The Waiting Room

Beta Thalassemia: Living with It and Asking for Help

This is the seventh and last part of our series about the condition based on our patient booklet “Fast Facts for Patients: Beta Thalassemia”. This article offers information on how to live with beta thalassemia (BT) and about asking for help.

Living with Beta Thalassemia

Getting a diagnosis of BT – whether for yourself or your child – can be a shock, even if you know BT is in your family background. You are likely to have a lot of questions. It’s important to find out as much as you can about BT and about your own situation.

To do that, it’s best to talk to a knowledgeable healthcare professional or use other trusted sources of information about BT. Genetic counseling can also help you to understand your condition and its implications.

It can be difficult to know which websites on BT are accurate and have up-to-date information.

BT is complicated so it’s easy to get confused. It may help to write down a list of the things you need to know or questions you want to ask and take it to your doctor’s appointment. It may also help to take someone with you, so you can compare notes afterwards.

Treatment is improving all the time for BT. Many children born with the condition are now expected to have a normal life span, and there are things you can do to help yourself stay as healthy as possible.

Have Treatment When You Need It

The best way to avoid complications is to stick to any treatment schedules and go to all your check-up appointments.

Important: Contact your doctor promptly if you have any signs of infection or other illness and make sure you keep your vaccinations up to date – especially if you’ve had your spleen removed.

Your Diet

When you have thalassemia you may have low levels of some vitamins and minerals, such as vitamin C, zinc, folic acid and vitamin D. This is partly because of the anemia and partly because of high iron levels and the treatment used to remove iron. Your doctor may check your levels and give you supplements of anything that you’re lacking.

Some doctors suggest avoiding foods that contain lots of iron and some think that this has little effect in preventing iron overload. It may be useful to check the iron content of packaged foods and medications and, in case of doubt, ask your healthcare team for advice.

It’s always best to discuss your diet with your BT healthcare team.

Keep Fit for Healthy Bones

Regular physical exercise has many benefits. It can improve your mood and help strengthen your bones. Alcohol and smoking are best avoided.

Asking for Help

Do ask questions and tell your healthcare team about anything that’s concerning you. They know how complex BT is and won’t mind, even if you ask the same questions more than once.

Questions for Your Doctor

• I’ve been told I’m a carrier of a BT gene – what are the implications for me and for my children?
• What is the likelihood of me having a/another child with BT?
• Is there anything that can be done to reduce the risk of having a child with BT?
• What type of BT do I/does my child have?
• What impact will BT have on me/my child?
• Are there any particular warning signs I need to be aware of at home?
• Will I/they need regular treatment?
• Will my/their need for treatment change as I/they get older?
• What are the likely side effects of treatment?
• What complications could there be and how likely are they?
• Will my child with BT be able to have children and what do they need to know beforehand?

Information based on Fast Facts for Patients: Beta Thalassemia (Karger, 2023).

Beta Thalassemia: New Developments in Treatment

This is the sixth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Beta Thalassemia”. This article lists new treatment developments as well as new treatments for beta thalassemia (BT).

New Treatment Developments

If you are interested in new treatments, you may want to ask your doctor about clinical trials. A new treatment must go through several phases of testing before it can be proven to work better than existing treatment and be adopted into routine care. A potential treatment will only move on to the next phase of research if it is safe and shows promise.

Clinical Trial Phases

The first phase of testing – phase I – is to make sure a new treatment is safe, find out about its side effects and decide the best dosage. These trials are usually small, with only a few people in each one.

• Phase II trials are larger and find out whether a new treatment is likely to work for a particular medical condition.
• Phase III trials test the new treatment against the standard existing treatment to see which works best. These are the largest trials and are often international, particularly for rare conditions.
• Phase III trials have to be randomized. In randomized trials, patients are put into different groups. A computer is used to decide who is in which group. You cannot choose which group you are in and so some people will not take the new treatment. Randomizing means that the researchers can be more sure that differences in the results at the end of the trial are caused by the treatment being tested.

New Treatments for Beta Thalassemia

There are a few new treatments being tested for BT:

• gene therapy
• treatment to improve red blood cell health and function
• treatment to reduce iron absorption.

Gene Therapy

This type of treatment is showing promising results in treating BT. Scientists take some of your own blood stem cells and insert a Hb gene into them in the laboratory. You then have treatment to destroy your bone marrow cells, before you have the engineered stem cells put back into your bloodstream through a drip.

The process is very similar to having a SCT from a donor, except that your own cells are used. This means the treatment is possible for people who don’t have a donor.

Like having a SCT, gene therapy isn’t easy treatment to get through. You need to have chemotherapy, with all the side effects that brings. However, after the procedure you won’t have to take drugs to damp down your immune system as you’ve had your own blood stem cells and not cells from someone else.

Several trials of gene therapy have been carried out in people with transfusion-dependent BT and other trials are continuing.

A gene therapy was approved in 2022 in the US for people with transfusion-dependent BT.

Improving Red Blood Cell Health

Clinical trials are looking into treating anemia with medication to improve the health, function and survival of red blood cells. In BT, it may mean you don’t need transfusions so often.

Mitapivat is a new treatment that is being tested in people with alpha thalassemia or BT. It’s a tablet that you take twice a day. It’s already used to treat another genetic condition, called pyruvate kinase deficiency.

Mitapivat increases the level of an enzyme that red blood cells need to function properly. This enzyme is low in thalassemic red blood cells.

Early trial results show that mitapivat may help to reduce anemia in people with BT who don’t need regular blood transfusions. Side effects found so far include difficulty sleeping, headache and dizziness.

Mitapivat is being tested in phase III trials for people with BT who don’t need regular transfusions, as well as those who do.

Reducing Iron Absorption

Researchers have identified a natural body hormone called hepcidin that reduces the absorption of iron from the digestive system and helps regulate iron levels in the body. Early trials used drugs that mimic hepcidin. These showed positive effects on iron levels in BT and also on red blood cell production.

A more recent approach uses treatments that target the main regulators of hepcidin. The first clinical trials of these treatments are under way.

Information based on Fast Facts for Patients: Beta Thalassemia (Karger, 2023).

Treatment of Beta Thalassemia

This is the fifth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Beta Thalassemia”. This article gives an overview of the treatment options for beta thalassemia (BT).

BT is complex and needs specialist care. Your treatment should be managed at a specialist center for blood disorders and overseen by a doctor with experience in these diseases.

Specialist centers will often have a thalassemia clinical nurse specialist who you can contact if you have any queries when you’re at home. Some centers also have psychologists and social workers who are familiar with the issues that BT can cause.

The two main treatments for BT are:

• blood transfusions to combat anemia and associated complications
• chelation therapy to control iron overload.

You may also receive:

• treatment for complications, such as an enlarged spleen and gallstones
• medication to improve the production of red blood cells
• stem cell transplant – an intensive treatment that is a potential cure for BT.

What treatment you have will depend on a number of things, including whether your BT is transfusion dependent or non-transfusion dependent.

Non-Transfusion-Dependent Beta Thalassemia

You won’t need regular blood transfusions if your bone marrow is making enough Hb for you to have a good quality of life and a low risk of disease-related complications. But this can change with time. As you get older, you may need to have transfusions more often. With any added physical stress, such as infection or pregnancy, you are also more likely to need a top-up of red blood cells from a transfusion.

Iron can build up in your body even if you don’t have regular transfusions. Your doctor will monitor your iron levels and treat any overload as necessary.

Transfusion-Dependent Beta Thalassemia

If your BT is transfusion dependent, you need lifelong treatment with blood transfusions to correct serious anemia and prevent disease-related complications. You will also need chelation therapy to keep your iron levels within safe limits. Having this treatment regularly is vital for preventing complications and ensuring normal growth, development and lifespan.

If your spleen becomes enlarged and hyperactive, your doctor may suggest removing it. But they will try to avoid surgery if at all possible. There are important long-term side effects associated with removing your spleen.

Stem cell transplant is now a possible cure for BT. But it is very intensive treatment and is only considered for BT major.

Blood Transfusions

Blood transfusions top up your levels of normal healthy Hb. How often you need blood transfusions will depend on your Hb level. Your doctors will want to keep this high enough to:

• prevent severe anemia
• allow normal growth and development
• prevent the bone changes associated with BT.

If you have transfusion-dependent BT, you may need blood as often as every 2–4 weeks. The number of units of blood you will need depends on your body size. Your Hb level is a better guide for your treatment than the time since your last transfusion.

The blood you receive is carefully matched specifically for you, so that you don’t have a reaction to the donor’s red cells.

Chelation Therapy

As explained in the iron overload section, iron can build up in your body if you have BT. Too much iron is toxic so you will need iron chelation therapy to remove it.

Your doctor will monitor your iron levels with regular blood tests. If your levels seem high, you may have an MRI scan to measure the iron concentration in your heart and liver. This will show whether you need to start chelation therapy.

If you have regular transfusions for your BT, you’ll need to start iron chelation therapy after you’ve had 10–20 units of blood. It is very important for your health to follow your doctor’s instructions about iron chelation therapy.

Your doctor will prescribe an iron chelating medicine for you. There are three different drugs available for chelation therapy. Two of them are available as oral medication and can be taken daily by mouth. One is a daily injection under the skin or it can be given through a drip (intravenous infusion or IVI). Sometimes, doctors prescribe two iron chelators in combination.

Stem Cell Transplant

There is now a potential cure for BT, called stem cell transplant (SCT). This is intensive treatment that isn’t available everywhere. Your doctor will carefully consider the decision to undertake SCT as the procedure has side effects, some of which can be life threatening. In the past SCT was reserved for younger children with BT. Today, young adults whose BT is well controlled are also considered for transplant.

Stem cells are cells in the bone marrow that are capable of developing into all the different types of blood cell, including red cells. In a transplant, the stem cells in your bone marrow are destroyed to make room for healthy cells from a donor. The donor has to be someone whose blood cells closely match yours, and this is usually a close family member. If you do not have a family member whose blood cells match yours, it is possible to search for an appropriate donor in bone marrow donor registries. Your doctor will need to find someone who is not related to you, but whose cells are a close match for yours.

The aim of SCT is that the donor stem cells will start to grow inside your bones and provide new blood stem cells to replace yours. This process is called ‘engraftment’. The new stem cells will be able to make all the different types of blood cells you need, including healthy red cells.

The chemotherapy you have as part of your transplant increases your risk of infection. You will need to be nursed in complete isolation for some time after having your stem cell infusion. Other side effects of SCT include hair loss, sore mouth, sickness, diarrhea, bruising, bleeding and infertility.

For some months after the procedure, you will need to take drugs to lower the activity of your immune system (this is called ‘immunosuppression’). This reduces the risk of your own cells attacking the ones from your donor. Doctors call this ‘rejection’.

Stimulating the Production of Red Blood Cells

A medicine called luspatercept has been approved in Europe, the USA, Australia and many other countries, to treat adults with transfusion-dependent BT.

Luspatercept helps red blood cells to develop better in the bone marrow and so reduces the need for transfusions in BT. Some patients who were previously transfusion dependent may even be able to manage without further blood transfusions.

You have luspatercept as a small injection under the skin (subcutaneously) every 3 weeks. Some people have side effects, including headache and bone pain. Your doctor will be able to tell you if luspatercept is available and whether it is suitable for you.

Luspatercept is now being investigated in clinical trials to see if it can help with non-transfusion-dependent BT and to see if it can be used in children.

Information based on Fast Facts for Patients: Beta Thalassemia (Karger, 2023).

Beta Thalassemia: Complications and Their Treatment

This is the fourth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Beta Thalassemia”. This article lists complications associated with beta thalassemia (BT) and how they can be treated.

Complications

There are a number of complications that you may develop if you have BT. Some of these are the result of the disease itself, particularly if you don’t have the treatment you need. Others are the result of a combination of the disease and its treatment.

Bone Changes

Children with BT major (and some with BT intermedia) who don’t receive treatment may have bone deformities that develop slowly over time. The skull expands and heavy brows develop. Your doctor may call this ‘bossing’. The cheekbones get bigger, which alters the shape of the face, nose and eyes. It also affects the placement of the teeth.

‘Bossing’ does not mean that the bones become harder – in fact they are thinner and more fragile. Your doctor may call this osteopenia or osteoporosis. This increases the risk of fractures, mainly in the spine, ribs, pelvis and long bones.

Osteopenia means that your bones have started to become thinner and more fragile. Osteoporosis means you have more severe bone thinning.

Why Do Bone Deformities Occur?

Normally, blood cells are made inside the bones by a tissue called bone marrow. In BT there are fewer circulating red blood cells and less Hb than normal. To try to make up for this, the bone marrow becomes overactive and produces more and more red blood cells. But as these are abnormal, they die early and don’t help to correct the anemia.

As the bone marrow continues to try to correct the anemia, it expands and this causes the bones to become bigger. It is this that causes the typical bone changes of BT. The more severe the form of BT, the more noticeable these changes will be. Treatment is with red blood cell transfusions.

An Enlarged Spleen

Some people with BT major may also develop an enlarged liver (hepatomegaly) and spleen (splenomegaly), leading to abdominal swelling. This happens because the spleen removes faulty red blood cells and also because the liver and spleen become alternative sites for red blood cell production.

A very enlarged spleen can cause abdominal discomfort and make anemia worse. So, it may have to be removed. Splenomegaly is more common and severe if you have non-transfusion-dependent BT. If you are having transfusions you will be receiving healthy normal red blood cells from donors and your spleen won’t have to work so hard.

If you have BT trait, you may also have a slightly enlarged spleen, but not enough to cause symptoms.

Gallstones

Gallstones can develop because of high levels of bilirubin in the liver caused by the chronic hemolysis. Hemolysis is the destruction of red blood cells.

If you have gallstones, you may feel bloated and sick (nauseated) and have abdominal pain. You may need surgery to have your gallbladder and the stones removed.

Blood Clots

There is an increased risk of blood clots (thrombosis) as you get older, particularly if you have non-transfusion-dependent BT. The risk is higher if you’ve had your spleen removed.

Benign Masses

Sometimes in BT, if the bone marrow isn’t able to make enough blood cells, they can be made outside the bone marrow, in the liver and spleen. This can cause the liver and spleen to get bigger. But it can also cause small slow-growing lumps of tissue to develop, usually in the chest near the spine. These lumps (masses) are harmless but they can sometimes press on spinal nerves and cause problems. Although they are completely benign (not cancerous), doctors need to distinguish them from tumors on scans and X-rays and this can be difficult. Blood transfusions can prevent these from developing.

When red blood cells are made in tissues other than the bone marrow, this is called extramedullary erythropoiesis. Common sites of extramedullary erythropoiesis include organs such as the liver and spleen, as well as lymphatic tissue, especially all along the spine.

Leg Ulcers

Untreated BT intermedia can lead to problems with wound healing. Even minor wounds on the legs, particularly the ankles, don’t heal and may get worse and become infected. These are treated with dressings to help them heal and antibiotics if infected.

Iron-Related Complications: Iron Overload

Normally, when ageing red blood cells are broken down in the body, the iron that’s released is recycled into new cells. When a person has regular blood transfusions, iron overload can also happen as donor red cells contain iron. Iron overload is when there is too much iron in your body. As the body can’t get rid of all the extra iron, it builds up and can cause damage.

Iron overload can also develop in people who don’t have regular transfusions (non-transfusion-dependent BT), but it develops more slowly. The buildup occurs because the overactive bone marrow sends signals to the gut to absorb much more iron from the diet. This happens because the body tries to correct the anemia by making more red blood cells and for this it needs iron.

Iron buildup can damage the liver, causing fibrosis. Fibrosis is scar tissue that replaces damaged liver tissue. If not controlled, fibrosis can develop into cirrhosis and liver failure.

Iron overload can also cause heart damage, leading to abnormal heart rhythms (arrhythmia) and eventually heart failure. Excess iron can also damage your bones and joints, increasing the risk of weakened bones (osteoporosis).

Hormone levels can be affected by iron overload too. Your thyroid hormone levels may be low, which can cause fatigue, weight gain and constipation.

You may be at a higher risk for diabetes. Iron affects the production of insulin in the pancreas, which controls blood sugar levels.

You may also have low levels of sex hormones. Puberty is often later than usual in children with BT. The low hormone levels may cause reduced fertility.

To help prevent all the problems caused by iron toxicity, your iron levels may need to be controlled with treatment called chelation therapy. Iron levels can be kept low and safe by the daily use of medicines called iron chelators.

Pregnancy-Related Complications

There are no particular complications from carrying a baby with BT. But if you have BT, pregnancy can put an extra strain on your body and make your symptoms worse. You may also have difficulty becoming pregnant, as iron overload can affect fertility (because of the effect on hormone levels).

You will need extra tests to check your heart, liver and bone health. If you are on chelation therapy, you will have to stop for the first half of the pregnancy because the medicines could be toxic for the baby.

Your Hb levels will be closely monitored and you may need transfusions more often, particularly as the pregnancy progresses.

Treatment for Complications

Some people need surgery for complications of BT, such as an enlarged spleen or gallstones.

Enlarged Spleen

A very enlarged spleen can cause abdominal discomfort and make anemia worse, so it may have to be removed. In BT, removing the spleen improves anemia and reduces the need for such frequent blood transfusions in some people.

Because BT is now much better controlled with transfusions, fewer people develop a very enlarged spleen and so splenectomy (surgery to remove the spleen) isn’t done as often. However, people with non-transfusion dependent thalassemia may also need a splenectomy, as their thalassemia isn’t managed with transfusions.

Splenectomy is a major operation and will require a stay in hospital and you will need time to recover. You may have open surgery (one larger incision) or laparoscopic surgery (several small incisions). Laparoscopic surgery is sometimes called keyhole surgery or bandaid surgery. With keyhole surgery, your hospital stay is generally shorter and recovery from surgery is faster.

There can be other problems after you’ve had your spleen removed.

In BT, removing the spleen increases your risk of developing blood clots (thrombosis). This risk is lifelong and is the main reason why the benefits of surgery must be carefully weighed against the risks.

The spleen is part of your body’s defense against infection so you are more at risk without it. To give you added protection, you will need some vaccinations, ideally before your surgery. If your child has their spleen removed, your doctor may also want them to take antibiotics daily for a couple of years after surgery to prevent infection. Or you may have an antibiotic prescription at home, so you can start taking them quickly if needed.

Gallstones

Stones in your gallbladder can be very painful and make you feel very unwell.

The treatment is usually surgery to remove your gallbladder. You may have open surgery or keyhole surgery.

Keyhole surgery usually means a shorter stay in hospital and a quicker recovery as there is no large incision.

Blood Clots

People with BT may develop blood clots. The risk is higher in certain circumstances, such as before planned surgery, during pregnancy or after having your spleen removed. Your doctor may suggest you take medicines to reduce the risk of your blood clotting. You will have to have these if you’ve had your spleen removed. These medicines are called anticoagulants and include low-dose aspirin and heparin-like medicines.

Information based on Fast Facts for Patients: Beta Thalassemia (Karger, 2023).

Beta Thalassemia: Screening and Diagnosis

This is the third part of our series about the condition based on our patient booklet “Fast Facts for Patients: Beta Thalassemia”. This article focuses on the screening for and diagnosis of beta thalassemia (BT).

Newborn Screening

In some parts of the world all newborn babies are screened for several genetic conditions. A nurse will prick the baby’s heel with a fine needle and squeeze out a drop of blood, which is then used for the testing. The heel prick test is not a reliable test for all types of thalassemia but it can pick up BT major.

Diagnostic Testing

Children with the most severe forms of BT can develop symptoms from 3 months of age.

If your child has symptoms that suggest they may have BT, your doctor will request blood tests. These tests look for iron deficiency to rule out the commonest cause of anemia.

The blood tests will also analyze the Hb level, the shape and size of the red blood cells and look for changes in the structure of the Hb molecule. Carriers of a BT gene change and people with BT have red blood cells that are smaller than normal. This is a particular feature of BT called microcytosis. The specific test for BT is usually HPLC – high performance liquid chromatography – or sometimes electrophoresis.

Microcytosis is the term used to describe red blood cells that are unusually small.

DNA Tests

More than 400 gene changes are associated with BT. DNA (genetic) tests need to be done on a blood sample to identify the specific ones you have. The sample may need to be sent to a specialized laboratory for these tests.

Pregnancy Screening

Depending on your ethnic background or family history, your doctor may suggest you have blood tests for thalassemia if you are planning to start a family.

Ideally, tests for BT should be carried out before the start of pregnancy. But in practice, most women usually have blood tests when they first go to their doctor after becoming pregnant. If your blood test shows anemia and/or small red blood cells, your doctor is likely to suggest further testing for BT. If you are found to have BT trait (one changed gene), the baby’s father will also need to be tested, to see if there is a risk your baby could be born with BT.

Genetic Counseling and Pregnancy

If your doctor suspects you have a BT gene change, they may suggest genetic counseling for you and your partner. The counselor will help you understand why you are considered a ‘couple at risk’ for BT and will explain what your test results mean.

If the blood test results show there is a risk that your child could be born with BT, the counselor will continue to provide support. You will also be able to discuss your options when planning a pregnancy. Some couples opt to have in vitro fertilization (IVF or a test tube baby) so that genetic testing can be carried out before the fertilized egg is implanted. This makes sure that the baby doesn’t have BT.

If you are already pregnant and there is a risk that the baby has BT, it’s possible for the baby to be tested while still in the womb. This is usually done in one of two ways:

• taking a small sample of the placenta (chorionic villus sampling)
• testing the fluid surrounding the baby (amniocentesis).

Which test you have depends on how far through the pregnancy you are. Both tests carry a small risk of miscarriage, so your doctor will only suggest testing if absolutely necessary.

There are some non-invasive tests that are under investigation, such as testing fetal DNA found in the mother’s bloodstream. These may be useful in future, but they are currently not accurate enough to use for thalassemia and give high levels of wrong results.

If tests suggest that a baby may be born with severe BT, your counselor may guide you through the difficult decision of whether to continue with the pregnancy. There is no single answer that suits every couple. The decision depends on lots of different factors, including cultural, social, spiritual and religious beliefs. Being fully informed about the disease will help you make a decision.

Information based on Fast Facts for Patients: Beta Thalassemia (Karger, 2023).

Types of Beta Thalassemia: Trait, Intermedia, and Major

This is the second part of our series about the condition based on our patient booklet “Fast Facts for Patients: Beta Thalassemia”. This article explains the different types of beta thalassemia (BT), this is: trait, intermedia, and major.

Symptoms of BT vary depending on which kind of gene change you have inherited. Because it’s complex and to make things simpler, doctors generally put people with BT into two groups, regardless of the gene changes they have – people who depend on regular blood transfusions and those who don’t. So, your BT may be described as transfusion dependent or non-transfusion dependent. People who need regular blood transfusions have more severe anemia (fewer healthy red blood cells).

You may also hear the terms beta thalassemia intermedia and beta thalassemia major.

• BT intermedia describes less severe disease that does not need regular blood transfusions (although you may need more transfusions as you get older). It generally occurs when one or both gene changes are less severe.
• BT major describes severe disease since early childhood requiring lifelong regular blood transfusions. It generally results from a combination of two severe gene changes.

Other Types of Inherited Blood Disorders

Sometimes people inherit a combination of a BT gene change and a change in a gene that causes another condition that affects Hb production. For example, some people have one BT gene change and the gene change that causes sickle cell disease: this combination causes a disease called sickle BT. Another condition is alpha gene triplication.

Beta Thalassemia Trait

If you have only one changed HBB gene, you are a healthy carrier of BT but do not have, and will never develop, the disease. This is called beta thalassemia trait or beta thalassemia minor.

Normally BT trait doesn’t cause symptoms so you may not know you have a BT gene change. A routine blood test may raise suspicions that you are a carrier but cannot prove this – you need to have specific DNA (genetic) tests carried out on a blood sample to find any thalassemia changes.

BT carriers are healthy people who don’t have thalassemia. You may have mild anemia, but this doesn’t generally need treatment. You may have a pale complexion.

Under a microscope, your red blood cells will look small (microcytosis). A doctor who doesn’t know your medical history may assume this is due to low iron, but it’s not and you don’t need iron supplements. In fact, you shouldn’t take iron supplements unless a specific blood test shows that you are definitely deficient.

What Is the Risk If I Have Children?

If you carry a mutated HBB gene you have a 1 in 2 risk (50%) of passing it on to a child for each pregnancy that you conceive.

If your partner also has BT trait, there is a 1 in 4 chance (25%) of a baby having BT and a 1 in 4 chance (25%) of them not inheriting the gene mutation at all.

Your doctor may suggest you have genetic counseling if you have BT trait.

What Can I Do to Help Myself?

You may feel tired if you have mild anemia, particularly if your body is under any extra strain, such as during pregnancy, or if you have an infection or have had surgery.

You can help yourself to stay healthy by

• eating healthily
• exercising regularly
• not smoking or drinking too much alcohol.

Should I Tell Other People?

When and how should you tell people that you are a thalassemia carrier? The simple answer is: whenever you are ready. Mostly, you don’t have to tell people if you don’t want to. But you particularly need to be open with your partner if you are thinking of starting a family in the future. They will need to be tested too.

Talking about a genetic problem can be difficult. People sometimes feel it’s their fault. But you have no control over the genes you inherit. You can use this booklet to help others understand more about BT.

Beta Thalassemia Intermedia

Symptoms of BT intermedia can appear at any point. You may not need transfusions as it depends on the severity of your anemia and whether you need to prevent or control long-term complications. Your doctor will advise you about this.

Signs and Symptoms

You may:

• look pale
• lack energy when active or exercising
• not grow as much as expected
• not gain as much weight as expected
• have abdominal swelling, caused by the spleen getting bigger.

These may be the only symptoms if the condition is diagnosed early.

The spleen enlarges because one of its functions is to recycle and remove old and faulty red blood cells.

Symptoms can get worse when the body is under stress, because the need for oxygen is higher. Stress includes having an infection, recovering from surgery and during pregnancy.

Beta Thalassemia Major

BT major is a lifelong condition, with symptoms usually appearing during the first 2 years of life.

Signs and Symptoms

BT major causes severe signs and symptoms because the body is not able to make normal Hb. It is a transfusion-dependent condition.

Babies with BT major become thin and pale during their first year because of severe anemia. They also show early signs of bone changes.

Why Is Treatment Important?

It’s important for all children and adults with BT major to have treatment to control the disease and try to prevent complications as far as possible. If you don’t, you are more likely to develop further problems as your body tries to cope with the faulty red blood cells.

Information based on Fast Facts for Patients: Beta Thalassemia (Karger, 2023).

Beta Thalassemia: What Is It and What Causes It?

This is the first part of our series about the condition based on our patient booklet “Fast Facts for Patients: Beta Thalassemia”. This article shows what beta thalassemia (BT) is and what causes it.

First, the Facts

1. Beta thalassemia (BT) is a blood condition you’re born with. It affects your red blood cells.
2. BT is a disease caused by changes (mutations) in genes that are passed on from parent to child. You have BT when you inherit a gene change from both of your parents.
3. There are two types of BT disease – BT major and BT intermedia. A person can also be a healthy carrier of BT without having the disease. This is called BT trait (or BT minor).
4. Treatment depends on the type of BT disease you have. People with BT major will require regular blood transfusions throughout their life.
5. New treatments for BT have recently been approved or are being tested in clinical trials around the world, with promising results.

What Is Beta Thalassemia?

Thalassemia is a condition you are born with. It affects red blood cells. There are two main types: alpha thalassemia and beta thalassemia (BT). This booklet is about BT.

In BT, the body doesn’t make enough normal hemoglobin (Hb). Hb is the protein in red blood cells that enables them to carry oxygen around the body. There are also too few healthy red blood cells.

This is called anemia. Anemia can be mild or serious. Serious anemia can damage organs and can be fatal.

Types of BT

There are different types of BT. How severe your condition is and how bad your symptoms are depends on the type you have. You may have no symptoms, or you may need lifelong treatment.

Why Isn’t the Hemoglobin Made Properly?

Each molecule of normal adult Hb is made up of four protein chains – two alpha chains and two beta chains. If you have BT, your body is not producing enough of the beta chain. That means you cannot make enough normal Hb, so less oxygen can be carried around your body.

What Causes Beta Thalassemia?

BT is a genetic condition. This means it is caused by a change (also called a mutation) in a gene. There can be different types of change – some cause the beta chains of Hb to be missing completely, while others cause a decrease in beta chain production.

What Are Genes?

Your genes carry instructions for the growth, development and function of your entire body.

Genes are found on chromosomes. Every cell in the human body has 23 pairs of chromosomes – so 46 chromosomes in total. Every chromosome has anywhere from 55 to 20 000 genes.

Genes are in pairs too – you inherit one copy from your mother and one copy from your father. A pair of genes is carried on a pair of chromosomes (one gene on each chromosome).

Each pair of genes carries the code to make a single protein.

The gene that carries the instructions for making the beta chain protein of Hb is called HBB.

Who Gets BT?

BT is more common in some parts of the world where malaria is, or has been, a problem (for example, the Mediterranean, the Middle East, North Africa, India and Southeast Asia) and in people with ancestry originating from these areas. This is because the gene changes that cause BT also give some protection against malaria.

Over time, the proportion of people in the population with a BT gene change has increased and, as people migrate around the world, BT has become more common in other regions too.

Inheriting Beta Thalassemia

BT is nearly always a recessive genetic condition. In recessive conditions, both genes in a pair have to be affected to produce disease. This means you have to inherit a mutated gene from both of your parents to have the condition. So, either your parents have BT themselves, or, more commonly, they are ‘carriers’ of a mutated HBB gene.

Carriers have one mutated HBB gene and one healthy HBB gene. Because they have one healthy gene, they can still make enough healthy Hb beta chain protein. They will never develop BT, but they can pass on the mutated gene to their children.

Being a carrier of a single mutated HBB gene is called beta thalassemia trait or beta thalassemia minor.

How Do Gene Changes Cause Beta Thalassemia?

There are many different changes to the HBB gene that can cause BT. How severely you are affected will depend on the type of gene change that you have. There are two main types of changes:

• Those that result in less beta chain protein than normal being made. Doctors write this as β+.
• Those that result in no beta chain protein being made. Doctors write this as β0.

Because there are two HBB genes, a person can have a combination of these types of change. You may have β+/β+, β+/β0 or β0/β0.

If only one gene of the pair is affected (BT trait), you may have β+/β or β0/β.

There is another possible gene change, called HbE. This results in the production of an abnormal type of Hb known as hemoglobin E. So, you can also have the gene combinations β+/E+ or β0/E+.

Information based on Fast Facts for Patients: Beta Thalassemia (Karger, 2023).

Living with Alpha Thalassemia

This is the ninth and last part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article provides information on living with alpha thalassemia (AT).

Some people with AT already know that it runs in their family. For others, it’s a complete shock when they are diagnosed with AT because of anemia symptoms or when a baby is diagnosed shortly after birth. Genetic counseling can help you to understand your condition and its implications, including the risk to any future children you may have.

You are likely to have a lot of questions. It’s important to find out as much as you can about AT and about your own situation.

AT is complicated and it’s easy to get confused. It may help to write down a list of the things you need to know or questions you want to ask and take it to your doctor’s appointment. It may also help to take someone with you, so you can compare notes afterwards.

Should I Tell Other People?

When should you tell people that you are a thalassemia carrier or have AT trait? The simple answer is: whenever you are ready. Mostly, you don’t have to tell people if you don’t want to. But you particularly need to be open with your partner if you are thinking of starting a family in the future. They will need to be tested too.

Talking about a genetic problem can be difficult. People sometimes feel it’s their fault. But you have no control over the genes you inherit. You can use this booklet to help others understand more about AT.

Important: Living a healthy life is important for everyone. When you have thalassemia, healthy choices are particularly important.

The best way to avoid complications is to stick to any treatment schedules and go to all your check-up appointments.

Important: Contact your doctor promptly if you have any signs of infection or other illness, and make sure you keep your vaccinations up to date – especially if you’ve had your spleen removed.

Your Diet

It’s important to look after your general health. Make sure you eat well.

People with thalassemia often have low levels of some vitamins and minerals, such as zinc. This is partly because of the anemia, and partly because of high iron levels and the treatment used to remove iron. Your doctor may give you supplements.

Some doctors suggest avoiding foods that contain iron, but others think that this has little effect in preventing iron overload. It’s best to discuss your diet with your own AT healthcare team.

Keep Fit for Healthy Bones

Regular physical exercise has many benefits. It can improve your mood and help strengthen your bones. Alcohol and smoking are best avoided.

Ask for Help If You Need to

Do ask questions and tell your healthcare team about anything that’s concerning you. They know how complex AT is and won’t mind, even if you ask the same questions more than once.

Questions for Your Doctor

• What type of AT do I/does my child have?
• How many gene changes are there?
• Are they deletional or non-deletional gene changes?
• What are the implications of the gene changes I have?
• What impact will AT have on me/my child?
• Will I/they need regular treatment?
• What are the likely side effects of treatment?
• What complications could there be and how likely are they?
• What is the likelihood of me having another child with AT?
• Is there anything that can be done to reduce the risk of having another child with AT?
• Will my child with AT be able to have children and what do they need to know beforehand?

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Symptoms and Treatment
• Alpha Thalassemia: Clinical Trials and New Treatments

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Alpha Thalassemia: Clinical Trials and New Treatments

This is the eighth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article shows what clinical trials are and which new treatments are on the horizon.

Clinical Trials

If you are interested in new treatments, you may want to ask your doctor about clinical trials. All new medical treatments have to be tested in clinical trials. A new treatment must go through several phases of testing before it can be proven to work better than existing treatment and be adopted into routine care. A potential treatment will only move on to the next phase of research if it is safe and shows promise.

New Treatments for Alpha Thalassemia

Slowing the Breakdown of Red Blood Cells

There has been some research looking into treating anemia in people with AT with medication to reduce the destruction of red blood cells.

Mitapivat is a new treatment that is being tested in people with AT or beta thalassemia. It’s a tablet that you take twice a day. It’s already used to treat another genetic condition that causes anemia, called pyruvate kinase deficiency.

This treatment helps to activate an enzyme that is needed for red blood cells to function properly. Early trial results show that it may be able to reduce anemia in people with AT who don’t need regular blood transfusions. Side effects found so far include difficulty sleeping, headache and dizziness.

Mitapivat is being tested in a Phase III trial for people with AT who do and do not require regular transfusions.

Stem Cell Transplant

The only way to potentially cure AT is with a stem cell transplant from a donor. Stem cell transplant is currently only suitable for AT major, as the treatment itself has many side effects, some of which can be life-threatening.

Stem cells are cells in the bone marrow that can develop into all the different types of blood cell in the body, including red blood cells.

When you have a transplant, the stem cells in your bone marrow are destroyed and replaced with healthy cells from the donor. The donor must be someone whose blood cells closely match yours, and this is usually a close family member.

The aim is for the donor stem cells to start to grow inside your bones and provide new blood stem cells to replace yours. This process is called ‘engraftment’. The new stem cells will produce all the different types of blood cells, including healthy red blood cells.

Until the new stem cells have started to work, you have a very high risk of infection. So, you need to be nursed in isolation for some time after having your stem cell infusion.

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Symptoms and Treatment
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Alpha Thalassemia: Symptoms and Treatment

This is the seventh part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article lists the symptoms and treatment of alpha thalassemia (AT).

How Will AT Affect Me or My Child?

Symptoms of AT vary depending on which type of AT you have. Some people have no symptoms while others have severe symptoms that need lifelong treatment.

Complications are health problems caused by the disease (AT) or by the treatment. Complications also vary from mild to severe.

Silent carrier. As a silent carrier, you won’t have any symptoms of AT and will have no health problems related to AT.

AT trait. With AT trait, symptoms vary from none to mild anemia. This can cause fatigue, particularly after exercise, and pale skin and you may feel weak.

HbH AT. Symptoms and complications are more severe in people with HbH AT. They include anemia, enlarged liver and spleen, gallstones, abnormal bone development, blood clots and iron overload (see below).

AT major. Children and adults with AT major will need regular treatment to prevent severe anemia. They are also at risk of all the complications that can happen with HbH AT.

Anemia

People with more severe HbH AT and AT major will have more severe anemia, which causes increased fatigue, difficulty breathing, weakness and dizziness.

Anemia can sometimes get worse with age or when the body is under stress: for example, if you have an infection or during pregnancy.

Babies born with HbH AT may have anemia but don’t usually need regular treatment.

Children and adults with AT major will need regular treatment for anemia.

Treatment

The main treatment for anemia is blood transfusions. Blood transfusions provide healthy red blood cells.

How Often Will I Need Blood Transfusions?

How often people with HbH AT (three gene changes) need blood transfusions varies. It depends on how severe their anemia is and it also depends on their age. Some people with HbH AT need regular transfusions by the time they reach their teens or 20s.

People with AT major (four gene changes) will need regular transfusions throughout their lives. Transfusions can happen every couple of weeks.

You receive blood through a small plastic tube inserted into one of the blood vessels in your arm. The procedure usually happens in a hospital or a special clinic for blood diseases. Babies, children and adults can have transfusions. The procedure will take a few hours each time.

Doctors also sometimes prescribe folic acid tablets to help with anemia. Folic acid is a kind of vitamin which helps to produce red blood cells.

Enlarged Liver and Spleen

HbH AT and AT major can cause the liver and spleen to get bigger than normal, and your abdomen may feel uncomfortable. You may have pain too. It happens because the spleen has to work hard to get rid of the faulty red blood cells and the liver has to work hard to process the resulting waste products.

Treatment

If an enlarged spleen is causing discomfort and pain, you may need surgery to remove it. The removal of a spleen is called splenectomy. Blood transfusions can also help to shrink an enlarged spleen. People who have had a splenectomy have a higher risk of infections. Your hematologist and general surgeon will discuss the risks and benefits with you.

Gallstones

These can develop because of high levels of bilirubin (a waste product from the processing of red blood cells). Some people with gallstones have no symptoms, but others may feel bloated and sick (nauseated) and have abdomen pain.

Treatment

The treatment is usually laparoscopic surgery (sometimes called keyhole or bandaid surgery) to remove your gallbladder. Keyhole surgery usually means that you recover more quickly because there is no major incision.

Abnormal Bone Development

Normally, blood cells are made inside the bones by a tissue called bone marrow. In AT there are fewer circulating red blood cells and less Hb than normal. To try to make up for this, the bone marrow becomes overactive and produces more and more red blood cells. But as these are abnormal, they die early and don’t help to correct the anemia. As the bone marrow continues to try to correct the anemia, it expands and this may cause the bones to become bigger, particularly in the face, causing a ‘heavy’ forehead and overgrowth of the brows and jaw. Your doctor may call this bossing.

With untreated AT, limbs can also be shorter than usual because the long bones stop growing early. Bones may also become weakened and break more easily. Your doctor may call this osteoporosis or osteopenia.

Treatment

If you or your child have HbH AT or AT major, you will have regular health checks so that any abnormal bone development is found early. Regular blood transfusions and the treatment for iron overload usually helps prevent bone problems.

Blood Clots

People with AT have a slightly increased risk of blood clots. The risk is higher in people who have had their spleen removed and the risk increases with age. Blood clots are more common in women.

Treatment

Treatment for blood clots varies but may include aspirin or low-dose blood thinners. These are called anticoagulants.

Leg Ulcers

HbH AT can cause problems with wound healing. Even minor wounds on the legs, particularly the ankles, don’t heal and may become infected and need antibiotics.

Iron Overload

Iron overload is a common complication of AT major and HbH AT.

Normally, when aging red blood cells are broken down in the body, the iron that’s released is recycled into new cells. When a person has regular blood transfusions, iron overload can happen as donor blood also contains iron. Iron overload is when there is too much iron in your body. It can also develop in people with HbH AT who do not have regular transfusions but it happens more slowly. The buildup occurs because the overactive bone marrow sends signals to the gut to absorb much more iron from the diet. This happens because the body tries to correct the anemia by making more red blood cells and for this it needs iron.

Why Is Iron Overload a Problem?

Too much iron is toxic to the body as the body is not able to remove it. The excess iron increases over time and can damage your organs.

Iron buildup can damage the liver. The damaged liver tissue is replaced by fibrous tissue, also called scar tissue. This process is called fibrosis. A research study found that around 1 in 5 people (20%) with HbH AT have liver tissue that has been replaced with fibrous tissue (fibrosis). If fibrosis gets worse, it can develop into liver cirrhosis and liver failure.

Iron overload can cause heart damage, leading to abnormal heart rhythms (arrhythmia) and eventually heart failure.

It can also damage your bones and joints. People with AT major and HbH AT are prone to weakened bones (osteoporosis). This is partly due to the thalassemia, but iron overload also contributes because iron can collect in the bones and cause damage.

Hormone levels can be affected by iron overload. Your thyroid hormone levels may be low, leading to fatigue, weight gain and constipation. You may also be more at risk of developing diabetes, because iron affects the production of insulin in the pancreas, which controls your blood sugar levels.

If you are receiving blood transfusions, you may have low levels of sex hormones. In children with AT, this can mean that puberty is later than usual. This is less common these days, because many children have well-managed anemia and iron levels after their AT diagnosis.

Treatment

To help prevent all the problems caused by iron toxicity, your iron levels may need to be controlled by a treatment called chelation therapy. There are three types of chelation therapy. You may have it through continuous intravenous infusion (directly into a vein), through your skin (subcutaneously) or by mouth (orally). Your doctor will discuss the choice of chelation therapy with you and any possible side effects.

Your doctor will monitor your iron level with blood tests. If it seems high, you may have an MRI (magnetic resonance imaging) scan to measure the iron concentration in your liver and/or your heart. This will show whether you need chelation therapy.

Important: If your doctor says you need chelation therapy, it is very important that you follow their instructions. Iron overload can be fatal.

Your Healthcare Team

AT is a complex health condition and needs specialist care. Your treatment should be managed by a specialist center for blood disorders and overseen by a consultant hematologist (a doctor that specializes in treating blood disorders and diseases).

Specialist centers will often have a thalassemia clinical nurse specialist, who you can contact if you have any questions when you’re at home.

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Clinical Trials and New Treatments
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Alpha Thalassemia: Screening and Diagnosis

This is the sixth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article focuses on the aspects of screening and diagnosis in alpha thalassemia (AT).

Newborn Screening

In some parts of the world, all newborn babies have a blood test for thalassemia. A nurse pricks the baby’s heel with a fine needle and squeezes out a drop of blood. This is used to test for other genetic conditions as well.

It is unlikely that the test will find one or two gene changes but it is likely to find HbH AT (three gene changes).

Diagnostic Testing in Children and Adults

A doctor may suggest testing for thalassemia because you (or your child) show some of the symptoms of AT or if a routine blood test shows that you or your child have mild microcytic anemia.

Often, doctors test for iron deficiency first because it’s a common cause of microcytic anemia. They will do other tests to look for HbH AT and AT trait.

These tests can’t show how many AT genes are affected though.

To identify the exact genetic changes, you’ll need to have DNA tests done on a blood sample.

Genetic Counseling

Before having screening tests for thalassemia, you may be offered genetic counseling. This is to make sure you understand any tests you might have and what the results may mean.

Usually, the partners of people with two gene changes on the same chromosome or three gene changes (HbH AT) will also need to have a DNA test.

The counselor will continue to provide support after testing if results show that there is a risk that your children could have three or four gene changes. You will be able to discuss the options when planning a pregnancy.

Some couples decide to have in vitro fertilization (also known as IVF or a ‘test-tube baby’) so that genetic testing can be carried out before the fertilized egg is implanted in the womb. Depending on the gene changes that the parents have, genetic testing can make sure that the baby doesn’t have AT major or doesn’t have any AT gene changes at all.

Pregnancy Screening

If you’re already pregnant, your doctor will want to do genetic testing early in the pregnancy in case your baby needs treatment before birth. This helps to prevent premature birth and avoid serious complications for the mother.

If there is a risk that the baby could have AT major, the doctor will suggest testing the baby while still in the womb.

There are different ways to do the test:

• taking a sample of blood from the umbilical cord (cordocentesis)
• testing the fluid surrounding the baby (amniocentesis)
• taking a sample of the placenta (chorionic villus sampling).

Which test you have depends on how far through the pregnancy you are. All the tests carry a small risk of miscarriage, so your doctor will only suggest testing if it is absolutely necessary.

Ultrasound analysis may be used and some non-invasive tests are currently under investigation, such as testing fetal DNA found in the mother’s bloodstream. These may be useful in future, but they are currently not accurate enough to use for thalassemia and give high levels of wrong results.

Invasive sampling means a sample of tissue or fluid is taken from inside the body. This is done via a cut in the skin or through a body opening.

Babies and AT Major

Birth defects are more likely in babies born with AT major, even if they have blood transfusions in the womb. The most common birth defects are minor abnormalities of the genitals in boys. For example, the opening of the urethra (the tube you pee through) can be on the underside of the penis. This is called hypospadias and can be fixed with surgery.

Around 1 in 6 babies (about 17%) have a limb abnormality. These vary in how severe they are. Examples include having hands of different sizes or part of a foot that hasn’t fully developed.

A baby with AT major who does not receive an intrauterine transfusion before he is born will be likely to die in the womb.

Depending on the results of the tests, your counselor may take you through the difficult decision of whether to continue with the pregnancy. There is no single answer that suits every couple. The decision depends on many factors, including cultural, social, spiritual and religious beliefs.

Pregnancy

A pregnant woman with AT needs special care during her pregnancy. Anemia can become more severe. A condition called pre-eclampsia is also more common, which can be fatal if not detected. Signs of pre-eclampsia include rising blood pressure and protein in the urine (signs of damage to the liver or kidneys).

The mother will have regular tests for these during her pregnancy and will often take medication to lower blood pressure.

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Symptoms and Treatment
• Alpha Thalassemia: Clinical Trials and New Treatments
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Alpha Thalassemia: Four Gene Changes

This is the fifth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article explains four gene changes in alpha thalassemia (AT).

If you have four gene changes, you have no genes that make alpha chains properly. This is called AT major or Hb Barts disease. This is the most serious form of AT.

What Does This Mean?

When a baby starts to develop in the womb, the first type of Hb its body makes is called embryonic Hb, which doesn’t include any alpha chains. By 16 weeks, the baby begins to make another type of Hb called fetal Hb, which needs alpha chains.

A baby with four gene changes can’t make alpha chains, so fetal Hb cannot develop. Instead, a type of Hb called Hb Barts is made. The baby will develop severe anemia and will die in the womb without treatment. Doctors call this ‘hydrops fetalis’ (or just ‘hydrops’ for short).

It may be possible for the baby to have red blood cell transfusions while still inside the womb (this is called intrauterine transfusion), so the chance of the baby living until birth is greatly increased. However, there is still a high risk of premature birth.

Your health will also be closely monitored throughout your pregnancy. Your medical team will do everything they can to lower the risk of complications for both you and the baby.

What Is the Risk If I Have Children?

If one parent has four gene changes and their partner has two gene changes on the same chromosome, for each pregnancy there is a:

• 1 in 2 chance (50%) the baby will have AT major (four gene changes)
• 1 in 2 chance (50%) the baby will have AT trait (two AT genes on the same chromosome).

If one parent has four gene changes and their partner has two gene changes on different chromosomes, every child will have HbH AT (three gene changes).

If one parent has four gene changes and their partner has HbH AT (three gene changes), for each pregnancy there is a:

• 1 in 2 chance (50%) the baby will have AT major (four gene changes)
• 1 in 2 chance (50%) the baby will have HbH AT (three gene changes).

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Symptoms and Treatment
• Alpha Thalassemia: Clinical Trials and New Treatments
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Alpha Thalassemia: Three Gene Changes

This is the fourth part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article focuses on three gene changes in alpha thalassemia.

If you have three gene changes, you have Hemoglobin H AT (HbH AT).

What Does This Mean?

The symptoms and complications you experience will depend on the type of gene change you have.

People with non-deletional HbH tend to have more severe disease than people with missing AT genes (deletional HbH).

You may have only mild anemia or it may be severe enough for you to need regular blood transfusions from a young age.

What Is the Risk If I Have Children?

If one parent has three gene changes but the other parent has no changes, for each pregnancy there is a:

• 1 in 2 chance (50%) the baby will be a carrier (one gene change)
• 1 in 2 chance (50%) the baby will have AT trait (two gene changes on the same chromosome).

If one parent has three gene changes and the other has one gene change, for each pregnancy there is a:

• 1 in 4 chance (25%) the baby will be a carrier (one gene change)
• 1 in 2 chance (50%) the baby will have AT trait (two gene changes)
• 1 in 4 chance (25%) the baby will have HbH AT (three gene changes).

If one parent has three gene changes and the other has two gene changes on the same chromosome, for each pregnancy there is a:

• 1 in 4 chance (25%) the baby will be a carrier (one gene change)
• 1 in 4 chance (25%) the baby will have AT trait (two gene changes on the same chromosome)
• 1 in 4 chance (25%) the baby will have HbH AT (three gene changes)
• 1 in 4 chance (25%) the baby will have AT major (four gene changes).

If one parent has three gene changes and the other has two gene changes, one on each chromosome, for each pregnancy there is a:

• 1 in 2 chance (50%) the baby will have AT trait (two gene changes changes, one on each chromosome)
• 1 in 2 chance (50%) the baby will have HbH AT (three gene changes).

If both parents have three gene changes, for each pregnancy there is a:

• 1 in 4 chance (25%) the baby will have AT trait (two gene changes on the same chromosome)
• 1 in 2 chance (50%) the baby will have HbH AT (three gene changes)
• 1 in 4 chance (25%) the baby will have AT major (four gene changes).

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Symptoms and Treatment
• Alpha Thalassemia: Clinical Trials and New Treatments
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Alpha Thalassemia: Two Gene Changes

This is the third part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article provides information on two gene changes in alpha thalassemia (AT).

If you have two gene changes, you are said to have AT trait, which is also called AT minor.

What Does This Mean?

Most people with two gene changes don’t have any serious health problems related to AT, apart from mild anemia (a shortage of healthy red blood cells). Anemia can cause fatigue, particularly after exercise).

Under a microscope, your red blood cells will look smaller than usual. Doctors call small red blood cells microcytosis. The cells look like this because of a lack of Hb.

Important: If you’re anemic, make sure your doctor knows that you have AT trait (or that there is thalassemia in your family if you haven’t been tested). If the doctor doesn’t know this, they may prescribe an iron supplement for your anemia but that’s something you definitely don’t need if you have AT because you may develop ‘iron overload’. Iron overload is harmful.

Microcytosis is the term used to describe red blood cells that are unusually small.

When one parent has two gene changes on the same chromosome and the other parent has no gene changes, for each pregnancy there is a:

• 1 in 2 chance (50%) the baby will have AT trait (two gene changes)
• 1 in 2 chance (50%) the baby won’t have any gene changes.

If both parents have two gene changes on the same chromosome, for each pregnancy there is a:

• 1 in 4 chance (25%) the baby will have AT major (four gene changes)
• 1 in 2 chance (50%) the baby will have AT trait with two gene changes on the same chromosome
• 1 in 4 chance (25%) the baby won’t have any gene changes.

If one parent has gene changes on each chromosome but the other parent has no gene changes, every child will be a carrier.

If both parents have gene changes on each chromosome, every child will have AT trait.

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Symptoms and Treatment
• Alpha Thalassemia: Clinical Trials and New Treatments
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change

This is the second part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article explains genes and genetic inheritance as well as one gene change in alpha thalassemia (AT).

Genes and Genetic Inheritance

Genes are carried on chromosomes. Every cell in our bodies has 23 pairs of chromosomes – so 46 in total. Every chromosome carries anywhere from 55 to 20 000 genes.

Genes are in pairs too. You inherit one copy from your mother and one copy from your father. A pair of genes is carried on a pair of chromosomes (one gene on each chromosome). Each pair of genes carries the code to make a single protein. Proteins are chains of chemical building blocks called amino acids and they are vital for the body to function.

Altogether, your genes carry the blueprint for the growth, development and function of your entire body.

Which Genes Are Involved?

Production of the Hb alpha chains is controlled by two pairs of genes – HBA1 and HBA2. The codes they carry are the same.

Each person inherits one copy of each gene from their father and another copy of each gene from their mother. This means that there are four gene copies that can potentially cause AT:

• Two HBA1 genes
• Two HBA2 genes.

Deletional and Non-Deletional Gene Changes

There are two important types of gene change in AT.

• If a gene is completely missing, it is called deletional thalassemia.
• If a gene is not missing but is damaged, it is called non‑deletional thalassemia. Non-deletional gene changes tend to cause more severe symptoms than deletional ones.

Location of Gene Changes

If you have two gene changes, the missing or damaged genes can both be on the same chromosome. This is called a ‘cis’ mutation (gene change). You may see this written as aa/– in your notes.

Or there may be one gene change on each chromosome. This is called a ‘trans’ mutation. You may see this written as a-/a in your notes.

Why Is It Important to Know More about My Condition?

If you are pregnant or planning to become pregnant, it is important to understand more about your genetic condition. Understanding more means you are better informed about the risks to your unborn child.

It is important for parents to know if the gene changes are on the same chromosome or on different chromosomes.

Ask your doctor about your gene changes and write the information down.

One Gene Change

If you have only one AT gene change, you are said to be a silent carrier. This is also called AT minima.

What Does This Mean?

You won’t have any signs of AT and will have no health problems related to it.

If you are a carrier and you have a child with someone who is also a carrier, for each pregnancy there is a:

• 1 in 4 chance (25%) the baby will have AT trait (two gene changes)
• 1 in 2 chance (50%) the baby will be a silent carrier (one gene change)
• 1 in 4 chance (25%) the baby won’t have any gene changes.

Very rarely, and only with certain kinds of gene change, there is a chance of having a child with AT.

Please check out the other posts of our series here:

• What Is Alpha Thalassemia?
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Symptoms and Treatment
• Alpha Thalassemia: Clinical Trials and New Treatments
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

What Is Alpha Thalassemia?

This is the first part of our series about the condition based on our patient booklet “Fast Facts for Patients: Alpha Thalassemia”. This article explains what alpha thalassemia (AT) is, what causes it and who gets it.

First, the Facts

1. Alpha thalassemia (AT) is a blood condition you are born with. You have to inherit a gene change from both parents to have AT.
2. If you inherit a gene change from one parent, you are a carrier but don’t have the condition. If your partner is also a carrier, you have a chance of having a child with AT.
3. AT is most common in people with ancestry from Southeast and South Asia, Africa, the Middle East and around the Mediterranean.
4. There are two pairs of genes involved in AT – you may have one, two, three or four gene changes. There are also different types of gene changes – the gene can either be missing or damaged.
5. How severe your AT is depends on the number and type of gene changes you have.
6. AT major (four gene changes) is typically fatal before or shortly after birth without intervention. It remains a lifelong condition but can now be managed with treatment.

Thalassemia

Thalassemia is a condition you are born with. It affects red blood cells. There are two main types: alpha thalassemia (AT) and beta thalassemia (BT). This post is about AT.

In AT, the body doesn’t make enough healthy hemoglobin (Hb) and there are too few red blood cells. Hb is the protein in red blood cells that enables them to carry oxygen around the body.

Why Isn’t the Hemoglobin Made Properly?

Hb is the protein molecule in red blood cells that carries oxygen from the lungs to the tissues of the body. Carbon dioxide is also transported by Hb from the tissues back to the lungs. Hb helps maintain the shape of a red blood cell.

Normal adult Hb is made up of four protein chains – two alpha chains and two beta chains. If you have AT, your body either makes abnormal alpha chains or doesn’t produce enough of them, so you can’t make enough healthy Hb.

When there aren’t enough healthy red blood cells and Hb, oxygen does not reach the tissues of the body, and a person can feel weak, tired and have difficulty breathing. This is called anemia. It can be mild or serious. Serious anemia can damage organs and can be fatal.

What Causes AT and Who Gets It?

Causes of AT

AT is a genetic condition. This means it is caused by a change (mutation) in one or more genes. There can be different types of change – some cause the alpha chains of Hb to be missing completely, while others cause a decrease in alpha chain production.

AT is more common in some parts of the world where malaria is, or has been, a problem (for example, the Middle East, northern Africa, India and Southeast Asia) and in people with ancestry originating from these areas. This is because the gene changes that cause AT also give some protection against malaria.

Over time, the proportion of people in the population with an AT gene change has increased and, as people migrate around the world, AT has become more common in other regions too.

Types of AT

The type of AT you have and how it affects you depends on:

• how many genes are changed and which ones
• the combination of genes that are affected
• whether each affected gene is completely missing or damaged.

Four Types of AT

Silent carrier. Blood tests are usually normal. You will often have no symptoms, but you can pass the damaged gene on to your child.

Alpha thalassemia minor/trait. You may have mild anemia with small red blood cells that may be mistaken for iron deficiency anemia. Two genes are affected.

Hemoglobin H (HbH) AT. There is just one working alpha gene. You may have moderate to severe anemia. You have a greater risk of having a child with AT major.

Alpha thalassemia major. All four genes are missing. This causes severe anemia. In most cases, a baby with this condition will die before birth unless they are treated in the womb.

Please check out the other posts of our series here:

• Alpha Thalassemia: Genes, Genetic Inheritance and One Gene Change
• Alpha Thalassemia: Two Gene Changes
• Alpha Thalassemia: Three Gene Changes
• Alpha Thalassemia: Four Gene Changes
• Alpha Thalassemia: Screening and Diagnosis
• Alpha Thalassemia: Symptoms and Treatment
• Alpha Thalassemia: Clinical Trials and New Treatments
• Living with Alpha Thalassemia

Information based on Fast Facts for Patients: Alpha Thalassemia (Karger, 2023).

Treating Pyruvate Kinase Deficiency: Managing the Complications

This is the fifth part of our series about the condition based on our patient booklet “Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency”, which is freely available online. This article lists how complications can be managed when treating pyruvate kinase deficiency.

Treating Excess Bilirubin in Newborns

Most newborn babies with PK deficiency develop jaundice because of the breakdown of red blood cells and the inability of their immature livers to conjugate bilirubin.

An increase in unconjugated bilirubin in a newborn can lead to significant neurological complications, including a problem called kernicterus (damage to the brain and central nervous system). Newborns with severe jaundice therefore need treatment to decrease the bilirubin levels.

Phototherapy (light therapy) exposes your baby’s skin to as much light as possible. It lowers bilirubin levels through a process called photo-oxidation. Oxygen is added to the bilirubin, making it easier for the baby’s liver to process the bilirubin.

There are two main types of phototherapy:

• conventional – the baby lies under a halogen or fluorescent lamp
• fiber-optic – the baby lies on a fiber-optic blanket so that light shines on the baby’s back.

Continuous multiple phototherapy may also be offered, using more than one light and a fiber-optic blanket at the same time.

Bilirubin levels will be tested every 4–6 hours after phototherapy has started, then every 6–12 hours once the levels start to decrease.

The treatment will be stopped when the bilirubin reaches a safe level, usually within 48 hours. Intravenous fluids and/or increased feeding may also help with the clearance of the bilirubin.

Exchange transfusion. When phototherapy does not adequately decrease the bilirubin level, a procedure called exchange transfusion is recommended to avoid the risk of kernicterus.

Small amounts of your baby’s blood are removed and replaced with blood from a donor (i.e. a blood transfusion) through an intravenous catheter that is placed in their umbilical cord, arms or legs. A protein called albumin may be transfused as well to help decrease the bilirubin level.

The process can take several hours, with regular checks on bilirubin levels to make sure they are falling. If bilirubin levels remain high, the procedure may need to be repeated.

In addition to reducing the bilirubin level, this procedure raises the hemoglobin level and treats anemia.

Treatment of Iron Overload

If you receive regular blood transfusions for your PK deficiency, you will need treatment to remove excess iron from your body. If you have iron overload in the absence of transfusions, you may find you need iron removal treatment for a period of time and are then able to stop the treatment, maybe restarting it again years later based on iron monitoring results.

Depending on the degree of iron burden, drugs that remove iron from the body (chelation therapy) and/or therapeutic withdrawal of blood to remove iron from the body (phlebotomy) may be prescribed. Whether phlebotomy is an effective treatment for iron removal in PK deficiency and how it compares to iron chelation therapy have not been studied. Therefore, most patients with PK deficiency are treated with chelation for iron removal, rather than with phlebotomy.

Chelation therapy. Chelation agents bind with the iron to form substances that can be excreted from the body easily. The table overleaf provides a list of chelation medicines. Even if you receive infrequent transfusions or you’ve never received a transfusion, you may still need iron chelation treatment.

Terminology Tip: Chelation comes from the Greek word “chele”, which means “claw”, in the sense of a pincer-like claw of a lobster or crab, and suggests gripping or holding something firmly. Chelation agents bind with metals such as iron to form substances that can be easily excreted from the body.

Phlebotomy (blood draws). Phlebotomy is an alternative treatment to remove excess iron if you do not receive transfusions. A small volume of blood is removed periodically (for example, every 4 weeks) intravenously to remove the iron. The volume of blood removed will depend on your size and your baseline hemoglobin level, but may be 50–300 mL. A sample of blood will be taken before the procedure to measure your hemoglobin. Phlebotomy is safe if you have not had a transfusion and your hemoglobin is high enough to tolerate blood removal.

Gallbladder Removal (Cholecystectomy)

Gallstones can be associated with nausea or abdominal pain after eating and/or complications if they become stuck in the biliary tract.

You will have an ongoing risk of developing gallstones because of continued hemolysis. Given this, surgical removal of the gallbladder is recommended in PK deficiency if you have gallstones.

If you are considering a splenectomy, you should have an ultrasound before the procedure to see if you have gallstones. Even if you do not, you could consider having a cholecystectomy at the same time as your splenectomy, given the likelihood that you will develop gallstones in future.

Vitamin Supplements

Folic acid is needed to make red blood cells. If you have an elevated reticulocyte count, you will need to ensure you have sufficient folic acid. Depending on the amount of folic acid in your diet, you may need to take folic acid supplements.

Vitamin D/calcium. Given the risk for low bone density in people with PK deficiency, you may find it beneficial to take vitamin D and calcium supplements for bone health. This will depend on how much vitamin D and calcium you have in your diet.

Exercise can also help to strengthen your bones. If your bone density is very low, your doctor may recommend other treatments.

A note of caution: People with PK deficiency tend to overload with iron, so you must avoid taking additional iron supplements in the form of multivitamins or prenatal vitamins.

Please check out the other posts of our series here:

• What Is Pyruvate Kinase Deficiency?
• What Causes Pyruvate Kinase Deficiency and How Is It Diagnosed?
• How Will Pyruvate Kinase Deficiency Affect Me or My Child?
• Treating Pyruvate Kinase Deficiency: Managing the Anemia

Information based on Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency  (Karger, 2019).

Treating Pyruvate Kinase Deficiency: Managing the Anemia

This is the fourth part of our series about the condition based on our patient booklet “Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency”, which is freely available online. This article depicts how the anemia can be managed when treating pyruvate kinase deficiency.

At present, there are no approved drugs that directly treat PK deficiency, but it is possible to manage your symptoms. The type of supportive treatment you are given will depend on how the disease affects you.

Transfusions

It is not your level of hemoglobin, but how well you tolerate the hemolytic anemia caused by PK deficiency that will determine whether you need to have blood transfusions. In PK deficiency, the increase in 2,3-DPG in red blood cells means that more oxygen is released to the body. As a result, you may be able to tolerate moderate anemia with few symptoms.

Transfusions in Newborns and Young Children

The goal is to avoid transfusions if possible, but during the first years of life, red blood cell transfusions may be required to manage severe anemia. The transfusions may be needed to support normal growth and development and/or to avoid symptoms of anemia, including fatigue and poor feeding. For some young children, decreasing the frequency of transfusions to permit a lower hemoglobin level will allow the doctor to assess the child’s reticulocyte response and the true baseline hemoglobin level.

Transfusions in Older Children and Adults

There is no standard criteria or schedule when it comes to deciding whether to give an older child or adult a transfusion. The degree of anemia and the associated symptoms can vary between individuals.

You may never need a transfusion or may only have a transfusion in the setting of a hemolytic episode or aplastic crisis. Alternatively, you may require regular transfusion therapy and may consider opting for a splenectomy.

Splenectomy

If you receive frequent blood transfusions and/or have significant symptoms related to anemia, you may benefit from having surgery to remove your spleen.

Old or damaged red blood cells will continue to be removed in the liver, and so splenectomy is only partially effective in improving the hemolytic anemia.

Both open surgery and laparoscopic (minimally invasive or keyhole) surgery are performed under general anesthesia. The type of surgery may depend on the size of your spleen; your doctor will discuss this with you.

Most patients will spend at least a few nights in hospital after surgery.

Laparoscopic surgery usually results in less pain, a faster recovery and a shorter hospital stay. Several small openings are made in the abdomen, and the surgeon will use a slender tool called a laparoscope, with a light and camera on the end, to look into the abdominal area. Other medical instruments will be passed through the other openings to disconnect the spleen from the body’s blood supply before removing it. The surgical openings are closed using stitches or sutures.

Open surgery. A larger cut is made, often underneath the rib cage, to remove the spleen. The method used will depend on your overall health and the size of your spleen.

Partial splenectomy (only part of the spleen is removed) has not been reported to be beneficial in patients with PK deficiency.

Benefits and risks. Your hematologist can help you and your family weigh the potential benefits and risks to decide if splenectomy is the right option for you.

Risk of infection. The spleen is an important organ that helps your body to fight infections. Splenectomy raises the risk of infection from certain bacteria, such as pneumococcus, meningococcus and haemophilus. These infections can be very serious, even life-threatening, and the risk will remain for your lifetime.

Although the absolute risk of serious infection after splenectomy is very low, it is much higher in people who have had a splenectomy than in the healthy population. For this reason, surgery in children should be delayed when possible until they are at least 5 years old.

In determining the timing of splenectomy, the risk of a serious infection must be balanced against the risks of red blood cell transfusions and iron loading. After splenectomy, other infections for which you will be at higher risk include malaria (from mosquitos) and babesiosis (from ticks) in endemic areas.

How can I protect myself from getting an infection? After a splenectomy, you are likely to be given antibiotics to protect against the possibility of a serious infection. Some doctors recommend twice daily antibiotics for a period of time after splenectomy; others advise continuing antibiotics for life. You must seek urgent medical attention for all fevers, to be assessed and treated with broad-spectrum antibiotics (see box below).

It is very important that you have the recommended vaccines before splenectomy and then stay up to date with your immunizations (vaccines) after surgery. Ask your hematologist and/or general physician whether your vaccines are up to date.

IMPORTANT: After splenectomy, you are at risk of serious infection. See a doctor immediately if you develop a fever over 38.5°C (101.5°F). You must seek medical attention even if you have other infectious symptoms, such as a cough or congestion, or you have multiple family members with similar symptoms. A sample of your blood will be sent for laboratory tests (blood culture and complete blood counts) and you will be given intravenous or intramuscular broad-spectrum antibiotics.

Risk of blood clots. As a filtering organ, your spleen plays a role in protecting you from blood clots (thrombosis). Blood clots can form in the large veins of the arms or legs (deep vein thrombosis), the blood vessels around the liver (portal vein thrombosis) or other concerning locations. Clots in the arteries can also occasionally develop.

The risk of developing a blood clot after splenectomy for PK deficiency is approximately 10%. Some individuals take aspirin or other medications after splenectomy to decrease this risk. Consider speaking to your doctor about this.

Stem Cell Transplantation

A bone marrow (stem cell) transplant can cure PK deficiency. This has been carried out successfully in studies in animals with PK deficiency, but the procedure is associated with significant risks, including the development of new chronic medical issues and the risk of dying from complications related to the transplant.

In total, 16 individuals with PK deficiency have undergone stem cell transplantation in Europe and Asia, with a range of conditioning (preparation) regimens and management strategies. These patients had a high rate of graft-versus-host disease (i.e. the donor cells attacked the host’s own cells), a chronic complication that can cause issues related to the skin, gastrointestinal tract and other organs.

Most doctors think that the risk–benefit ratio is currently weighted in favor of splenectomy over stem cell transplantation. However, over time, the risks associated with transplantation may decrease and this may be an option for more patients.

Please check out the other posts of our series here:

• What Is Pyruvate Kinase Deficiency?
• What Causes Pyruvate Kinase Deficiency and How Is It Diagnosed?
• How Will Pyruvate Kinase Deficiency Affect Me or My Child?

Information based on Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency  (Karger, 2019).

How Will Pyruvate Kinase Deficiency Affect Me or My Child?

This is the third part of our series about the condition based on our patient booklet “Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency”, which is freely available online. This article shows how pyruvate kinase deficiency will affect you or your child.

The symptoms and complications that you or your child experience may be very different from someone else with PK deficiency, as they vary widely between people. The hemolytic anemia caused by PK deficiency can vary from mild to severe, with a typical hemoglobin level of 6–12 g/dL. Normal hemoglobin levels in healthy individuals vary by age and sex, ranging from 10.5–16 g/dL.

Can You Predict Symptom Severity?

Patients and doctors often wonder if there are any laboratory tests or findings early in childhood that might predict the likelihood of certain symptoms, or indicate whether transfusions or a splenectomy might be needed later in life. Researchers are currently looking at these relationships.

To date, studies have found no relationship between the level of pyruvate kinase enzyme activity and the degree of hemolysis. One reason for this is that the most enzyme-deficient red blood cells break down before pyruvate kinase enzyme activity can be measured (i.e. the results of your enzyme activity test come from your healthiest or most PK-sufficient red blood cells).

People with more disruptive PKLR gene mutations are more likely to have complications.

People with lower hemoglobin levels have a higher likelihood of complications. However, anyone with PK deficiency can develop the complications described below.

Jaundice/Scleral Icterus

You may develop yellowing of the whites of your eyes (scleral icterus) and/or yellowing of your skin (facial jaundice) as a result of your PK deficiency. These signs may be apparent all the time or just in times of illness, dehydration or stress.

Although removal of the spleen (splenectomy) improves anemia for most people with PK deficiency, it does not resolve the issue of jaundice/scleral icterus, as the hemolytic process continues after splenectomy.

Why Do Some People Have More Jaundice than Others?

The degree of jaundice or scleral icterus is linked to your total unconjugated bilirubin level. This is determined both by the degree of hemolysis and by your ability to metabolize bilirubin, which is genetically determined.

People with Gilbert syndrome have an inherited abnormality (two copies of a non-working gene) that reduces the production of an enzyme involved in the processing of bilirubin in the liver (i.e. bilirubin is metabolized more slowly). Gilbert syndrome is common (affecting 5–15% of the population), so it is possible for someone to inherit both PK deficiency and Gilbert syndrome. People with Gilbert syndrome often have worsening of their everyday jaundice around the time of puberty.

Splenomegaly

Your spleen may become enlarged (splenomegaly) as a result of more red blood cells being broken down in the organ. The spleen can further increase in size during hemolytic episodes and/or if you have a viral infection. The spleen is typically enlarged in PK deficiency, but if you have a normal-sized spleen that does not exclude the diagnosis of PK deficiency or the likelihood of increased breakdown of red blood cells in the spleen. If you have severe anemia, removal of the spleen may be beneficial even if your spleen is a normal size.

An enlarged spleen does not typically cause pain. However, if your spleen is significantly enlarged, it may compress the stomach, making you feel full quickly when you eat. An enlarged spleen can also act as a sponge, causing transfused red blood cells and other blood cells (platelets and white blood cells) to get stuck, resulting in lower blood counts.

An enlarged spleen, when it can be felt below the rib cage, can be more at risk of injury, so your doctor is likely to recommend avoiding contact sports.

Hemolytic Episodes

Hemolytic episodes or crises develop in response to stressors or triggers of hemolysis. These are most often infections and, therefore, are more frequent in childhood. Pregnancy can also be a common hemolytic trigger.

During these episodes, you may find your everyday symptoms, such as fatigue, paleness, scleral icterus, jaundice and/or dark urine, get worse. Your spleen may also increase in size. Blood tests will reveal:

• decreased hemoglobin/hematocrit
• increased reticulocyte count
• increased bilirubin
• increased lactate dehydrogenase (a marker of red blood cell breakdown in the blood vessels).

Aplastic Crisis

An aplastic crisis is caused by parvovirus B19 infection (also known as Fifths disease). This common viral infection typically causes a high fever and facial rash.

In people with PK deficiency, parvovirus infection decreases hemoglobin and reduces or stops reticulocyte production in the bone marrow.

This infection can only occur once in your life and self-resolves like other viral infections. Testing for antibodies to parvovirus can diagnose a current or recent infection or a history of previous infection (i.e. immunity to the virus).

In PK deficiency, aplastic crises often require blood transfusions.

Gallstones

Gallstones are a frequent complication in children and adolescents with PK deficiency due to the increased release of unconjugated bilirubin.

Unlike dietary-related gallstones in middle-aged adults, you can develop pigmented (bilirubin) gallstones at any age. The risk of gallstones is life-long due to ongoing hemolysis and will continue even if you have your spleen removed.

Some people with gallstones have no symptoms, or you may have nausea or abdominal pain after eating. Gallstones can also get stuck in the organs and ducts that create and store bile (the biliary system) and can cause significant worsening of baseline jaundice.

Gallstones can also be associated with other complications, such as infection of the gallbladder (cholangitis) or inflammation of the pancreas (pancreatitis). If you are diagnosed with these problems your doctor is likely to recommend surgical removal of your gallbladder (cholecystectomy).

Iron Overload

Transfusion-related iron overload. Red blood cells contain iron, so every time you receive a blood transfusion you are putting more iron into your body. The body does not have a mechanism to remove the excess iron, so it can build up and damage your organs. The iron is most commonly deposited in the liver, but it can also be deposited in the heart and hormone-producing organs (endocrine organs).

Iron loading is not associated with symptoms until a significant amount of iron is deposited, so if you receive regular transfusions it is important you are closely monitored for iron loading and remain on treatment (chelation) to remove iron.

Non-transfusion-related iron overload. Even if you do not receive transfusions as part of your treatment, you may still be at risk for iron loading. Regular iron monitoring is important. Transfusion-independent iron loading is common in people with PK deficiency; it can occur at any age and in patients with any hemoglobin level.

Although transfusion-independent iron loading is not well studied in PK deficiency, it is thought that the body responds to the anemia by absorbing more iron, even though there is no iron deficiency. It is not clear why some people with PK deficiency absorb more iron than others. Care should be taken to avoid iron supplements (including multivitamins with iron) and excessive ingestion of foods high in iron (e.g. liver and red meat).

Extramedullary Hematopoiesis

When your body has to make an excessive number of red blood cells every day, blood cell production (hematopoiesis) can begin to occur outside of the bone marrow in organs such as the liver or spleen, or in other locations, such as around the spine or in the chest. This finding is usually diagnosed by a radiology scan and/or a tissue biopsy.

Extramedullary hematopoiesis is not a frequent complication in PK deficiency but is also not uncommon.

Low Bone Density

Low bone density is another potential complication of PK deficiency. The reason for this is not clear but it may be associated with the increased rate of red blood cell production in the bone marrow. You may find it beneficial to pay close attention to your vitamin D and calcium intake.

Infrequent Complications

Pulmonary hypertension (high blood pressure in the arteries in the lungs and the right side of the heart) is an infrequent complication of PK deficiency. It can be detected on routine screening tests, or may cause symptoms including shortness of breath and fatigue. Leg ulcers related to PK deficiency occur in some people, but the cause is not well understood; leg ulcers occur in other types of hemolytic anemia as well.

Other, less common, signs and symptoms may occur so be sure to ask your doctor about any symptoms or problems that you have.

Psychological Problems

The effects of chronic anemia and/or the treatments associated with PK deficiency can affect your psychological wellbeing. If you are feeling sad, or having difficulty sleeping or other mood-related symptoms, please consult your doctor.

Please check out the other posts of our series here:

• What Is Pyruvate Kinase Deficiency?
• What Causes Pyruvate Kinase Deficiency and How Is It Diagnosed?

Information based on Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency  (Karger, 2019).