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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Stem cell transplant cures children with sickle cell anemia, says Alberta hospital

7 girls, 2 boys cured in what lead doctor considers unprecedented treatment

By Lisa Monforton,

Cardelia Fox has a tattoo on the inside of her right forearm with the words "Set free." 

It's a reminder of how a cutting-edge transplant at the Alberta Children's Hospital cured her of sickle cell anemia and a life of hospital stays and blood transfusions.

The chronic genetic blood disorder caused Fox to have three childhood strokes — the first when she was only six months old. She would have two more at age six and 10.

Until the age of 17, she had been in and out of hospital and previously needed to have monthly life-saving blood transfusions.

The year Fox turned 17 she was one of the first patients to undergo the stem cell transplant procedure at the Alberta Children's Hospital.

The success of the procedure has captured interest from around the world, says Dr. Greg Guilcher, a pediatric oncologist who leads the sickle cell blood and marrow transplant program in Calgary.

Dr. Greg Guilcher is the lead doctor for the stem cell transplant procedure at Alberta Children's Hospital.

"To our knowledge, no one else is offering this protocol in children with sickle cell anemia," said Guilcher, who is also an assistant professor in the departments of oncology and pediatrics at the University of Calgary's Cumming School of Medicine.

What sets the Calgary procedure apart from other sickle cell anemia cures in young children is the lead up to the transplant. 

"​This protocol uses the 'lightest' doses of medication — no chemotherapy but immune suppressing drugs only, with a low dose of radiation," said Dr. Guilcher in a statement. 

While the protocol was developed and is used in the U.S., Dr. Guilcher said he's not aware of any other hospital using it on children.

More exciting is the fact that there have been no incidents of stem cell rejection. 

"We're getting phone calls and emails from around the world from interested parents and other doctors. We think we're ahead of the curve in offering this curative therapy as a standard of care."

Sickle cell anemia is a chronic illness where blood vessels can become blocked when blood cells change into a sickle shape, potentially affecting every organ and causing strokes, lung disease heart strain and spleen and bone damage. With advanced drug therapy treatment, life expectancy is 55- to 60-years-old.

The success of the procedure, which was first performed in Calgary in 2009, has cured seven girls and two boys to date.

Life-changing, says patient

"Before the stem cell transplant I felt like I was trapped," says Fox, whose sister Tamika Allen was a perfect match — a rare one in five occurrence within families. "Without this treatment I would likely still be at Foothills getting blood transfusions every month."

Tamika Allen, left, was a perfect stem cell match to her sister Cardelia Fox, which allowed her to have a procedure curing her of sickle cell anemia. (CBC)

Once Allen found out she was a full match, she didn't think twice about helping her sister.

Without a family match, the transplant procedure is generally considered too risky to perform.

"When we learned I was a match there was never any question of whether or not I'd do it," said Tamika, now 22. "Of course I'm going to do this for my sister. It was such a good feeling to be able to help make her life better — now I call her my mini-me."

Rising incidence in Canada

People of African descent are most often affected by sickle cell anemia. One parent can pass on the mutation and not cause the illness, but the illness results when both parents pass it on.

Fox's grandmother died at the age of 35 because of complications from the disease.

In 2008, the Sickle Cell Clinic at the children's hospital regularly treated 16 children.

Now there are more than 80, primarily because of immigration, says Dr. Mike Leaker. He is the head of the clinic, which sees patients from Alberta, Saskatchewan and eastern B.C.

"We now have some excellent medications that can change the course of the illness for many patients," said Leaker. "But a drug is still a treatment, not a cure. For families the word 'cure' is incredibly powerful."

Guilcher is expecting continued interest in the procedure from around the world

Sickle Cell Anemia: From Basic Science to Clinical Practice

Cure for sickle cell in adults validated

Source:

University of Illinois at Chicago

Summary:

Physicians have cured 12 adult patients of sickle cell disease using a unique procedure for stem cell transplantation from healthy, tissue-matched siblings. The new technique eliminates the need for chemotherapy to prepare the patient to receive the transplanted cells and offers the prospect of cure for tens of thousands of adults suffering from sickle cell disease.

Ieshea Thomas was the first adult to be cured of sickle cell disease with the chemotherapy-free procedure at UI Health.

Credit: Image courtesy of University of Illinois at Chicago

Physicians at the University of Illinois Hospital & Health Sciences System have cured 12 adult patients of sickle cell disease using a unique procedure for stem cell transplantation from healthy, tissue-matched siblings.

The transplants were the first to be performed outside of the National Institutes of Health campus in Maryland, where the procedure was developed. Physicians there have treated 30 patients, with an 87 percent success rate. The results of the phase I/II clinical trial at UI Health, in which 92 percent of treated patients were cured, are published online in the journal Biology of Blood & Marrow Transplantation.
The new technique eliminates the need for chemotherapy to prepare the patient to receive the transplanted cells and offers the prospect of cure for tens of thousands of adults suffering from sickle cell disease.
About 90 percent of the approximately 450 patients who have received stem cell transplants for sickle cell disease have been children. Chemotherapy has been considered too risky for adult patients, who are often more weakened than children by the disease.
"Adults with sickle cell disease are now living on average until about age 50 with blood transfusions and drugs to help with pain crises, but their quality of life can be very low," says Dr. Damiano Rondelli, chief of hematology/oncology and director of the blood and marrow transplant program at UI Health, and corresponding author on the paper.
"Now, with this chemotherapy-free transplant, we are curing adults with sickle cell disease, and we see that their quality of life improves vastly within just one month of the transplant," said Rondelli, who is also the Michael Reese Professor of Hematology in the UIC College of Medicine. "They are able to go back to school, go back to work, and can experience life without pain."
Sickle cell disease is inherited. It primarily affects people of African descent, including about one in every 500 African Americans born in the U.S. The defect causes the oxygen-carrying red blood cells to be crescent shaped, like a sickle. The misshapen cells deliver less oxygen to the body's tissues, causing severe pain and eventually stroke or organ damage.
Sickle Cell Natural Healing: A Mother's Journey
Doctors have known for some time that bone marrow transplantation from a healthy donor can cure sickle cell disease. But few adults were transplanted because high-dose chemotherapy was needed to kill off the patients' own blood-forming cells -- and their entire immune system, to prevent rejection of the transplanted cells, leaving patients open to infection.
In the new procedure, patients receive immunosuppressive drugs just before the transplant, along with a very low dose of total body irradiation -- a treatment much less harsh and with fewer potentially serious side effects than chemotherapy.
Next, donor cells from a healthy and tissue-matched sibling are transfused into the patient. Stem cells from the donor produce healthy new blood cells in the patient, eventually in sufficient quantity to eliminate symptoms. In many cases, sickle cells can no longer be detected. Patients must continue to take immunosuppressant drugs for at least a year.
In the reported trial, the researchers transplanted 13 patients, 17 to 40 years of age, with a stem cell preparation from the blood of a tissue-matched sibling. Healthy sibling donor-candidates and patients were tested for human leukocyte antigen, a set of markers found on cells in the body. Ten of these HLA markers must match between the donor and the recipient for the transplant to have the best chance of evading rejection.
In a further advance of the NIH procedure, physicians at UI Health successfully transplanted two patients with cells from siblings who matched for HLA but had a different blood type.
In all 13 patients, the transplanted cells successfully took up residence in the marrow and produced healthy red blood cells. One patient who failed to follow the post-transplant therapy regimen reverted to the original sickle cell condition.
None of the patients experienced graft-versus-host disease, a condition where immune cells originating from the donor attack the recipient's body.
One year after transplantation, the 12 successfully transplanted patients had normal hemoglobin concentrations in their blood and better cardiopulmonary function. They reported less pain and improved health and vitality.
Four of the patients were able to stop post-transplantation immunotherapy without transplant rejection or other complications.
"Adults with sickle cell disease can be cured without chemotherapy -- the main barrier that has stood in the way for them for so long," Rondelli said. "Our data provide more support that this therapy is safe and effective and prevents patients from living shortened lives, condemned to pain and progressive complications."

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Story Source:
The above post is reprinted from materials provided by University of Illinois at Chicago. The original item was written by Sharon Parmet. Note: Content may be edited for style and length.

Scientists find new way to use CRISPR gene editing to help fix sickle cell disease

An international team of scientists led by researchers at St. Jude Children's Research Hospital has found a way to use CRISPR gene editing to help fix sickle cell disease and beta-thalassemia in blood cells isolated from patients. The study, which appears online today in Nature Medicine, provides proof-of-principle for a new approach to treat common blood disorders by genome editing.
"Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin," said Mitchell J. Weiss, M.D., Ph.D., chair of the St. Jude Department of Hematology and one of the study's lead authors. "It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia, genetic forms of severe anemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits."
Fetal and adult hemoglobin are two different molecular forms of the essential oxygen-carrying molecule in red blood cells. Hemoglobins are made up of different combinations of four molecular subunits. Sickle cell disease and beta-thalassemia are caused by mutations in a gene encoding an adult-expressed subunit termed "beta." Disease becomes apparent after birth as the levels of adult hemoglobin take hold and levels of fetal hemoglobin decline. These mutations can affect the survival of red blood cells and inhibit oxygen delivery to tissues, causing impaired function of different organs with devastating consequences for patients. Fetal hemoglobin lacks beta subunits and has gamma subunits instead. Thus, beta-thalassemia or sickle cell disease–associated mutations, which impair the production or function of the beta subunit, do not cause problems with fetal hemoglobin, which can transport oxygen effectively in adults.
Experts have known for some time that inhibiting or reversing "gamma-to-beta" switching of hemoglobin subunits can raise levels of fetal hemoglobin in adults and significantly ameliorate the debilitating symptoms of beta-thalassemia or sickle cell disease.

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"Our work has identified a potential DNA target for genome editing–mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia," added Weiss. "We have been able to snip that DNA target using CRISPR, remove a short segment in a "control section" of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells." When the scientists edited the DNA of blood-forming stem cells derived from patients with sickle cell disease, they were able to activate those genes and produce red blood cells that had enough fetal hemoglobin to be healthy.
Recently, scientists have used several gene editing approaches to manipulate blood-forming stem cells for the possible treatment of sickle cell disease and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching. All of these approaches remain untested in patients.
"Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system," said Weiss. Using genome editing to restore the hereditary persistence of fetal hemoglobin is an attractive possibility, because it can be achieved relatively easily using current technologies. The condition is known to be benign in people who inherit similar naturally occurring mutations.
At this stage, the scientists emphasize that it is still too early to begin clinical trials of the new gene editing approach. The researchers want to refine further the gene editing process and perform other experiments to minimize potentially harmful off-target mutations before in-human clinical trials are considered. Additionally, it will be important to compare different approaches head-to-head to determine which one is safest and most effective.

Source:

St. Jude Children's Research Hospital

 

Pediatric sickle cell study stopped early due to positive results

Hydroxyurea shown as viable option for some children with sickle cell anemia

Source:

Medical University of South Carolina

Summary:

For some children with sickle cell disease, the drug hydroxyurea is as effective as blood transfusions to reduce blood flow speeds in the brain, a national sickle cell disease study has found. Increased blood flows are a major risk factor for stroke in these children, report investigators. 

 

 

FULL STORY

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Pediatric/hematologist Dr. Sherron Jackson of the Medical University of South Carolina examines a patient with sickle cell disease.

Credit: Photograph by Sarah Pack, Medical University of South Carolina

Pediatric/hematologist Dr. Sherron Jackson of the Medical University of South Carolina examines a patient with sickle cell disease.

Credit: Photograph by Sarah Pack, Medical University of South Carolina

"It was a privilege to be a part of this well-designed and executed study. Russell Ware presented the results at the ASH meeting, and 18 years ago, almost to the day, I presented the STOP study results to the same meeting," said Robert J. Adams, M.D., study principal investigator, MUSC professor of neurosciences and director of the South Carolina Stroke Center of Economic Excellence. "That study showed how effective transcranial Doppler risk stratification, followed by regular red cell transfusions in those with high risk blood flow, can be in the prevention of stroke in these children. This became known as the STOP protocol and its wide adoption has been associated with a sharp drop in ischemic strokes in children with sickle cell disease. The drawback of indefinite transfusions however, was a limitation to wider use of the STOP protocol. This study shows that some children can be moved from transfusion to medication after at least a year. The combined understanding and evidence from these two studies brings us closer to achieving the National Institutes' goal of a 'stroke free generation' in sickle cell disease."

Standard treatment for children with sickle cell disease who are at high risk of stroke consists of regular blood transfusions. Children who receive regular blood transfusions are then at risk for iron overload. Chelation, or iron-reduction, therapy is needed for those receiving transfusions. The National Institutes of Health (NIH)-supported study sought to answer whether hydroxyurea would provide the same benefit as blood transfusions, given these additional treatment impacts. Hydroxyurea is the only drug approved by the Food and Drug Administration to treat sickle cell disease. The Transcranial Doppler with Transfusions Changing to Hydroxyurea (TWiTCH) study was stopped early due to positive preliminary results in November 2014.
Researchers from 26 clinical sites supported by the NIH's National Heart, Lung, and Blood Institute (NHLBI) recruited and studied 121 children ages 4 to 16 years old and divided them into two groups: one that received transfusions and one that was transitioned from transfusions to daily doses of hydroxyurea.
"No child should ever have to face the prospect of suffering through a stroke," said Gary H. Gibbons, M.D., director of the NHLBI. "Our institute is striving to achieve a stroke-free generation of children living with sickle cell disease. Studies like this are vital for moving us toward this worthwhile goal."
Study authors indicated that the findings suggest that hydroxyurea could be effective at reducing risk of stroke for other patient populations, though this was not a primary goal of the study.

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Story Source:
The above post is reprinted from materials provided by Medical University of South Carolina. Note: Materials may be edited for content and length.

Educating Public on Sickle Cell Disease Risk

In sub-Saharan Africa, members of the public who are carriers of the hereditary disease sickle cell disease must be educated aggressively through public health campaigns to raise awareness of the risks of parenting offspring with the disease if their partner is also a carrier.

This is according to research published in the International Journal of Medical Engineering and Informatics. There are many physical and emotional public health components of sickle cell disease, explains William Ebomoyi of the Department of Health Studies College of Health Sciences, Chicago State University, Illinois, USA. Moreover, there ethical and legal considerations surrounding the screening of newborns for this potentially lethal disease.

Sickle-cell disease (SCD), also known as sickle-cell anemia (SCA) or drepanocytosis is an inherited condition in which a child of parents both of whom are carriers of the associated hemoglobin gene who inherits both copies will produce abnormal red blood cells that are rigid and often sickle-shaped. The disorder causes both acute and chronic health problems, such as repeated infections, severe attacks of pain and potentially stroke and death. Carriers of just one copy of this particular hemoglobin gene tend to have greater resistance to the lethal parasitic disease malaria compared to people without a copy of the gene. However, around 2 percent of the population of sub-Saharan Africa is born with SCD. Moreover, incidence is rising across the globe as populations migrate.

In the age of genomics, however, Ebomoyi suggests that raising awareness of the risks of having children with SCD if both parents are carriers is important. "An aggressive health education of the public is required to maintain a shared responsibility for their courtship behaviour by alerting potential suitors of their heterozygous status," he suggests. He adds that, "Major sickle cell education programmes need to be integrated into the curriculum of elementary, secondary and tertiary academic institutions."

Successful outcome prompts early end to sickle cell anemia clinical trial

Conclusive data show that hydroxyurea therapy offers safe and effective disease management of sickle cell anemia (SCA) and reduces the risk of stroke, prompting early termination by the National Heart Lung and Blood Institute (NHLBI) of a key clinical trial studying the drug's efficacy.

NHLBI officials issued the announcement today, about one year before the study was originally scheduled to end. Going by the title TWiTCH (TCD With Transfusions Changing to Hydroxyurea), the Phase III randomized clinical trial at 25 medical centers in the U.S. and Canada compared standard therapy (monthly erythrocyte transfusions) with the alternative (daily hydroxyurea) for children with elevated transcranial Doppler (TCD) velocities and high risk of stroke.

"Early results indicate that TWiTCH is a success. Hydroxyurea works as well as blood transfusions to lower TCD velocities, which lowers the risk of the child having a stroke," said Russell E. Ware, MD, PhD, principal investigator of the study and director of Hematology at Cincinnati Children's Hospital Medical Center, which served as the study's Medical Coordinating Center.

"A group of outside experts has been reviewing the TWiTCH data every few months to ensure the safety of children in the clinical trial and to monitor the data," Ware explained. "This group met recently and after careful consideration of the interim data results, recommended that the study be stopped since hydroxyurea worked as well as transfusions to lower TCD velocities." The NHLBI and National Institutes of Health (NIH) agreed with the recommendation.

"No child should ever suffer a stroke, which is why it was so important for the NHLBI to support the TWiTCH trial," said Gary Gibbons, MD, director of the NHLBI. "This critical research finding opens the door to more treatment options for clinicians trying to prevent strokes in children living with the sickle cell disease."

The study enrolled its first patient in September 2011 and included children between ages 4 and 16 years with sickle cell anemia and abnormally elevated TCD velocities, which increases their risk of developing a stroke. The current standard therapy for children with elevated TCD velocities is monthly blood transfusions. A total of 121 children were randomized: half received the standard therapy of transfusions while the other half received the alternate treatment with daily hydroxyurea, which has not yet been approved for children with sickle cell anemia.

The clinical data-collection portion of the study was originally scheduled for 24 months, but collection is now being stopped early, after only half of the children have completed the treatment phase.

"We did not know if hydroxyurea would reduce the risk of stroke as well as transfusions, so TWiTCH was an important research study," said Barry R. Davis, MD, PhD, principal investigator for the Data Coordinating Center at the University of Texas Health Science Center at Houston (UTHealth) School of Public Health. "The study has now shown that hydroxyurea has a similar benefit as transfusions, so the study is closing early since the main research question has been answered."

An important reason for testing hydroxyurea is that the current standard therapy of monthly blood transfusions to reduce stroke risk can lead to problems such as antibody formation and iron overload, which are increasingly recognized as a source of morbidity in young patients with SCA.
Over the past decade, the laboratory and clinical efficacy of hydroxyurea has been demonstrated in children and adults with SCA. Originally developed as a drug to treat cancer and infections, hydroxyurea boosts fetal hemoglobin production in SCA, which prevents the red blood cells from acquiring the sickled shape that fuels the many complications. Hydroxyurea has been previously shown to have clinical efficacy for a variety of sickle-related complications, but TWiTCH is the first Phase III trial that demonstrates its benefits for children with cerebrovascular disease and increased stroke risk.

Sickle Cell Anemia Treatment So Successful in Kids That Trial Is Halted

Hydroxyurea pills worked as well as transfusions in reducing stroke risk, researchers report

 (HealthDay News) -- A clinical trial of hydroxyurea therapy for children with sickle cell anemia has been halted a year early because the results show it is a safe and effective way to manage the disease and reduce the risk of stroke.
The announcement about the research, which was conducted at 25 medical centers in the United States and Canada, was made this week by the U.S. National Heart, Lung, and Blood Institute (NHLBI).
Researchers compared monthly blood transfusions with daily hydroxyurea pills among children with sickle cell anemia who were at high risk of stroke. To determine this, they measured the velocity of blood flow to the brain in these young patients.
With sickle cell anemia, red blood cells become stiff and sickle-shaped, blocking blood flow throughout the body. Hydroxyurea was first developed as a cancer drug, but with sickle cell anemia it reduces the number of these abnormally shaped red blood cells, the researchers said.
Early results showed that hydroxyurea "works as well as blood transfusions which lowers the risk of the child having a stroke," principal investigator Dr. Russell Ware, director of hematology at Cincinnati Children's Hospital Medical Center, said in a center news release.
"This critical research finding opens the door to more treatment options for clinicians trying to prevent strokes in children living with the sickle cell disease," NHLBI Director Dr. Gary Gibbons said in the news release.
The study began in September 2011 and enrolled 121 children, aged 4 to 16, with sickle cell anemia who showed an increased risk of stroke.
SOURCE: Cincinnati Children's Hospital Medical Center, news release, Nov. 19, 2014

HealthDay

Correcting the genetic error in sickle-cell disease might be as simple as amending text.

After some tragic early setbacks techniques that allow precise genetic manipulation have created a surge of research.

 Tiny changes in DNA can have huge consequences. For years, scientists have been trying to 'fix' these mutations in the hope of treating and potentially curing some of humanity's most devastating genetic diseases. After some tragic early setbacks , techniques that allow precise genetic manipulation have created a surge of research.



 DNA sequences showing the sickle-cell disease mutation (marked with an asterisk, top) and the sequence corrected (below) using gene-editing technology.

Although most existing treatments for genetic diseases typically only target symptoms, genetic manipulation or 'gene therapy' goes after the cause itself. The approach involves either inserting a functional gene into DNA or editing a faulty one that is already there, so the conditions most likely to prove curable are those caused by a single mutation. Sickle-cell disease is a perfect candidate: it is caused by a change in just one amino acid at a specific site in the β-globin gene. This results in the production of abnormal haemoglobin proteins that cause the red blood cells that house them to twist and become sickle shaped. The distorted cells get sticky, adhere to each other and block blood vessels, preventing oxygenated blood from flowing through.

Gene therapy has been used successfully in a handful of patients with immune disorders, and sickle-cell disease is among researchers' next targets. The most advanced of these projects is slated to begin clinical trials by the end of the year, and other trials are set to follow. The approaches being developed to treat sickle-cell disease take one of two forms. Conventional gene therapy, also known as gene addition, typically involves inserting new genes. Usually, a harmless virus is modified with the gene to be inserted, and this 'viral vector' is mixed with cells from the patient in vitro. The virus searches out the cells and inserts the gene into the cells' DNA, after which the cells are transplanted into the patient. Conversely, gene editing is more nuanced: in a molecular cut-and-paste, researchers cut out the faulty DNA sequence and then insert a piece of laboratory-created DNA. In both approaches, the modified DNA dictates the formation of a normal, working protein.
In sickle-cell disease, the only cells that need their DNA edited are blood stem cells — also known as haematopoietic stem cells — which are found in bone marrow. These cells continually form new red blood cells to replace those that are lost, and reprogramming just a small fraction of them will create enough perfectly formed red blood cells to eliminate disease symptoms. “Achieving genome editing via direct repair of blood stem cells represents a high hurdle,” says George Daley, director of the Stem Cell Transplantation Program at Boston Children's Hospital in Massachusetts, “but perhaps not an impossible one.”

Although these approaches are promising, several important issues must be addressed before they can be used to treat patients, such as ensuring that the therapies accurately hit their targets and do not cause irreparable harm to the cells or introduce additional genetic information that could cause problems such as cancer.

Injecting genes

Gene addition is poised to become the first sickle-cell gene therapy to be tested in humans. At the regenerative medicine and stem cell research centre of the University of California, Los Angeles, molecular geneticist and physician Donald Kohn is developing protocols for a clinical trial of this technique that is due to start enrolling patients by the end of 2014. Doctors will first harvest bone marrow from the hip bones of patients with sickle-cell disease and then extract haematopoietic stem cells from the marrow. Using a viral vector, they will insert a new, working haemoglobin gene into the cells' DNA; the old, faulty haemoglobin gene will still be present, but it will go silent as the new gene takes over. The modified cells will then be infused back into the patient's bloodstream and will migrate to the bone marrow, where they can provide a continual source of healthy red blood cells.
Kohn says that this approach has the potential to cure sickle-cell disease, and with significantly fewer side effects than a bone marrow transplant — currently the only cure (see page S14). He has tested the technique by injecting modified human haematopoietic stem cells into mice, and found that they were free of sickle cells 2 to 3 months later¹. The limiting factor in mice, Kohn says, is that they can only sustain human grafts for that long. In humans, he thinks the correction should last a lifetime — as long as 50 to 70 years.

One of the challenges in treating sickle-cell disease with gene therapy is that it is necessary to extract bone marrow to retrieve haematopoietic stem cells. With most other diseases, patients can be given drugs that entice these cells to leave the marrow and enter the bloodstream, where they can be easily harvested. But in patients with sickle-cell disease, these drugs can trigger sickle-cell crisis, an acutely painful episode during which the damaged cells stick together and block blood vessels; the crisis can be accompanied by anaemia, chest pain, difficulty breathing, blood trapped in the spleen and liver, even stroke. So researchers must harvest the bone marrow itself, which can be difficult and slow, and limits the number of cells that can be collected at one time. Kohn says that they still do not know whether this approach will yield enough haematopoietic stem cells for reprogramming. And, like other bone marrow transplant procedures, the patient still needs to undergo chemotherapy to kill off the remaining bone-marrow cells to help the genetically altered ones survive once they are reintroduced into the body.

Talented fingers

Further away from clinical trials, but potentially a lot more exciting, is gene editing. The concept was introduced in the 1990s, when artificial DNA-cutting enzymes known as zinc finger nucleases (ZFNs) were first engineered. ZFNs bind to a specific section of DNA and create a break at both ends (see 'Molecular cut-and-paste'). Cells will start to repair the break, at which point a specific sequence of laboratory-made DNA can be slotted into the gap. After the DNA is repaired, the cells start to create healthy copies of the gene.

In parallel to his work on gene addition, Kohn is exploring the use of ZFNs to edit sickle-cell genes. In collaboration with the firm Sangamo BioSciences in Richmond, California, he has shown that around 7% of haematopoietic cells can be repaired in culture using this technique, using a viral vector to get the ZFNs into the cells. Because the repaired cells continue to replicate, this small proportion could be enough to eventually produce a sufficient amount of working red blood cells. Kohn says that patients have shown major improvements when just 10–20% of their donor cells successfully engrafted and started to make new, healthy cells.

The advantage of gene editing over gene addition (a less complex approach) is that it provides an actual fix rather than a work around. But ZFNs are expensive and difficult to program. In 2010, a gene-editing protein called TALEN (transcription activator-like effector nuclease) was developed, which uses a similar mechanism as ZFNs but is cheaper and easier to work with. It was quickly adopted for use in sickle-cell disease.

At the Salk Institute for Biological Studies, in La Jolla, California, stem-cell biologist Juan Carlos Izpisua Belmonte uses TALENs in concert with viral vectors called HDAdVs (helper-dependent adenoviral vectors) to correct the sickle-cell mutation. Instead of harvesting haematopoietic stem cells from bone marrow, Izpisua Belmonte's team takes easily harvestable cells, such as blood, skin or fat cells, and then turns them into induced pluripotent stem (iPS) cells, which can be converted into any cell type. The researchers correct the haemoglobin gene defect in vitro using gene editing, then differentiate the repaired iPS cells into blood stem cells. From there, the researchers have a couple of choices. The repaired cells could simply be infused into a patient's bloodstream, where they would make their way into the bone marrow and start to make healthy haematopoietic cells.

But Izpisua Belmonte is also working on a cure that could work inside the bone marrow itself. His team is combining TALENs with a different viral vector, HDAdVs, to boost the success rate of gene editing, and the researchers are working on a plan to administer their hybrid vector directly into the bone marrow, so the genetic fix would take place inside the patient's body. Although each infusion into the marrow might correct only 1% of the cells, ten such procedures over the course of several months — something Izpisua Belmonte and his research associate Mo Li think is feasible in terms of time and cost — could alleviate the symptoms of sickle-cell disease. “Little by little, you are correcting the disease in vivo,” says Izpisua Belmonte. So far, this 'hybrid vector' technique has shown promising efficacy in umbilical-cord blood stem cells.

Sickle-cell disease results when both copies of the haemoglobin gene are faulty, and fixing just one of the genes is sufficient to make a big health improvement. As Li points out, people who carry one copy of the mutated gene, a genetic condition referred to as 'sickle-cell trait', do not show symptoms. “In fact, many of the world's best sprinters have the sickle-cell trait, he says. “Our approaches will most likely restore one mutated copy to its wild-type sequence, leaving the other copy untouched.”
CRISPRs (clustered regularly interspaced short palindromic repeats) are the most recent addition to the gene-editing toolbox. Whereas ZFNs and TALENs use a protein to lock on to a specific section of DNA, CRISPRs use a 'guide RNA'. These guide RNAs are much easier to program than the proteins in TALENs and ZFNs, as well as being cheaper and more efficient. CRISPRs also make it possible to perform multiple genetic manipulations in one go. CRISPRs work in combination with the Cas9 (CRISPR-associated 9) nuclease: after the CRISPR locks on to the target gene, Cas9 snips both strands of the DNA, disabling the gene. The approach is less than two years old, yet many researchers are now working with CRISPRs in parallel with other in vitro techniques.

Chris Calleri/Georgia Institute of Technology

A researcher corrects a mutation in the β-globin gene that causes sickle-cell disease.

There are safety hurdles to be overcome before gene editing is used in humans, especially because it involves a permanent change in the genome. The thorniest issue is 'off-target activity' — unintended changes to the genome away from the target gene.

Gang Bao, a biomedical engineer at the Georgia Institute of Technology in Atlanta, is developing gene-editing strategies for sickle-cell disease and is paying particular attention to the challenge of limiting off-target effects. He notes that if erroneous cuts happen in a cancer-causing gene, they could potentially trigger tumour growth. Even a rate of off-target activity lower than 1% could still pose serious health risks. So that the technology can move forward, researchers need to have a better understanding of off-target effects. There are two main issues: determining exactly where the off-target cuts occur and at what rate.

Bao's group has created software to predict where the off-target effects might occur for the different gene-editing techniques. In a paper published in May, his team reported that their software predicted 114 potential off-target sites across the whole genome for the CRISPR/Cas9 system, and experiments confirmed 15 of them by sequencing the cleaved DNA².

Izpisua Belmonte's team is also looking at the rate of unwanted mutations caused by gene-editing techniques. The group created iPS cell lines and then edited half of the cells using HDAdVs and TALENs³, but left the other half unedited. The edited cells had no more mutations than the unedited ones, indicating that — in contrast to Bao's findings for CRISPRs — the use of TALENs does not seem to make cells any less safe. Although human testing is still a few years off, they say that these results give them optimism about the potential for gene editing to work.
The other major challenge for gene-therapy researchers is ensuring that the edited stem cells survive and generate healthy red blood cells after they are reinserted into the bone marrow. Edited cells often die because of the amount of stress they undergo during therapy. Researchers might be able to improve the cell-survival rate by delivering other types of cells at the same time, and the speed of gene editing also seems to be important: the longer the cells are cultured in vitro, the less likely they are to survive. “Let's see if we can perform the whole procedure in four hours instead of four days,” says Bao.

Future repair toolboxes

Based on his research so far, Bao thinks that CRISPRs are the best method for generating DNA breaks, but they are also more likely to cause off-target activity. TALENs are less efficient than CRISPRs, but they seem to have fewer off-target effects. The rate of on-target activity for CRISPRs is between 40% and 80%, whereas the on-target rate for TALENs is between 20% and 50%, Bao says. The rate of off-target activity varies depending on the type of cells and the nuclease used. “If we have a way to overcome the off-target and [cell-survival] problems, CRISPR is a very promising technology,” he says.

Kohn has compared ZFNs, TALENs and CRISPRs, and thinks all three have therapeutic potential for patients with sickle-cell disease. The techniques are all good at slicing DNA; now the remaining challenges are delivering them to the target cell and accurately repairing the gene after the break.
Ultimately, for sickle-cell gene therapy to become reality, the details must be sorted out on a large scale. Tinkering with human genes can yield both devastating and remarkable results, and the difference between the two often lies in a single nucleic acid of a single gene. This places a heavy responsibility on the shoulders of every researcher in the field, but the vast potential of gene therapy makes that burden worthwhile.

East and West African sickle cell anaemia are genetically similar

African collaboration unpicks disease variations by combining local genomic research with large-scale genome-wide association techniques

 Sickle cell anaemia is most common in Africa and up to 11,000 children are born with the condition every year in Tanzania alone. Yet most of what is known about the genetic basis of this inherited disease comes from studies of US-based or UK-based African-Caribbean populations.

In African-American populations genetic variations can influence the ability to produce foetal haemoglobin by as much as 50 per cent, but knowledge of this effect in East African populations is scant. A collaboration between research teams in Tanzania and the UK applied the power of the genome-wide association techniques to the genomes of 1,213 individuals in Tanzania to confirm whether or not the same variations are at work in an East African population and to identify possible new ones.

Sickle cell anaemia is painful and disabling disease caused by variations in a gene involved in producing adult haemoglobin. But people who have greater levels of the foetal form of haemoglobin in their bloodstream are less affected. This first large-scale genomic study based in Tanzania has revealed a number of regions in the genome that appear to have an effect on foetal haemoglobin levels and will guide future research into African populations.

"By carrying out a large-scale genome-wide association study we have, for the first time, been able to identify powerfully the prevalence of genetic variants involved in sickle cell anaemia in the Tanzanian population and how that compares with other populations," says Siana Nkya Mtatiro, co-first author of the paper from Muhimbili University of Health and Allied Sciences. "We have also identified suggestive additional variants, which can now be studied further by the research community in the search for interventions for sickle cell anaemia in patients in Africa and worldwide."
 
The research confirmed the association of genetic variations near the genes BCL11A and HBS1L-MYB with sickle cell anaemia in the Tanzanian population but found that variations in HBB, which are associated with the disease in African-American populations, are not significant in East African populations. In addition, the study hinted at additional associations that require confirmation in other populations.









  The collaboration between research teams in Tanzania and the UK carried out a genome-wide association study of 1,213 individuals in Tanzania with sickle cell anaemia and confirmed that BCL11A and HBS1L-MYB are connected with the disease. [Muhimbili University of Health and Allied Sciences]

"We were unable to validate any of our new suggestive associations in a group of UK samples we used for comparison. This suggests we need bigger studies to more completely understand the genetics of this disorder," says Jeff Barrett, senior author from the Wellcome Trust Sanger Institute.
The work was a joint effort drawing on the skills and techniques developed by Tanzania- and UK-based teams and the free flow of information between them. The samples were gathered in Tanzania and genotyped at the Sanger Institute, the genome-wide scan was carried out by the UK-based team and subsequent data analysis was carried out the African-based researchers.

"This work demonstrates how scientists in Africa can collaborate both with one another and with colleagues in Europe to provide greater insight into the genomic landscape of health and disease in Africa, the cradle of humanity," says Julie Makani, senior author on the study from Muhimbili University of Health and Allied Sciences. "We hope that our approach could be used as a model for other researchers working to understand the genetic basis of health and disease in Africa."
The research was supported by the Wellcome Trust, which encourages collaborations between researchers on different continents to apply cutting-edge genomic techniques in low- to middle- income countries. Trust-funded research in this area aims to increase our understanding of diseases that might otherwise be neglected.

"This is an important contribution to sickle cell disease research, which clearly demonstrates how successful genomics research collaborations - in this case between researchers in Tanzania and the Wellcome Trust Sanger Institute - can be achieved," says Jimmy Whitworth, Head of Population Health at the Wellcome Trust. "The results of this study will form a firm foundation for further studies of the genetic basis for sickle cell disease and potential avenues for treatment in sub-Saharan Africa."

Sickle cell trait tied to kidney disease among blacks

African Americans with sickle cell trait - generally thought to be benign, unlike sickle cell disease - may still be at increased risk of kidney disease, a new study suggests.

African Americans with sickle cell trait - generally thought to be benign, unlike sickle cell disease - may still be at increased risk of kidney disease, a new study suggests.

Based on data for more than 2,000 people, researchers found that about 19 percent of those with sickle cell trait had kidney disease, compared to about 14 percent of people without the trait.
The study team calculates that sickle-cell trait raises the risk of kidney disease by nearly 60 percent. They reported their results in JAMA and during a presentation at Kidney Week in Philadelphia.
“We set out to do this, because there has been some uncertainty and controversy around the health consequences of sickle cell trait, which is a genetic condition related to sickle cell disease,” said one of the study’s authors, Dr. Alexander Reiner from the Fred Hutchinson Cancer Research Center in Seattle.

Sickle-cell disease is an inherited disorder in which red blood cells contain an abnormal type of hemoglobin. The defective cells frequently take on a sickle- or crescent-shape and can block small blood vessels, which can lead to tissue damage or even stroke.

People with sickle cell disease have inherited two defective genes, one from each parent, whereas those with sickle cell trait inherit only one problematic gene and one healthy one - which helps to offset the effect of the malfunctioning gene.

Sickle cell disease affects about one of every 500 blacks, according to the U.S. Centers for Disease Control and Prevention. Sickle cell trait affects one in 12 blacks.

“Even though sickle cell trait has been considered to be relatively benign, it has been known that kidney complications, such as having blood in the urine, was more common in people with sickle cell trait versus people without sickle cell trait,” said the study’s lead author, Dr. Rakhi Naik from Johns Hopkins University in Baltimore.

Naik told Reuters Health that the red blood cells of people with sickle cell trait would look completely normal under a microscope.

“The theory is that under very highly stressful situations (such as a low oxygen levels) . . . there may be some localized sickling that happens in the kidney that is leading to functional impairment,” she said.

For the new study, the researchers combined data from five large U.S. studies that included 15,975 self-identified African Americans - 1,248 of them with sickle cell trait - who were followed for 12 to 26 years.

At the outset, people with sickle cell trait were 57 percent more likely overall to have chronic kidney disease than people without a defective gene. People who didn't have kidney disease at the start were 80 percent more likely to develop it if they had the sickle trait.
Kidney disease tended to appear later in life among those with sickle cell trait than it tends to do in sickle cell disease, Naik noted.

The findings were similar in each of the studies included in the analysis. Researchers accounted for other genetic factors that are tied to chronic kidney disease among African Americans and found that they did not explain the link.

The new study concludes, however, that together, other genetic factors, socioeconomic factors and sickle cell trait may explain the overall increased risk of kidney disease seen among African Americans, Reiner said.

“Exactly how much of the increased burden of kidney disease sickle cell trait explains or is explained by other factors is still an open question that will require additional study,” he said.
Testing for sickle cell disease is common in the U.S., Naik said. “As a byproduct, people with sickle cell trait are identified,” she added.

Without additional research, it’s difficult to say whether people with sickle cell trait should be screened for kidney disease, Naik said.

“They may want closer monitoring of kidney function if someone has been identified to be a sickle cell trait carrier,” Reiner said. He added that there is no specific treatment or intervention to prevent kidney failure or further decline in kidney function.

He said these findings may lead to greater awareness of the potential health impact of sickle cell trait.
“It’s a reasonably common condition in the Africa American community,” Reiner said. “It may be important in terms of greater community awareness and education, which may be important for general health.”

Additionally, he said, the findings may spur future research into how sickle cell trait might affect other systems in the body.
SOURCE: bit.ly/1EzO9tS JAMA, online November 13, 2014.

Developing first comprehensive guidelines for management of sickle cell disease

The National Heart, Lung, and Blood Institute has released the first comprehensive, evidence-based guidelines for management of sickle cell disease from birth to end of life. Sickle cell anemia is the most common form of sickle cell disease, a serious disorder in which the body makes sickle-shaped red blood cells.

 

Shirley Miller with Dr. George Buchanan, Professor of Pediatrics and Internal Medicine, holder of the Children's Cancer Fund Distinguished Chair in Pediatric Oncology & Hematology.

 The National Heart, Lung, and Blood Institute (NHLBI) has released the first comprehensive, evidence-based guidelines for management of sickle cell disease from birth to end of life, based on recommendations developed by a nationwide team of experts co-chaired by a UT Southwestern Medical Center hematologist.

 Appearing today in JAMA, the guidelines are intended for general use by pediatricians, physicians treating adults, hematologists, emergency room personnel, hospitalists, and other health care providers. The new management guidelines consist of more than 500 specific directions for physicians who are caring for patients with sickle cell disease.

"The aim is to improve the care of all people with sickle cell disease, young and old, and to raise awareness among the entire medical profession regarding the need for better care and more research, so that someday everyone with sickle cell disease can receive the best possible care and lead a normal and productive life," said Dr. George Buchanan, Professor of Pediatrics and Internal Medicine.

Although currently most patients are diagnosed at birth and survive until adulthood, many sickle cell disease patients die in their 30s and 40s of acute complications or chronic organ damage. Dr. Buchanan and the team of expert panelists want to alter that statistic through improved and comprehensive treatment.

One survivor who beat those numbers is 58-year-old Shirley Miller, who worked at UT Southwestern with Dr. Buchanan from 2002 to 2010 as a program manager, patient advocate, and outreach coordinator.

"I lived my life in fear because I thought age 30 was it. I wasted a lot of time wondering how the end would happen. My parents never told me my life expectancy; I went to the library and looked it up," said Ms. Miller, who is now helping to launch a comprehensive sickle cell adult program in Charlotte, North Carolina.

Diagnosed at age three, and the only one of five siblings with the disease, she grew up without physical education classes and did not participate in sports. She made friends slowly and was embarrassed when others went through puberty before her. She credits her parents with helping her believe she could make it, and she credits the care she later received as an adult at UT Southwestern.

"Comprehensive care is the key to successful management of sickle cell disease, known as sickle cell disease. Currently, there are not enough physicians who specialize in the care of adults with sickle cell disease, which means that many are seen by primary care physicians or other specialists," said Ms. Miller. "These guidelines will provide physicians with a tool for basic understanding of the disease etiology and possible complications to look for when managing a patient. I attribute my survival to the comprehensive care that I received from this teaching and research university, which is on the cutting edge of so many developments. The knowledge and expertise available here have made all the difference."

The expert panel for the new guidelines is a 12-member team, all known for their experience in diagnosing and treating people with sickle cell disease. Panel members included two pediatric hematologists, four adult hematologists, an obstetrician, a psychiatrist, an emergency department nurse, two blood transfusion specialists, and one family physician. These experts were supported by a large staff of NHLBI leaders and other personnel, including experts in finding and analyzing the available scientific evidence that could help improve the lives of people with sickle cell disease.
Sickle cell disease is the world's most common serious condition due to a single gene mutation. An estimated 70,000 to 100,000 people in the U.S. have sickle cell disease. Of these, about 1,000 receive care annually at UT Southwestern. Dr. Buchanan has led the institutional pediatric and research sickle cell disease programs for 37 years.

More than 2 million Americans carry the sickle cell trait.
"African-Americans are far more likely than Caucasians to have the sickle cell trait, which is not a disease but a carrier state. One has to receive a copy of the abnormal gene from both parents to have the disease," said Dr. Buchanan, who holds the Children's Cancer Fund Distinguished Chair in Pediatric Oncology & Hematology.
"Every state now has mandatory newborn screening for the disease," said Dr. Buchanan, Director of the Barrett Family Center for Pediatric Oncology at UT Southwestern.
Dr. Buchanan was instrumental in ensuring that Texas became the third state to adopt newborn screening in 1983. Approximately 150 infants with sickle cell disease are diagnosed in Texas each year. Nearly one third of them receive their care at Children's Medical Center in Dallas.

When sickle cell disease progresses, it can delay puberty and cause acute and chronic complications, including debilitating pain, life-threatening infections, damage to vital organs, and stroke. Stem cell transplants offer a potential cure; however, the high cost, lack of suitable donors (ideally the donor is a sibling), and the risk of complications make these transplants relatively infrequent. The newly published comprehensive guidelines recommend better pain control; prevention and treatment of acute and chronic complications; general health maintenance; judicious use of blood transfusions; and teaching patients to manage their disease through behavioral changes.

The committee also strongly advocates for prescribing hydroxyurea, an oral medication taken once daily that has become the standard of care. Hydroxyurea reduces the impact of the disease by improving the anemia, and reducing the risk of pain events and acute chest syndrome. It can also decrease the need for transfusions and hospital admissions.
"These national guidelines are directed not just to hematologists but to all medical practitioners who might encounter sickle cell disease patients, to inform them about hydroxyurea and how to best offer general medical care to them," Dr. Buchanan said. "We have a lot of work to do to educate physicians."

September is National Sickle Cell Awareness Month, and the guidelines will be discussed and disseminated at professional conferences, as well as being available on the NHLBI website and in JAMA, the journal of the American Medical Association.
According to NHLBI, sickle cell anemia is the most common form of sickle cell disease, a serious disorder in which the body makes sickle-shaped red blood cells. "Sickle-shaped" means that the red blood cells are shaped like a crescent. Normal red blood cells are disc-shaped and look like doughnuts without holes in the center, moving easily through blood vessels. Red blood cells contain an iron-rich protein called hemoglobin, which carries oxygen from the lungs to the rest of the body. Sickle cells contain abnormal hemoglobin called sickle hemoglobin or hemoglobin S. They tend to block blood flow in the blood vessels of the limbs and organs, causing pain, organ damage, and increased risk for infection. In the U.S., the disease occurs in about one out of every 500 African-American births and in more than one out of every 36,000 Hispanic-American births.

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The above story is based on materials provided by UT Southwestern Medical Center. Note: Materials may be edited for content and length.