Thalassemia Symptoms in Children vs. Adults: What to Watch For at Every Stage

 If you're reading this because a blood test came back with unexpected results — for your child, yourself, or someone you love — one of the first questions is usually simple: what does this actually feel like, and when?

The honest answer is: it depends. Thalassemia isn't one experience. Two people with the same diagnosis on paper can have very different lives, and the same person's symptoms can look different at age 2, 15, and 40. This guide walks through how symptoms tend to show up at each stage, so you know what's typical, what's worth a call to the doctor, and what's simply part of managing a lifelong condition.

For a refresher on the types of thalassemia mentioned here, see our complete overview of thalassemia and our guide to thalassemia minor vs. major.

Why Symptoms Vary So Much by Age

Thalassemia symptoms come from one root cause — reduced or abnormal hemoglobin production, which limits how well red blood cells carry oxygen. But how much that affects a person depends on the type and severity of thalassemia they have, and severity is closely tied to age of onset. The more severe forms tend to announce themselves early, often before a child's second birthday, while milder forms may stay silent for decades or never cause noticeable symptoms at all.

Symptoms in Infants and Young Children

Thalassemia Major (Cooley's Anemia)

This is the form most likely to cause visible symptoms early. According to the National Heart, Lung, and Blood Institute (NHLBI), children with more serious types of thalassemia often develop symptoms by around age 2, and many of the most serious forms are picked up through newborn screening before symptoms even appear.

When symptoms do show up in infancy, they commonly include:

• Pale skin, or yellowing of the skin and eyes (jaundice)
• Poor feeding and slow weight gain
• Irritability or unusual fussiness
• A swollen abdomen, caused by an enlarged spleen or liver
• Dark urine

Left unmanaged, these can progress to more serious issues — including stunted growth and complications affecting the heart, liver, and spleen — which is exactly why early diagnosis and ongoing care from a pediatric hematologist matter so much.

Thalassemia Intermedia

Symptoms of thalassemia intermedia tend to appear later than major and are usually milder day-to-day, but they still add up: pale or yellowish skin, an enlarged liver and spleen, gallstones, bone changes, and in some cases leg ulcers later in childhood or adolescence.

Thalassemia Minor (Trait)

This is the form most people never notice. Children with thalassemia minor may have mild anemia on a blood test but often have no symptoms at all — no fatigue, no visible signs, nothing that would prompt a visit to the doctor outside of routine bloodwork. It's frequently discovered by accident, or during carrier screening for family planning.

Adolescence: A Transition Period

For children with more significant forms of thalassemia who are receiving regular transfusions, adolescence is often when the cumulative effects of the condition — rather than new symptoms — start to matter more. Iron builds up in the body from years of transfusions, and this is often when doctors start watching more closely for early signs of iron-related complications, discussed below. This is also a stage where growth and puberty can be delayed compared to peers, which can be difficult emotionally even when it's medically expected.

Symptoms and Complications in Adults

Adults living with thalassemia, particularly thalassemia major or intermedia, are often managing two things at once: the underlying anemia, and the long-term effects of the disease and its treatment over time.

Iron Overload and Organ Effects

Because the body has no natural way to remove excess iron, and regular transfusions add iron faster than it can be processed, iron accumulation becomes a central concern in adulthood. Research has linked untreated iron overload to complications in the liver, heart, and endocrine glands. This is one of the most important reasons ongoing monitoring — not just symptom management — remains part of adult care.

Bone Health

Bone disease is common in adults with thalassemia major. Research published in Haematologica found that osteopenia and osteoporosis affect an estimated 40–50% of adults with thalassemia major, with contributing factors including anemia itself, iron overload, and hormone changes. Signs can include back pain, height loss, or fractures from minor injuries.

Endocrine and Fertility Effects

Iron overload can affect hormone-producing glands over time. A review published in Endocrine Reviews (Oxford Academic) notes that hypogonadism — reduced function of the reproductive glands — is the most common endocrine complication in transfusion-dependent thalassemia, with studies estimating it affects roughly a quarter to over half of patients in some cohorts. Thyroid function, blood sugar regulation, and growth hormone levels can also be affected, which is why adults with thalassemia are typically followed by an endocrinologist alongside their hematologist.

Emotional and Mental Health

It's worth naming something that often gets left out of symptom lists: living with a chronic condition since childhood, alongside physical complications that can appear in adulthood, has a real emotional weight. This isn't a symptom of thalassemia itself, but it's a common and valid part of the experience worth discussing with your care team.

Children vs. Adults: A Quick Comparison

	Children	Adults
Typical onset	Often by age 2 for severe forms	Ongoing management or newly surfacing complications
Common signs	Pallor, jaundice, poor growth, enlarged spleen	Fatigue, bone pain, hormone-related symptoms
Main clinical focus	Diagnosis, growth, starting treatment	Managing iron overload, organ monitoring
Mild forms (minor/trait)	Usually no symptoms	Usually no symptoms

When to Talk to a Doctor

Whether you're watching a child or managing your own health, it's worth reaching out to a hematologist if you notice new or worsening fatigue, unexplained pale skin or jaundice, bone pain, slowed growth in a child, or any new symptom that feels different from your usual baseline. Regular monitoring — even when you feel fine — is a core part of managing thalassemia at any age.

Medical Disclaimer

This article is for general educational purposes and is not a substitute for professional medical advice, diagnosis, or treatment. Thalassemia symptoms and complications vary significantly between individuals. Please consult your hematologist or care team about any symptoms you or your child are experiencing, and before making any decisions about monitoring or care.

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Frequently Asked Questions

What are the first signs of thalassemia in a baby? The earliest signs of more serious forms often include pale skin, poor feeding, slow weight gain, and a swollen abdomen, usually appearing by around age 2.

Does thalassemia minor (trait) cause symptoms? Usually not. Most people with thalassemia minor have mild anemia detectable only on blood tests, without noticeable symptoms.

Can thalassemia symptoms first appear in adulthood? Milder forms can go unnoticed for years and sometimes surface during routine bloodwork, pregnancy screening, or when investigating unrelated fatigue. More severe forms are almost always identified in early childhood.

What are the long-term complications of thalassemia major in adults? Common long-term concerns include iron overload affecting the heart and liver, bone density loss, and endocrine issues such as thyroid or reproductive hormone changes — all of which are actively monitored as part of ongoing care.

Are thalassemia symptoms different in children versus adults? Yes. In children, especially with severe forms, symptoms often center on growth, anemia, and organ enlargement. In adults, the focus shifts toward long-term complications from the condition and its treatment, such as iron overload and bone health.

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Sources

• National Heart, Lung, and Blood Institute (NHLBI) — Thalassemia: Symptoms, nhlbi.nih.gov/health/thalassemia/symptoms
• Nationwide Children's Hospital — Beta Thalassemia in Children
• Children's Health / Children's Minnesota — Thalassemia in Children
• Haematologica — Iron overload and osteoporosis in thalassemia major patients, haematologica.org/article/view/7229
• Endocrine Reviews (Oxford Academic) — Bone Disease in Thalassemia: A Molecular and Clinical Overview
• American Society of Hematology (ASH) — Impact of Bone Disease and Pain in Thalassemia

 

Thalassemia Minor vs Major: Key Differences Explained

"Minor" and "major" are two of the first words people hear after a thalassemia diagnosis or a carrier screening result — and they can sound almost casual, like the difference between a small problem and a big one. In reality, they describe very different genetic situations with very different day-to-day implications. Here's what actually separates them.

If you haven't already, our overview of what thalassemia is is a good starting point before this post — it covers the basics this one builds on.

The Short Version

The difference comes down to how many altered genes you've inherited, not how "bad" your case happens to be by chance.

• Thalassemia minor (also called thalassemia trait): you've inherited one altered gene. This is a carrier condition that typically causes mild anemia symptoms, if any. NHLBI
• Thalassemia intermedia: a middle ground, causing moderate anemia, usually from inheriting two altered genes with milder effects. NHLBI
• Thalassemia major (Cooley's anemia, for the beta form): you've inherited two altered genes, one from each parent. This causes serious anemia symptoms and typically requires lifelong medical management. NHLBI

Thalassemia Minor: The Carrier Form

If you have thalassemia minor, you have one normal gene and one altered gene. Red blood cells are smaller than normal (microcytic) and lower in hemoglobin (hypochromic), but most people with thalassemia minor have no symptoms at all, or only mild, easy-to-miss ones. NHLBI

This is actually one of the more important — and more commonly misunderstood — parts of the thalassemia spectrum, because it's frequently mistaken for iron-deficiency anemia. The blood work can look superficially similar, but the underlying cause and the right response are completely different. Treating thalassemia minor as if it were iron deficiency can lead to unnecessary iron supplementation or unneeded diagnostic testing — which is exactly why an accurate diagnosis from a doctor, rather than a guess based on a single test result, matters here. NHLBINHLBI

People with thalassemia minor generally don't need ongoing treatment. The main relevance of a minor/trait diagnosis is for family planning — if you're a carrier and your partner is too, there's a meaningful chance of having a child with a more serious form. We'll cover exactly what that looks like in our upcoming carrier screening post.

Thalassemia Intermedia: The Middle Ground

Thalassemia intermedia doesn't get talked about as much as minor or major, but it's a real and distinct category — not just "a mild version of major." It was first identified decades ago, when clinicians needed a term for patients who were too severely affected to be called minor but too mildly affected to be called major. nih

People with thalassemia intermedia are grouped with what's sometimes called non-transfusion-dependent thalassemia — some have only mild anemia and need occasional transfusions, if any, while others present earlier in childhood with more noticeable effects on growth and development. Unlike thalassemia major, intermedia generally doesn't require regular lifelong transfusions, though iron overload and related complications can still develop over time, just more gradually. β-Thalassemia Intermedia: A Bird’s-Eye View +2

Because intermedia covers such a wide range of severity, it's genuinely one of the harder forms to generalize about — which makes an individual hematologist's assessment more important here than almost anywhere else on the spectrum.

Thalassemia Major: The Most Serious Form

Thalassemia major — also known as Cooley's anemia for the beta form — happens when both copies of the relevant gene are significantly altered. Without treatment, this leads to growth delays, paleness, jaundice, an enlarged liver and spleen, and skeletal changes from the bone marrow working in overdrive to compensate.

With proper care, the picture is very different. Regular blood transfusions are the main treatment for thalassemia major, giving the body red blood cells with healthy hemoglobin on an ongoing basis. A stem cell transplant is currently the only treatment that can potentially cure thalassemia, though it isn't the right option or available match for every patient. Because regular transfusions lead to iron building up in the body over time, iron chelation therapy — treatment to remove excess iron — becomes a standard part of managing thalassemia major long-term. nihnih

This is a lot to take in, and it's also, importantly, a manageable one. Thalassemia major is typically caught early — often through newborn screening — which means treatment usually starts before symptoms become severe.

Why the Distinction Actually Matters

Beyond the label itself, minor vs. intermedia vs. major changes real things: whether you need ongoing hematology care, whether family planning conversations matter, and what kind of monitoring makes sense going forward. If you're not sure which category applies to you or your child, that's worth confirming directly with your care team rather than inferring it from symptoms or a single test result — the categories can overlap enough at the edges that it takes clinical judgment, not just a lab value, to sort out.

Frequently Asked Questions

Is thalassemia minor dangerous?
Generally no — most people with thalassemia minor have mild symptoms or none at all and don't need treatment. Its main significance is usually for family planning, since two carriers can have a child with a more serious form.

Can thalassemia minor turn into major?
No. Your form of thalassemia is set by the genes you inherited at birth — it doesn't progress from minor to major over time the way some conditions worsen with age.

Is thalassemia intermedia the same as thalassemia major?
No, though there's overlap. Intermedia generally involves less severe anemia and, for many patients, doesn't require the same regular lifelong transfusion schedule that major typically does — though severity varies enough that it needs individual evaluation.

Does thalassemia minor need treatment?
Usually not. It's typically monitored rather than actively treated, though your doctor may still want to confirm the diagnosis to rule out other causes of similar blood test results.

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This article is for general educational purposes and isn't a substitute for medical advice. If you have questions about your specific diagnosis or symptoms, please talk to your hematologist or care team.

Sources:

• National Heart, Lung, and Blood Institute (NHLBI), NIH — Causes, Treatment
• ScienceDirect Topics — Thalassemia Minor (clinical overview)
• NCBI Bookshelf — Guidelines for the Clinical Management of Thalassaemia (Thalassaemia Intermedia)
• PMC — β-Thalassemia Intermedia: A Bird's-Eye View

 

What Is Thalassemia? Types, Causes & Complete Overview

If you've just been told you or your child has thalassemia — or that you're a carrier — you probably have more questions than answers right now. That's normal. Thalassemia is a lifelong condition, but it's also one of the most well-understood inherited blood disorders in medicine, and most people who have it go on to live full lives with the right care and support.

This guide is meant to be the starting point: a clear overview of what thalassemia is, why it happens, and what the different types mean. We'll link out to deeper posts on diagnosis, treatment, and daily life as they're published, so think of this as your home base.

What Is Thalassemia?

Thalassemia is an inherited blood disorder that affects how your body makes hemoglobin — the protein inside red blood cells that carries oxygen around your body. If you have thalassemia, your body doesn't produce enough normal hemoglobin, which means your red blood cells can't do their job as well, and you end up with fewer healthy red blood cells overall. This is a form of anemia, and depending on the type and severity, it can range from something you'd barely notice to a condition that needs lifelong medical care.

It's worth pausing on one distinction that trips a lot of people up: thalassemia is not the same as the anemia caused by low iron or poor diet. Iron-deficiency anemia happens because your body doesn't have enough iron to make hemoglobin. Thalassemia happens because of a genetic change that affects how hemoglobin is built, regardless of how much iron you have. This matters clinically too — taking iron supplements for thalassemia-related anemia, without a doctor's guidance, can actually cause harm rather than help, since iron overload is already a risk for many people with thalassemia. If you're not sure which one you're dealing with, that's a conversation for your doctor, not a guess based on symptoms alone.

What Causes Thalassemia?

The genetics — how it's passed down

Thalassemia is inherited, meaning it's passed from parent to child through genes. Hemoglobin is built from two types of protein chains, alpha and beta, and thalassemia happens when a genetic change disrupts the production of one of these chains.

Because it takes specific gene combinations to cause the more serious forms, thalassemia typically requires that both parents pass along an altered gene. If a child inherits just one altered gene, they usually become a carrier (sometimes called having "thalassemia trait" or "thalassemia minor") — generally with mild or no symptoms, but able to pass the gene to their own children. If a child inherits altered genes from both parents, the condition is usually more serious. <cite index="5-1">For beta thalassemia specifically, each child of two carrier parents has a 25% chance of inheriting two normal genes, a 50% chance of becoming a carrier, and a 25% chance of inheriting the more serious form</cite>. This is exactly why carrier screening before pregnancy matters so much — we'll cover that in a dedicated post.

Why some communities are affected more than others

<cite index="5-1">Thalassemia occurs most often among people of South Asian, Italian, Greek, Middle Eastern, and African descent</cite>, and it's also common throughout Southeast Asia. Researchers believe this pattern exists because carrying a single altered gene historically offered some protection against malaria — which is part of why these gene variants persisted in regions where malaria was widespread. <cite index="18-1">Globally, an estimated 270 million people carry a thalassemia or related hemoglobin gene variant, with somewhere around 80 to 90 million of those being beta thalassemia carriers specifically</cite>. If your family traces back to any of these regions, carrier screening is worth asking your doctor about — even if no one in your family has ever been diagnosed, since many carriers have no symptoms at all.

The Main Types of Thalassemia

Thalassemia isn't one single condition — it's a spectrum, and the terminology can be confusing at first.

Alpha thalassemia vs. beta thalassemia: <cite index="4-1">these are the two main types, and each depends on which part of the hemoglobin protein — alpha globin or beta globin — isn't being made correctly</cite>. Alpha thalassemia tends to be more common in people of Southeast Asian, South Asian, and African descent; beta thalassemia is more strongly associated with Mediterranean, Middle Eastern, and South Asian ancestry, though there's real overlap.

Trait / minor, intermedia, and major: within each type, severity is usually described in these terms:

• Trait (minor): you carry one altered gene. <cite index="5-1">This usually causes only mild anemia symptoms, if any</cite>.
• Intermedia: a moderate form, with anemia that's more noticeable but doesn't always require the same intensive treatment as major forms.
• Major: the most serious form, <cite index="5-1">also known as Cooley's anemia when referring to beta thalassemia major</cite>, which typically requires regular blood transfusions and lifelong monitoring.

On the alpha thalassemia side specifically, the most serious form — where very little or no alpha globin is produced — is called Hb Bart syndrome, which is diagnosed before or at birth and is extremely serious; the milder serious form is hemoglobin H disease, which usually causes moderate to serious symptoms but is compatible with life. We'll go deeper on each of these distinctions, including alpha vs. beta specifically, in an upcoming post.

Common Symptoms

Symptoms vary enormously depending on type and severity — that's part of what makes thalassemia hard to explain in one sentence. <cite index="3-1">Some people have no symptoms at all, while children with more serious forms often start showing signs by around age two</cite>. When symptoms do appear, they can include:

• Fatigue and weakness
• Pale or yellowish skin (jaundice)
• <cite index="3-1">A larger-than-normal spleen or liver, which can cause a swollen abdomen</cite>
• Slow growth in children
• Bone changes, particularly in the face, in more serious untreated cases

We're keeping this list general on purpose — symptoms in children and adults show up differently enough that it deserves its own post, which is coming soon.

How Thalassemia Is Diagnosed

Diagnosis usually starts with routine bloodwork — often a complete blood count (CBC) that turns up unusually small red blood cells (a clue doctors call microcytosis) — followed by more specific tests like hemoglobin electrophoresis, which identifies the different types of hemoglobin in your blood, and sometimes genetic testing to confirm which genes are involved. <cite index="3-1">More serious forms are frequently caught through routine newborn screening</cite>, which is part of why many parents first hear the word "thalassemia" in their baby's first days of life.

We'll walk through exactly what these tests measure and what your results might mean in a dedicated diagnosis post — this section is just the map, not the full territory.

How Thalassemia Is Managed

Management depends heavily on type and severity, and this is genuinely a conversation to have with a hematologist rather than something to self-manage from general information online. In broad strokes, care can include regular monitoring, blood transfusions for more serious forms, treatment to manage the iron overload that transfusions can cause over time, and in some cases, a bone marrow or stem cell transplant. Newer approaches, including gene therapy, are also changing what's possible for some patients.

We'll cover transfusions, iron overload management, and the latest treatment developments — including gene therapy — in their own posts, since each deserves real depth. If you take one thing from this section, let it be this: thalassemia management is highly individual, and your care team is the right source for decisions about your specific situation.

Living With Thalassemia

A diagnosis — for yourself or your child — can feel overwhelming at first. It's worth saying plainly: this is a condition people build full, meaningful lives around, not despite. Community matters here, and so does hearing from people who've actually lived it.

If you want to hear directly from someone managing thalassemia major day to day, Daniella Macolino's story is a good place to start, alongside Robert Mannino's patient profile — both offer a more personal window into what daily life can look like than a clinical overview ever could. We'll also be publishing a dedicated post on the emotional and mental health side of living with a chronic condition, because that part deserves just as much attention as the physical side.

Frequently Asked Questions

Is thalassemia the same as anemia? Not exactly. Thalassemia causes a type of anemia, but "anemia" is a broad term that covers many causes, including iron deficiency, which is a completely different issue with a different treatment approach.

Can thalassemia be cured? For most people, thalassemia is a lifelong condition managed through monitoring and treatment rather than cured. Bone marrow/stem cell transplant can be curative for some patients in specific circumstances, and gene therapy is an emerging option — both are worth discussing with a hematologist to understand if they're relevant to your situation.

Is thalassemia contagious? No. It's a genetic condition passed from parent to child — it can't be transmitted between people through contact, illness, or any other exposure.

Can two carriers have a healthy child? Yes — carrier status doesn't guarantee an affected child. As noted above, when both parents are carriers, there's still a meaningful chance of a child inheriting no altered genes or being a carrier without symptoms. Genetic counseling can walk through the actual odds for your specific situation.

Is thalassemia the same as sickle cell disease? No, though they're often mentioned together. Both are inherited hemoglobin disorders and both are more common in overlapping populations, but they involve different genetic changes and different disease patterns. We'll cover this comparison in more depth in an upcoming post.

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This article is for general educational purposes and isn't a substitute for medical advice. If you have questions about a diagnosis, symptoms, or treatment, please talk to your hematologist or care team.

Sources:

• National Heart, Lung, and Blood Institute (NHLBI), NIH — What Is Thalassemia, Causes, Symptoms
• StatPearls (NCBI Bookshelf) — Thalassemia
• Global Globin Network / PMC — carrier prevalence estimates

Three people with inherited diseases successfully treated with CRISPR

By Michael Le Page

Sickle cell disease can distort red blood cells

Stocktrek Images, Inc/Alamy

Two people with beta thalassaemia and one with sickle cell disease no longer require blood transfusions, which are normally used to treat severe forms of these inherited diseases, after their bone marrow stem cells were gene-edited with CRISPR.

Result of this ongoing trial, which is the first to use CRISPR to treat inherited genetic disorders, were announced today at a virtual meeting of the European Hematology Association.

“The preliminary results… demonstrate, in essence, a functional cure for patients with beta thalassaemia and sickle cell disease,” team member Haydar Frangoul at Sarah Cannon Research Institute in Nashville, Tennessee, said in a statement.

Beta thalassaemia and sickle cell disease are conditions caused by mutations that affect haemoglobin, the protein that carries oxygen in red blood cells. Those with severe forms require regular blood transfusions.

However, a few people with the disease-causing mutations never show any symptoms, because they keep producing fetal haemoglobin in adulthood. Normally, fetal haemoglobin stops being produced soon after birth.

This discovery has inspired the development of treatments based on boosting fetal haemoglobin. In this trial, run by collaborating companies CRISPR Therapeutics and Vertex, bone marrow stem cells are removed from people and the gene that turns off fetal haemoglobin production is disabled with CRISPR.

The remaining bone marrow cells are killed by chemotherapy, then replaced by edited cells. This is done to ensure that new blood cells are produced by the edited stem cells, but the chemotherapy can have serious side effects including infertility.

The first two patients with beta thalassaemia no longer need blood transfusions since being treated 15 and five months ago. Nor does the patient with sickle cell disease, nine months after treatment.

The results are excellent, says Marina Cavazzana at the Necker-Enfants Malades Hospital in Paris, France, whose team has treated a 13-year-old boy with sickle cell disease using a different approach.

Although the three patients did experience some adverse effects due to the chemotherapy, the CRISPR gene editing appears safe. However, the patients may need to be monitored for the rest of their lives to be sure it has no adverse effects, says Cavazzana.

Altogether five people have now been treated. The trial was put on hold because of the coronavirus pandemic, but has now resumed.

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Longer Life Expectancy is Possible for Some Sickle Cell Disease Patients, Case Study Contends

By Alice Melao

A published case study reports that patients with mildly symptomatic sickle cell disease (SCD) can exceed the U.S. median life expectancy  of 47 years for patients with the disease if it is managed properly.

The report published in Blood, the Journal of the American Society of Hematology, “Case series of octogenarians with sickle cell disease,” analyzes four women diagnosed with milder forms of SCD who have lived as long as 86 years.

“For those with mild forms of SCD, these women show that lifestyle modifications may improve disease outcomes,” stated Samir K. Ballas, MD, professor emeritus in the Department of Medicine at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, and principal author of the case study.

Ballas went on to explain that strong and long-term family support are important factors for the reported long life expectancy and high quality of life of the SCD patients. Moreover, strict adherence to medication and appointments also were reported as being highly important for the disease outcome.

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“It is very likely that their healthy lifestyles were important contributors to their longevity,” said Ballas. “All of the women were non-smokers who consumed little to no alcohol and maintained a normal body mass index. This was coupled with a strong compliance to their treatment regimens and excellent family support at home,” he said.

The four cases studied in this report were considered by Ballas to be “desirable” disease states. “These women never had a stroke, never had recurrent acute chest syndrome, had a relatively high fetal hemoglobin count [which helps to prevent cells from sickling], and had infrequent painful crises. Patients like this usually — but not always — experience relatively mild SCD, and they live longer with better quality of life,” Ballas said.

Nevertheless, Ballas points out that this study included only four participants and all were women. Given so, more studies with a broader group of study is still required.

In summary, Ballas is hopeful that the stories of these four women can serve as examples for SCD patients. “I would often come out to the waiting room and find these ladies talking with other SCD patients, and I could tell that they gave others hope, that just because they have SCD does not mean that they are doomed to die by their 40s — that if they take care of themselves, and live closely with those who can help keep them well, that there is hope for them to lead long, full lives,” the author concluded.

Promising Gene Therapy For Sickle Cell Ready for Clinical Trial

By Alexandra Anderson PhD

A new engineered gene therapy virus, inserted into blood stem cells and then transplanted into mice with sickle cell disease, markedly reduced red blood cell damage according to the study “Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype,” published in theJournal of Clinical Investigation.

A clinical gene therapy trial is expected in the coming year in which researchers will use a gene manipulated harmless virus to prevent the “sickling” of red blood cells. The new gene therapy is based on research going back to the 1980s which revealed that people with a milder form of sickle cell disease carried a fetal form of hemoglobin.

Hope and Destiny: The Patient and Parent's Guide to Sickle Cell Disease and Sickle Cell Trait
This form is present in the human fetus and normally tapers off after birth. It differs most from “adult” (beta) hemoglobin because it is able to bind oxygen to a larger extent and is not seen to “sickle”.

In later studies, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center researchers showed that suppressing a gene (BCL11A) that acts as an “off-switch” on the fetus hemoglobin, could restart the production again. With this approach the team was able to replace much of adult hemoglobin with the fetus form, in mice with sickle cell disease.

Dr. David A. Williams and colleagues from the center later adopted the approach.

“BCL11A represses fetal hemoglobin and also activates ‘adult’ hemoglobin, which is affected by the sickle-cell mutation,” Williams, the study’s senior author, said in a news release. “So when you knock BCL11A down, you simultaneously increase fetal hemoglobin and repress sickling hemoglobin, which is why we think this is the best approach to gene therapy in sickle cell disease.”

The new team tried to turn this insight into a therapy approach but they faced a problem. They discovered that the BCL11A gene also plays an important role in blood stem cells — which caused serious problems with the general blood development.

After some engineering in which the team used different gene techniques to silence the “switch-off” gene, without influencing the general blood development, they inserted the whole package into a lentivirus made for safe use in humans. Blood stem cells treated with this gene therapy were then successfully transplanted into mice and reduced the signs of sickle cell disease.

Additionally, in red blood cells from mice and four patients with the disease, the fetal hemoglobin surpassed the sickling “adult” hemoglobin, making up at least 80 percent of the total hemoglobin in the cell. According to the researchers, these results are more than enough to avoid the disease.

Williams believes this gene therapy approach will substantially increase the ratio of non-sickling versus sickling hemoglobin in patients, and his team is now taking the final steps toward FDA clearance for a clinical gene-therapy trial in sickle cell disease, that is expected to begin in early 2017.

New Biophysical Markers Could Help Develop Treatments for Sickle Cell Disease

by Dr. Trupti Shirole

Sickle cell disease is an inherited blood disorder that affects an estimated 80,000 to 100,000 Americans each year. People with sickle cell disease have an abnormal form of hemoglobin, a protein found in red blood cells that carry oxygen throughout the body.

Normal red blood cells are flexible discs that easily bend and stretch to flow through the body's narrow blood vessels. In sickle cell disease, the abnormal hemoglobin forms fibers that cause the blood cells to take on a flattened, sickled shape and stiffen when they lose oxygen. This change in shape and rigidity causes the red blood cells to be stuck in the blood vessels and prevents the transport of oxygen to the surrounding tissue. This can cause anemia and extreme pain and impact the health of the body's tissue and organs. 

Currently, hydroxyurea is the only FDA-approved drug for sickle cell disease. The drug reduces sickling in red blood cells and is used to treat pain and reduce the need for blood transfusions in some patients, but it does not work in all patients. Researchers have been divided over what mechanisms cause the drug to work. Some believe it works by reactivating fetal hemoglobin, which is better at transporting oxygen than the abnormal hemoglobin that causes sickling. Others believe it works by increasing the volume of red blood cells, reducing the concentration of sickle hemoglobin. 
An interdisciplinary, international group of researchers has found new biophysical markers that could help improve the understanding of treatments for sickle cell disease, a step toward developing better methods for treating the inherited blood disorder.

"There is a critical need for patient-specific biomarkers that can be used to assess the effectiveness of treatments for sickle cell disease," said Subra Suresh, president of Carnegie Mellon University and co-author of the study. "This study shows how techniques commonly used in engineering and physics can help us to better understand how the red blood cells in people with sickle cell disease react to treatment, which could lead to improved diagnostics and therapies."

The findings from engineers, physicists and clinicians from Carnegie Mellon, the University of Pittsburgh, the Massachusetts Institute of Technology, Florida Atlantic University, Korea University, the Korea Advanced Institute of Science and Technology, and Harvard University will be published this week in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).

In the current study, the international research team evaluated the biophysical properties - shape, surface area and volume - and biomechanical properties - flexibility and stickiness - of red blood cells under normal oxygenated conditions using electromagnetic waves to measure small differences in physical properties. The technique, known as common-path interferometric microscopy, allowed researchers to get a three-dimensional view of the cells.

Using blood samples from patients with sickle cell disease, the researchers separated red blood cells into four groups based on their density. Normal, disc-shaped red blood cells were the least dense, while severely sickled cells were the most dense. They then took samples from people receiving hydroxyurea treatment and those not receiving treatment. The red blood cells of those receiving treatment showed an improvement in all of the biophysical and biomechanical properties tested across all density levels. Furthermore, improvement in the physical properties of red blood cells of people treated with hydroxyurea correlated more with an increase in the red blood cell volume than with levels of fetal hemoglobin.

"Our findings shine a light on the mechanism behind hydroxyurea action, which has long been debated in the scientific community," said Ming Dao, principal research scientist in MIT's Department of Materials Science and Engineering and co-author of the study. "It's exciting to see that using the latest optical imaging tools, we can now confirm which one is the dominating mechanism. Understanding the key mechanism of action will allow us to explore novel and improved therapeutic approaches for sickle cell disease."

The researchers hope that these biophysical markers can be combined with biochemical and molecular-level markers to assess things like the severity of a patient's sickle cell disease, determine whether or not a patient will respond to hydroxyurea treatment and monitor the effectiveness of that treatment.

Sickle Cell Natural Healing: A Mother's Journey
 Source: Eurekalert

Gene editing of blood stem cells can correct disease-causing mutations

Recent advances in gene editing technology, which allows for targeted repair of disease-causing mutations, can be applied to hematopoietic stem cells with the potential to cure a variety of hereditary and congenital diseases. Gene editing can overcome many of the obstacles associated with gene addition therapies, but this young field still faces many challenges before it is ready for human testing, as discussed in a Review article published in Human Gene Therapy.

The article entitled "Gene Editing of Human Hematopoietic Stem and Progenitor Cells: Promise and Potential Hurdles" is part of a special joint issue on stem cell gene therapy in Human Gene Therapy and Stem Cells & Development guest edited by Luigi Naldini, MD, Scientific Director, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy. A special "upside-down" print issue will be distributed at ESGCT/ISSCR Florence 2016 in October.
Gene Editing, Epigenetic, Cloning and Therapy 

Kyung-Rok Yu, Hannah Natanson, and Cynthia Dunbar, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, describe how earlier gene addition strategies and the hurdles they encountered have informed the current development of gene editing approaches. The authors present the state-of-the-art in gene editing technology and the potential to apply these novel techniques to repair genetic flaws in hematopoietic stem cells, which give rise to the different types of cells in blood, and then to test those strategies in human clinical trials.
"Gene editing is the hottest new technology in gene therapy. The use of this approach to genetically modify hematopoietic stem and progenitor cells is very promising, but requires a careful assessment," says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA. "This mini-review by Dr. Dunbar's group at NIH provides a very insightful analysis of recent advances and current limitations of this approach

Smartphone App may offer needle free way to screen Blood for Anemia

Carolina Henriques:

Engineers and computer scientists from the University of Washington (UW) have developed what they are calling a HemaApp, designed to detect hemoglobin concentration using simply a smartphone camera and a little extra lighting — rather than needles or an expensive, specialized machine.

Measuring hemoglobin, a protein found in red blood cells, is particularly important for people with anemia and other blood disorders, who require frequent blood draws. The app is also thought to detect abnormal hemoglobin properties, which could help screen for diseases such as sickle cell anemia.

Described in an article that won a  ‘Best Paper’ award, HemaApp will be presented at the Association for Computing Machinery’s 2016 International Joint Conference on Pervasive and Ubiquitous Computing (UbiComp 2016), taking place on Sept. 15 in Germany.

Healthcare providers now measure hemoglobin levels by drawing blood with a needle or an intravenous line, or by using Masimo Pronto, an U.S. Food and Drug Administration (FDA)-approved device that measures hemoglobin noninvasively by clipping a sensor onto a person’s finger. The device, however, is too expensive for many medical facilities worldwide.

“In developing countries, community health workers have so much specialized equipment to monitor different conditions that they literally have whole bags full of devices,” Edward Wang, the study’s lead author and UW electrical engineering doctoral student, said in a press release. “We are trying to make these screening tools work on one ubiquitous platform — a smartphone.”

HemaApp works by analyzing the color of  blood when light is shone from the phone’s camera — with a little help, for now, from external lighting — through a patient’s fingers, and then estimating hemoglobin concentrations. By analyzing how colors are absorbed and reflected across wavelengths, it can detect concentrations of hemoglobin and other components, like plasma.

HemaApp was tested in an initial trial including 31 patients. Requiring only one smartphone modification, HemaApp performed as well as the Masimo Pronto, the researchers said.

To make sure that the technology works on different skin tones and body masses, the team developed processing algorithms that use the patient’s pulse to differentiate between the properties of the patient’s blood and the physical aspects of the patient’s finger.

The UW team tested the app under three different scenarios: using the smartphone camera’s flash alone, in combination with a common incandescent lightbulb, and with a low-cost LED lighting attachment – additional light sources fall onto other sections of the electromagnetic spectrum that aren’t now found on all smartphone cameras.

“New phones are beginning to have more advanced infrared and multi-color LED capabilities,” said Shwetak Patel, the paper’s senior author and an endowed professor in Computer Science and Engineering and Electrical Engineering at UW. “But what we found is that even if your phone doesn’t have all that, you can put your finger near an external light source like a common lightbulb and boost the accuracy rates.”

In the initial studies, HemaApp’s hemoglobin measurements had a 69% correlation to a patient’s complete blood count (CBC) test, a 74% correlation when using a common incandescent light bulb, and an 82% correlation using a small circle of LED lights attached to the phone. Masimo Pronto scored an 81% correlation to the blood test.

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The app is not meant to replace blood tests, but results suggest that it could be an effective and affordable screening tool to determine if blood testing is needed.  When used in anemia screening, HemaApp accurately identified 79% of the cases of low hemoglobin levels and 86% when aided with light sources.

“Anemia is one of the most common problems affecting adults and children worldwide,” said Doug Hawkins, a UW Medicine, Seattle Children’s Hospital, and Seattle Cancer Care Alliance pediatric cancer specialist. “The ability to screen quickly with a smartphone-based test could be a huge improvement to delivering care in limited-resource environments.”

MegaFood - Blood Builder, Promotes Healthy Blood Cell Production & Circulation, 90 Tablets (Premium Packaging) Further research steps include further testing of HemaApp to collect additional data and improve accuracy rates. The research project received financial assistance from the Washington Research Foundation.