Common anemia: Drug represents first potential treatment

Common anemia: Drug represents first potential treatment

An experimental drug designed to help regulate the blood's iron supply shows promise as a viable first treatment for anemia of inflammation, according to results from the first human study of the treatment published online today in Blood, the Journal of the American Society of Hematology

Anemia is a condition that occurs when red blood cells are in short supply or do not function properly. When an individual has anemia, the body does not get enough oxygen, since there are fewer red blood cells to carry the iron-rich protein hemoglobin that helps distribute oxygen throughout the body. This can result in symptoms such as weakness and fatigue.

The most common form of anemia in the hospital setting is anemia of inflammation, which occurs when the body's immune response is activated during illness or infection. When the body fights a disease, it deploys an inflammatory response that triggers increased secretion of a hormone called hepcidin that reduces the amount of iron available in the bloodstream. As iron is needed for the production of red blood cells in the bone marrow, many patients develop anemia.

The only current treatment strategy for anemia of inflammation involves targeting the underlying disease or infection; however, recent research has sought to explore additional options for patients whose inflammation is difficult to control or when the cause of inflammation is unknown. As the principal regulator of iron, hepcidin has become a target for researchers developing novel therapies for blood disorders. One hepcidin inhibitor, called lexaptepid pegol (lexaptepid), has demonstrated efficacy in treating anemia of inflammation in animal studies. Lexaptepid inactivates hepcidin, thereby maintaining the transport of iron to the bloodstream.

In order to evaluate lexaptepid's potential in humans, investigators induced a safe and temporary model of anemia of inflammation in 24 healthy male adults and randomized them to receive lexaptepid or placebo. Volunteers received a low dose of Escherichia coli (E. coli) endotoxin to induce controlled inflammation and received either lexaptepid or placebo 30 minutes later. After nine hours, iron in the blood stream had decreased in the placebo group, whereas this decrease could be prevented by treatment with lexaptepid.

In addition to determining whether lexaptepid interfered with hepcidin production, researchers also sought to determine whether the drug influenced the immune response. All volunteers experienced similar flu-like symptoms, increased body temperature and white blood cell count, and higher concentrations of inflammatory and signaling proteins, demonstrating to investigators that lexaptepid did not interfere with the immune response process.

"It is quite encouraging that lexaptepid helped maintain appropriate levels of iron in the bloodstream of healthy volunteers without compromising the immune response," said lead study author Lucas van Eijk, MD, of Radboud University Medical Center in Nijmegen, Netherlands. "We are hopeful that, with further study, this first-of-its-kind therapy could significantly improve quality of life for patients suffering from chronic illnesses."

Blood Transfusions Could Reduce Strokes in Kids With Sickle-Cell Anemia

Blood Transfusions Could Reduce Strokes in Kids With Sickle-Cell Anemia

A new trial involving nearly 200 children with sickle-cell anemia found that monthly blood transfusions could reduce the chance of strokes by more than half in children who have the condition, according to U.S. News.

Sickle-cell anemia — a disorder in which red blood cells adopt a rigid, sickle shape that blocks flow, causing strokes and other complications — is most common in children of African and Central or South American descent. According to the U.S. National Heart, Lung and Blood Institute, 1 out of 500 African-American children in the U.S. is born with sickle-cell anemia. “Silent strokes” — which lack discernible symptoms but have also been known to reduce a child’s IQ — affect 30% of those with the condition.

Researchers involved in the study, published in the New England Journal of Medicine, used an MRI scan to identify 196 children ages 5 to 15 with a history of silent strokes, and gave about half of them monthly blood transfusions over three years. Out of the group that had monthly blood transfusions, only six had another stroke during the study, in comparison with 14 children in the control group who had another stroke.

Allison King, a co-author of the study, explained in a statement released by Washington University School of Medicine that the blood transfusions helped to increase the number of healthy red blood cells and “lower the percentage of sickle-shaped cells in the patient’s bloodstream.”

The team stressed that all children with sickle-cell anemia — which was previously thought to be untreatable — should be regularly screened for signs of silent stroke. “Now that we have identified a viable treatment option, early detection of silent cerebral strokes should become a major focus for clinicians and families of children with sickle-cell disease,” Michael Noetzel, a chairman of the study’s neurology committee, said in a statement.

Researchers added that additional long-term studies were needed to determine whether regular blood transfusions could also prevent reduced IQ, which was not a focus of the study.

RED BLOOD CELL DEVELOPMENT

Two beneficial variants of a gene controlling red blood cell development have spread from Africa into nearly all human populations across the globe, according to a new study led by King's College London. The international team studied the genomes of world populations to look for the origin of changes in a key regulator gene which stimulate fetal haemoglobin production into adulthood. Fetal haemoglobin is normally found in fetuses and infants, but some patients with inherited blood disorders who are able to keep making it as adults experience milder symptoms of their condition.

Sickle cell anemia is an inherited blood disorder in which red blood cells behave abnormally and can clog blood vessels, leading to acute unpredictable painful spells called a sickle cell crisis which typically last a week. The recurrent sickle crises and chronic anemia lead to serious complications in the joints, bones, lungs, eyes, brain, liver and kidneys, and early death. Thalassaemia is a group of inherited blood disorders where insufficient haemoglobin -- the oxygen-carrier in blood cells -- is produced, leading to anemia. Symptoms of beta thalassaemia can range from moderate to severe, with the most severe form requiring blood transfusions for the rest of the person's life. The only 'cure' for both sickle cell anemia and beta thalassaemia is a bone marrow transplant, but this option is only available to a small number of patients.

Studies have shown that carriers of these conditions are protected against malaria; having one copy of the sickle cell gene significantly increases your chances of surviving malaria. As a result, these blood disorders are more prevalent in parts of the world where malaria is common. However, sickle cell disease is rapidly emerging as a public health issue both globally and in the UK where it is the most common severe genetic disorder, affecting an estimated 13,000 people.

The new study, published in the Annals of Human Genetics, looked at genetic factors that can reduce the severity of these blood disorders. Typically, our bodies make fetal haemoglobin whilst in the womb, but then switch to another form of haemoglobin, adult haemoglobin, at birth. However, we continue to produce very small amounts of fetal haemoglobin in adulthood, some more than others. Patients who have the genetic factors that increase fetal haemoglobin production tend to have milder symptoms of their blood disorder.

While studying patients of African and of South Asian descent, the authors noticed that one such factor, a genetic variant controlling the red blood cell regulator gene MYB -- 'MYB enhancer variant' -- on Chromosome 6, is of similar genetic structure not only in both patient groups, but also in healthy individuals, including those of Northern European origin, where thalassaemia and sickle cell disease are rare. This led the authors to suspect that beneficial MYB enhancer variants, which promote fetal haemoglobin in the body, are a general feature of human populations across the world and that they might have a common origin.

To test this hypothesis, the team searched for genetic signatures of such variants in public genome data generated from world populations to see whether they existed in other ethnic groups. They found signatures for two different types of MYB enhancer variants, HMIP-2A and HMIP-B, in major human population groups and in nearly all ethnic groups covered by the data. Both variants occur in Sub-Saharan Africa, but only at low frequencies. In much of the rest of the world the alleles have combined, forming HMIP-2A-B, and this combination is relatively common in Europe, South Asia and China. HMIP-2B separately is common in Far-East Asian peoples and in Amerindians, illustrating their connection across the Bering Strait.

The team also tested recent genome sequence data from our extinct cousins, the Neanderthals and Denisovans, and from the Great Apes, but detected neither HMIP-2A nor HMIP-2B. From this, the authors conclude that MYB enhancer variants that modulate the severity of sickle cell and beta thalassaemia have arisen twice in modern humans, in Africa, and then spread to the rest of the world. However, this likely occurred long before inherited blood disorders became prevalent, and thus the environmental factors that favoured such variants in these early humans are not clear.

The next stage of the research will explore which selection pressures or benefits might have contributed to the present population distribution of the variants. Selection pressures could include nutritional factors, such as the availability of iron in the diet, or specific demands on red blood cell production, such as adaptation to high altitudes.

Dr Stephen Menzel, co-author from the Department of Molecular Haematology at King's College London, says: "Patients who have milder versions of blood disorders, thanks to their ability to keep producing fetal haemoglobin, carry genetic clues that are helping us to understand the function of the genes and biological pathways involved in these diseases."

Professor Swee Lay Thein, co-author and Consultant Haematologist at King's College Hospital NHS Foundation Trust, says: "King's Health Partners cares for the largest cohort of sickle cell patients in the UK, with an estimated 2,500 patients. Although a newborn in the UK can now expect to live to adulthood, in adults the disorder has evolved into a chronic debilitating disease with acute or chronic pain and organ complications. We hope our research will help to develop biomarkers and ultimately, preventative treatments for inherited blood disorders."

LIVING WELL WITH SICKLE CELL

Living Well with Sickle Cell Disease

People with sickle cell disease can live full lives and enjoy most of the activities that other people do. The following tips will help you, or someone you know with sickle cell disease, stay as healthy as possible.

Find Good Medical Care

Sickle cell disease is a complex disease. Good quality medical care from doctors and nurses who know a lot about the disease can help prevent some serious problems. Often the best choice is a hematologist (a doctor who specializes in blood diseases) working with a team of specialists.

Get Regular Checkups

Regular health checkups with a primary care doctor can help prevent some serious problems.

• Babies from birth to 1 year of age should see a doctor every 2 to 3 months.
• Children from 1 to 2 years of age should see a doctor at least every 3 months.
• Children and adults from 2 years of age or older should see a doctor at least once every year.
  

Prevent Infections

Common illnesses, like the flu, can quickly become dangerous for a child with sickle cell disease. The best defense is to take simple steps to help prevent infections.

Learn Healthy Habits

People with sickle cell disease should drink 8 to 10 glasses of water every day and eat healthy food. Try not to get too hot, too cold, or too tired.

Children can, and should, participate in physical activity to help stay healthy. However, it’s important that they don’t overdo it, rest when tired, and drink plenty of water.

a brief history of sickle cell disease

In the annals of medical history, 1910 is regarded as the date of the discovery of sickle cell disease, making 2010 the 100th anniversary of that discovery, but just what does it mean to say the disease was “discovered”? The disorder we call “Sickle Cell Disease” often abbreviated as SCD, had been present in Africa for at least five thousand years and has been known by many names in many tribal languages. What we call its “discovery” in 1910 occurred, not in Africa, but in the United States. A young man named Walter Clement Noel from the island of Grenada, a dental student studying in Chicago, went to Dr. James B. Herrick with complaints of pain episodes, and symptoms of anemia. Herrick was a cardiologist and not too interested in Noel’s case so he assigned a resident, Dr. Ernest Irons to the case. Irons examined Noel’s blood under the microscope and saw red blood cells he described as “having the shape of a sickle”. When Herrick saw this in the chart, he became interested because he saw that this might be a new, unknown, disease. He subsequently published a paper in one of the medical journals in which he used the term “sickle shaped cells”.
As more cases began to surface, the mystery of just what this disease was only deepened. It was clear that for whatever reason, it occurred only or primarily in persons of African origin. In 1927, Hahn and Gillespie discovered that red blood cells from persons with the disease could be made to sickle by removing oxygen. This was exciting because red cells are the oxygen transporters of the body. The trouble was, that there were people –often relatives of the patient – whose red cells had this trait of sickling when deprived of oxygen but who had no disease. This condition became known as “sickle trait”.
In the late 1940’s and early 1950’s the nature of the disease began to become clearer.
In 1949, two articles appeared independently showing conclusively that SCD was inherited and that people with sickle trait were heterozygous (carriers or AS) for the gene whereas people with the disease were homozygous – i.e., had a double dose of the gene (SS). One was published by a military doctor in what was then known as Portuguese East Africa (now Mozambique) named Col. E. A. Beet. His article was in an African medical journal. The other was by Dr. James V. Neel, Chairman and founder of the Department of Human Genetics at the University of Michigan. It was in his department that I worked for seven years and was on the staff of one of the first Centers for Sickle Cell Disease in 1972. Neel published his article in the prestigious American journal Science. As a result of the much wider readership of that journal, Neel usually gets the credit for the discovery although most authors are careful to cite both and many people think that Neel and Beet worked together. As an aside, some years ago, I visited Dr. Neel (he has died since), and I remarked that I always tell my classes about his discovery and the 1949 article and the dual publication by Beet. He smiled, got up from his desk and opened a file drawer. He pulled out a reprint of a 1947 paper he had written, also from Science as I recall, and showed me where he had said, “this [referring to data in the paper] almost certainly shows that sickle cell anemia is hereditary. I prefer to cite this paper these days,” he said with a puckish grin on his face.
Two years later, in 1951, the famous Nobel Prize-winning chemist, Dr. Linus Pauling and his colleague Dr. Harvey Itano, discovered that the red, oxygen-carrying protein called “hemoglobin” had a different chemical structure in persons with SCD. This led Dr. Pauling to coin the term “molecular disease” for disorders that resulted from proteins with abnormal chemical structures. Today, thousands of such diseases are known but in 1951, SCD was the first. The details of the abnormality were worked out by Dr. Vernon Ingram in 1956. In the 1970’s, more details of how this abnormal structure affects the red blood cells were revealed and better tests for the detection of the disease were developed. In the years following, better ways of treating sickle cell patients and potential treatments appeared. The life span and the quality of life of patients were improved. Genetic counseling became an important tool for informing people about the risks of having a child with sickle cell disease. Today, 100 years later, physicians and scientists continue to move forward in new understanding of the disease and new ways to treat it. The goal of a total cure has not been reached but great progress has been made. Perhaps within the lifetime of some of us, that goal will be reached.
In summary, in 1910, Herrick described an anemia characterized by bizarre, sickle-shaped cells. The role of deoxygenation was discovered in the 1920’s by Hahn and Gillespie. The hereditary nature of the disease was suspected but not demonstrated until 1949 by Dr. James V. Neel. The association with hemoglobin was discovered by Linus Pauling and Harvey Itano in 1951 and the actual amino acid substitution by Vernon Ingram in 1956. Thus the 100th anniversary marks the discovery of this ancient disease from Africa by western medicine and naming of the disease for a simple agricultural implement to which a medical resident in 1910 likened the shape of the abnormal cells he saw under the microscope.