hemoglobin electrophoresis. These tests assist in identifying beta-thalassemia among other hemoglobinopathies.

What to expect with Beta Thalassemia Major (Cooley Anemia)

In the past, people with beta-thalassemia major, a serious blood disorder, typically lived until their teens. For example, from 1965 to 1975, the typical survival age was around 17 years old in the US. In Italy during the 1960s, the average age was 12.

Today, however, the life expectancy for these individuals has greatly improved. This increase is largely due to doctors, nurses, and other health professionals working together to provide the best possible care. Advancements in treatment, like iron removal therapy, better patient and professional awareness, managing complications, and improved blood product screening techniques, have all played a part in this improvement.

In fact, the average life expectancy for patients in Palestine has gone from 7-8 years in 1996 to 19-20 years in 2015. In the UK, the mortality rate fell significantly from 12.7 deaths per 1000 people during the 1990s to 4.7 deaths per 1000 people in the early 2000s.

Possible Complications When Diagnosed with Beta Thalassemia Major (Cooley Anemia)

Patients receiving treatments for blood disorders such as beta-thalassemia should be aware of potential side effects or complications. These complications can result from ineffective red blood cell production, overstimulation of the bone marrow, and blood transfusions. There are two categories of complications from blood transfusions: acute complications, such as severe allergic reactions, and chronic complications, which include various diseases associated with too much iron in the body.

The main chronic problem that arises from regular red blood cell transfusions is iron overload. This occurs because the transfused red blood cells contain iron, which can amass in the body over time. When the iron builds up beyond the body’s capability to remove it, the iron starts to deposit in several organs. Often, this includes the heart, pancreas, liver, and brain. Heart failure due to iron overload is the most common cause of death in patients with these conditions, particularly if they are not treated in time.

When there’s too much iron in the liver, it can lead to serious health conditions such as liver fibrosis, cirrhosis, and eventually liver cancer. Deposits of iron in the body can also lead to a range of health issues, including diabetes, disrupted hormonal production, and delays in growth and development. Keeping iron levels in the body balanced is key to preventing these serious health complications.

Regular blood transfusions can also cause the body to produce antibodies against specific red blood cell antigens, a complication known as alloimmunization. This can be mitigated by ensuring that patients with thalassemia receive antigen-compatible blood.

Transfusions can also expose patients to viral, bacterial, and parasitic infections. Therefore, blood donations should always be screened for HIV, Hepatitis B and C, and other endemic infections, following the guidelines of the World Health Organization and Thalassemia International Federation.

Patients with beta-thalassemia, especially those who receive insufficient transfusions, are non-transfused, or have had their spleen removed are at risk of developing a hypercoagulable state, which is an increased tendency of the blood to form clots. Other complications include injury to the lungs related to transfusion (TRALI), fever, and delayed reactions to transfusions.

To summarize, below are the common complications of beta-thalassemia treatments:

  • Acute reactions such as severe allergies
  • Sepsis (severe blood infection)
  • Hemolysis (breakdown of red blood cells)
  • Chronic complications including iron overload-related diseases
  • Heart, pancreas, and liver damage due to iron overload
  • Alloimmunizations (production of antibodies against red blood cell antigens)
  • Transfusion-related infections
  • Increased risk of blood clots
  • Transfusion-associated lung injury
  • Fever and other delayed transfusion reactions

Preventing Beta Thalassemia Major (Cooley Anemia)

Awareness about a disease called beta-thalassemia (BT) is quite limited, especially in developing countries. People with BT require frequent emotional and social support due to the long-term treatment involved. Healthcare workers should try to provide this support by making helpful resources like pamphlets, booklets, lectures, and videos available to the patients and their caregivers.

Since BT can be prevented in unborn children through checks before marriage or during pregnancy, it’s crucial for countries to focus on educating their communities in order to decrease the number of BT cases. Parents and patients need to understand how the disease is passed down through families and that there’s a risk of it happening in future pregnancies. They should be offered checks during pregnancy and counselling about their genes. In areas of Iran and Bahrain, they have seen a significant decrease in the number of newborns affected by the disease by standardising checks before marriage.

Frequently asked questions

Beta Thalassemia Major (Cooley Anemia) is a severe form of thalassemia that results from inheritance from both parents. It can cause a range of problems, including severe anemia, significant destruction of red blood cells, bone abnormalities, and an enlarged liver and spleen.

About 68,000 children are born with the severe form of this disease each year.

The signs and symptoms of Beta Thalassemia Major (Cooley Anemia) include: - Pale skin - Shortness of breath - Irritability - Failure to grow or develop properly - Enlarged liver and spleen (hepatosplenomegaly) - Frequent fevers - Difficulty with feeding - Bloating of the abdomen If left untreated or poorly managed, patients with Beta Thalassemia Major may also experience: - Stunted growth - Skin discoloration to a brown shade - Yellowing of the skin and eyes (jaundice) - Sores on the legs (leg ulcers) - Knee deformity (genu valgum or knock knee) In addition to these symptoms, Beta Thalassemia Major can also cause deformities in the long bones and face, such as an enlarged forehead (frontal bossing), high cheekbones, a sunken nasal bridge, and an excessively large upper jaw. These changes give the face a distinctive chipmunk-like appearance. Furthermore, due to the ongoing damage to red blood cells (chronic hemolysis), patients with Beta Thalassemia Major often develop gallstones.

Beta Thalassemia Major (Cooley Anemia) is inherited when a person inherits two copies of the mutated beta-globin gene, one from each parent.

The doctor needs to rule out the following conditions when diagnosing Beta Thalassemia Major (Cooley Anemia): 1. Sideroblastic anemia 2. Iron-deficiency anemia (IDA) 3. Anemia of chronic disease (ACD) 4. Other forms of disorders related to hemoglobin (the protein in red blood cells that carries oxygen)

The types of tests needed for Beta Thalassemia Major (Cooley Anemia) include: 1. Complete blood count (CBC) to assess red blood cell size and hemoglobin levels. 2. Blood smear to examine the shapes and sizes of red blood cells and identify abnormal types of cells. 3. Hemoglobin electrophoresis or high-performance liquid chromatography (HPLC) to analyze the types and amounts of hemoglobin in the blood. 4. Radiographic imaging, such as X-rays and MRI, to provide additional information about the condition, including bone abnormalities and iron deposits in organs. 5. Prenatal screening and genetic counseling for early detection and prevention of inherited conditions like beta thalassemia.

Beta-thalassemia major, also known as Cooley anemia, is primarily treated through regular blood transfusions. These transfusions provide healthy red blood cells that can temporarily compensate for the ones the patient's body cannot produce. This slows down the body's own ineffective blood production, reduces oxidative stress, and helps symptoms like bone deformities. More importantly, it can help patients live longer.

The side effects when treating Beta Thalassemia Major (Cooley Anemia) include: - Acute reactions such as severe allergies - Sepsis (severe blood infection) - Hemolysis (breakdown of red blood cells) - Chronic complications including iron overload-related diseases - Heart, pancreas, and liver damage due to iron overload - Alloimmunizations (production of antibodies against red blood cell antigens) - Transfusion-related infections - Increased risk of blood clots - Transfusion-associated lung injury - Fever and other delayed transfusion reactions

The prognosis for Beta Thalassemia Major (Cooley Anemia) has greatly improved over the years. In the past, individuals with this condition typically lived until their teens, but now the average life expectancy has increased significantly. Advancements in treatment, better patient and professional awareness, managing complications, and improved blood product screening techniques have all contributed to this improvement. The average life expectancy for patients in Palestine has gone from 7-8 years in 1996 to 19-20 years in 2015. In the UK, the mortality rate has also decreased significantly.

A hematologist.

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