Thalassemia patients in Sri Lanka

Age No Longer Should Be A Barrier To Stem Cell Transplantation For Older Patients With Blood Cancers

2011-11-04T07:55:00.000+05:30

Age alone no longer should be considered a defining factor when determining whether an older patient with blood cancer is a candidate for stem cell transplantation. That's the conclusion of the first study summarizing long-term outcomes from a series of prospective clinical trials of patients age 60 and over who were treated with the mini-transplant, a "kinder, gentler" form of allogeneic (donor cell) stem cell transplantation developed at Fred Hutchinson Cancer Research Center. The findings are published Nov. 2 in JAMA, The Journal of the American Medical Association.

"Age is no longer a barrier to allogeneic transplant," said Mohamed Sorror, M.D., M.Sc., an assistant member of the Hutchinson Center's Clinical Research Division and corresponding author of the paper.

Sorror and colleagues found that the five-year rates of overall and disease-progression-free survival among mini-transplant patients were 35 percent and 32 percent, respectively. Patients in three age groups 60 to 64, 65 to 69 and 70 to 75 had comparable survival rates, which suggested that age played a limited role in how patients tolerate the mini-transplant. Increased medical problems unrelated to cancer (comorbidities) and a higher degree of cancer aggressiveness were the two factors that affected survival among those older patients. For example, patients who had less-aggressive cancer and fewer comorbidities had a five-year survival rate of 69 percent, while patients with more aggressive cancer and a significant number of comorbidities had a survival rate of 23 percent, regardless of age.

Although a long-term survival rate of one-third of patients may seem low, these patients all would have died of their diseases within a matter of months without a transplant. "The majority of patients were referred for a transplant after they had exhausted all forms of conventional therapy," said Sorror, who works in the research group led by Rainer Storb, M.D., who developed the mini-transplant.

"While there is much room for improvement, particularly with regard to relapse, these results are encouraging given the poor outcomes with non-transplantation treatments, especially for patients with high-risk AML (acute myeloid leukemia), fludarabine-refractory CLL (chronic lymphocytic leukemia) or progressive lymphoma," the authors wrote.

The mini-transplant, known in medical circles as nonmyeloablative transplantation, was developed by researchers at the Hutchinson Center for older and medically sicker patients who otherwise could not tolerate the standard, more-toxic, high-dose regimens used to prepare patients for transplantation.

Scientists correct sickle cell disease in mice

2011-10-19T07:49:00.000+05:30

U.S. scientists have found a way to get mice with a form of sickle cell disease to make normal red blood cells, offering a potential new way to treat the blood disorder in people, they reported on Thursday.
Adults with sickle cell disease make mutant, sickle-shaped forms of hemoglobin, the protein in red blood cells that is vital for carrying oxygen to the body's tissues.
These deformed cells block small blood vessels, causing pain, strokes, organ dysfunction and premature death.
But this problem occurs only after birth.
During development, a fetus uses one gene to make a fetal form of hemoglobin, but switches to another after birth, and problems with this adult gene are what lead to sickle cell disease.
A team led by Dr. Stuart Orkin of Harvard Medical School, Children's Hospital and the Howard Hughes Medical Institute in Boston, earlier had discovered that a protein called BCL11A is responsible for making the switch from fetal hemoglobin to adult hemoglobin.
In the latest study, published in the journal Science, the team looked to see what would happen if they blocked production of the BCL11A protein in mice with sickle cell disease.
They found that when the protein was disabled, the mice switched back to producing fetal hemoglobin. And mice that once exhibited symptoms of sickle cell disease improved.
"This discovery provides an important new target for future therapies in people with sickle cell disease," Dr. Susan Shurin, acting director of the NIH's National Heart, Lung, and Blood Institute, which co-funded the study, said in a statement.
"More work is needed before it will be possible to test such therapies in people, but this study demonstrates that the approach works in principle."
Sickle cell disease affects 100,000 Americans and 3 million to 5 million people globally. It is most prevalent in people of African, Hispanic, Mediterranean and Middle Eastern descent.
There is no widely available cure. Bone marrow transplants work for some patients, but the treatment is risky and only available to patients with relatives who can donate compatible and healthy bone marrow to them.

FDA Approves New Treatment Option for Patients with Thalassemia

2011-10-17T09:18:00.001+05:30

Gina Cioffi
Cooley's Anemia Foundation

The Cooley's Anemia Foundation Applauds FDA Approval of Ferriprox, Iron Chelator for People with Thalassemia. The Foundation Believes a Wider "Menu" of Treatment Options is Crucial for Each Individual Patient to Receive Optimal Treatment

New York, NY (PRWEB) October 14, 2011

The Cooley’s Anemia Foundation (CAF), the only national non-profit dedicated solely to fighting the genetic blood disorder thalassemia, applauds a Food and Drug Administration (FDA) decision today to approve the new drug application for the oral chelator, Ferriprox. This action follows a 10-2 vote on September 14, 2011 by the Oncology Drugs Advisory Committee to recommend the approval of this drug.

“As the premier voice of the thalassemia community in the United States, we are thrilled that our patients will have the benefit of this drug which has proven beneficial to patients throughout the world,” says CAF National President Anthony J. Viola. “The FDA clearly responded to the overwhelming need for this drug in our patient population and has provided those patients needing daily drug therapy to remove iron, an option that has improved cardiac health and prolonged life in thousands of patents over the past decade.”

Ferriprox is an iron chelator, which is a drug that is used to help rid the body of excess iron, a serious and often fatal complication in thalassemia. Because individuals with the severe form of thalassemia are born with a life threatening anemia, they require lifelong blood transfusions as often as every two weeks. These transfusions overload the body with iron; if it is not removed, it settles in the organs, causing heart and liver failure, as well as numerous other complications.

For many years, the only FDA-approved chelator was Desferal, which must be administered by pumping the drug into the body for 8-12 hours, 5-7 nights per week. In 2005, the FDA approved Exjade, a chelator that is administered orally.

Ferriprox is also an oral chelator. In addition to being easier to administer than Desferal, Studies published in Europe demonstrate that use of Ferriprox has been shown to protect the heart from iron accumulation, a crucial concern for individuals with thalassemia.

“The major cause of death in our patient population is iron-related heart failure,” says Viola. “And with a very significant percentage of our population unable to use either Desferal or Exjade, there is a vital need for another option; that option is Ferriprox.”

“We have seen too many patients die too young,” Viola concludes. “Our patients’ lives depend upon having more treatment options available to them. The FDA addressed the unmet medical needs of these desperately ill patients and provided approval for a drug that will help them. Their decision has the opportunity to extend our patient’s lives and significantly improve their quality of life.”

Founded in 1954, the Cooley’s Anemia Foundation (http://www.cooleysanemia.org; (212-279-8090) is the only national non-profit organization dedicated solely to thalassemia. The Foundation’s mission is advancing the treatment and cure for this fatal blood disease, enhancing the quality of life of patients and educating the medical profession, trait carriers and the public about Cooley's anemia/thalassemia major.

Thalassemia in Pregnancy - Organ Functions

2011-10-14T08:09:00.000+05:30

Cardiac function and transfusion requirements

During pregnancy, the fluid component of the blood normally increases. This can increase the degree of anemia, which leads to the need for more frequent blood transfusions. Increased anemia can also result in the heart having to work harder to get adequate oxygen to all of the body's tissues. Increased blood volume can also put stress on the heart. In thalassemia, the heart may already be under stress from the damaging effects of iron overload. Therefore, it is important to have cardiac function checked prior to and throughout pregnancy. Regular attend-ance at scheduled transfusion appointments is also critical in order to reduce anemia and lessen the work that the heart must do.

Liver function

A liver biopsy may be indicated prior to pregnancy to assess the degree of iron overload. This information may be helpful in deciding whether or not to discontinue iron chelation. A liver biopsy can also help determine if there has been damage from iron deposition or previous hepatitis infection. Blood tests throughout pregnancy can also assess liver function.

Endocrine function

Individuals with thalassemia have an increased chance of developing insulin-dependent diabetes as a result of iron overload. The stress of pregnancy can worsen this condition, which can be detrimental to the health of the mother and developing baby. It is important to stabilize diabetes prior to becoming pregnant and to maintain adequate treatment throughout pregnancy. Thyroid function can also be impaired due to iron overload in the woman with thalassemia.

Splenic function

The spleen removes abnormal red blood cells from the circulation and performs important immune functions. Individuals who have thalassemia have unusually large numbers of abnormal red blood cells. The spleen becomes very active in removing these cells. This activity can enlarge the spleen making it more effective at removing even larger numbers or cells, causing a hemolytic anemia. During pregnancy, there is a greater need for hemoglobin both for normal growth and development of the fetus and due to the fact that the blood volume of the mother will increase dramatically. During this time, transfusion requirements in the pregnant woman is increased, particularly during the last trimester of pregnancy. If transfusion in adequate, the bone marrow will be suppressed and the work of the spleen can be decreased. Occasionally, this will lead to some decrease in spleen size and activity.

Anemia in Postmenopausal Women Linked With Poor Nutrition

2011-10-13T15:29:00.001+05:30

Emma Hitt, PhD
Anemia is linked to poor nutrition in postmenopausal women, according to a recent observational study of the Women's Health Initiative (WHI).
Cynthia A. Thomson, PhD, RD, with the University of Arizona, in Tucson, and colleagues reported their findings in the April issue of the Journal of the American Dietetic Association.
According to the researchers, nutritional anemia includes those types associated with prolonged inadequate intake of folate, vitamin B₁₂, iron, protein, and vitamin C.
Dr. Thomson and colleagues hypothesized that a greater number of dietary inadequacies of these nutrients would be associated with a greater risk for incident and persistent anemia.
To evaluate their hypothesis, the researchers used data from the WHI observational cohort study (WHI-OS), which contained a longitudinal sample of postmenopausal women. A total of 93,676 postmenopausal women between the ages of 50 and 79 years were recruited at 40 clinical sites across the United States. Women were enrolled from 1993 until 1998, and data collection was completed in 2000.
Diet was assessed by a food frequency questionnaire for iron, vitamin B₁₂, folate, red meat, and cold breakfast cereal. Dietary intake for women older than 50 years was used as a reference to measure inadequacies. Anemia was defined as a blood hemoglobin concentration of less than 120 g/L in women. Persistent anemia was defined as anemia present at each measurement.
Anemia was identified in 3979 (5.5%) of the participants. Inadequate intake of anemia-associated nutrients was less frequent in non-Hispanic whites (7.4%) vs other racial or ethnic groups (14.6% - 16.3%).
Smoking, age, and body mass index were associated with anemia. Women with anemia reported a lower dietary intake of red meat, folate, vitamin B₁₂, vitamin C, and iron. In addition, deficiencies in dietary intake of 1 nutrient were associated with a 21% greater risk for persistent anemia (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.05 - 1.41), whereas 3 deficiencies in dietary intake resulted in a 44% increase in the risk for persistent anemia (OR, 1.44; 95% CI, 1.20 - 1.73).
Deficiencies in total intake of 1 nutrient were associated with a 34% increased risk for persistent anemia (OR, 1.34; 95% CI, 1.14 - 1.56). Regarding deficiencies in total intake of 3 nutrients, the risk increased to 56% (OR, 1.56; 95% CI, 1.25 - 1.95).
Editorial: Nutrient Measurements Costly
According to editorialists Lisa Tussing-Humphreys, PhD, RD, with the US Department of Agriculture–Agriculture Research Service, in Los Angeles, California, and Carol Braunschweig, PhD, RD, with the University of Illinois, in Chicago, this study provides "one of the largest prospective assessments of diet and anemia in US postmenopausal women."
They add that the findings "lend credibility to the use of an FFQ [food frequency questionnaire] for large epidemiological studies investigating the relationship between diet and anemia risk."
However, according to the editorialists, the mean nutrient intakes reported indicate that "a portion of the anemia observed in the WHI-OS cohort was not diet-related," they write. "For example, it is well known that decreases in hemoglobin occur from nutrient deficiencies only when stores are nearly exhausted."
In addition, although the accurate assessment of anemia allows clinicians to classify the type of anemia and recommend suitable treatment options, inclusion of these measurements in large epidemiologic studies is "cost-prohibitive and unlikely."

Hemoglobinopathy and thalassemia detection

2011-10-06T15:56:00.002+05:30

Traditional methods and a novel method — capillary electrophoresis technology

By Aigars Brants, PhD

In humans, two pairs of unlike globin chains combine with four heme groups to form hemoglobin (Hb), a protein that is carried by red cells and picks up oxygen in the lungs and delivers it to the peripheral tissues. One of the globin chain pairs in hemoglobin is always alpha (with the exception of the very first weeks of embryogenesis), while the second pair is “non-alpha.” That is, it can be made of beta- (ß), delta- (d), or gamma (g) chains.

In the healthy newborn, Hb F (a2g2) is the major hemoglobin (~75%). Fetal hemoglobin (Hb F) is replaced by Hb A (a2ß2) and Hb A2 (a2d2) during the first six to 12 months of life. In healthy adults, hemoglobin is comprised of Hb A (~97%) and Hb A2 (~2.7%), with only trace amounts of Hb F, if any.

Two types of disorders may affect globin chains—qualitative and quantitative. Qualitative disorders, i.e., hemoglobinopathies, result from any of the following: i) substitution of one amino acid for another (as in Hb S and Hb C); ii) deletion of a portion of the amino acid sequence (as in Hb Gun Hill); iii) abnormal hybridization between two chains during meiosis (as in Hb Lepore); and iv) abnormal elongation of the globin chain (as in Hb Constant Spring). Obviously, any alterations listed above lead to changes in molecule structure or charge and they can be detected with the appropriate methodology.

Currently, over 1,400 Hb variants are listed in the globin chain database, with the majority of them being beta chain variants.

Thalassemias are quantitative disorders affecting the rate of otherwise normal hemoglobin synthesis. The ß-thalassemia carrier state is a benign condition with mild anemia, red blood cell hypochromia and microcytosis, and an elevated Hb A2 level. In comparison, severe disease (ß-thalassemia major) requires lifelong blood transfusions and chelation therapy.

Since increase in Hb A2 concentration is indicative of beta-thalassemia, it is useful to obtain an accurate relative Hb A2 value. With many testing methods, common Hb variants can interfere with an accurate Hb A2 quantitation. It is also important to account for delta chain Hb variants in the sample; if any are present, the delta chain variant concentration (percentage) must be added to the Hb A2 value to obtain an accurate total Hb A2 concentration.

Alpha-thalassemia affects the synthesis of alpha globin chains, and the severity of disease is dependent on the extent of gene deletion. Loss of two out of four alpha-chains encoding genes results in an a-thalassemia trait, characterized by microcytosis with little or no anemia. Loss of three genes results in Hb H (4ß chains) disease, a moderate hemolytic anemia, while loss of all four genes is incompatible with independent life.

Electrophoretic hemoglobin separation methods

Electrophoresis has long been the method of choice in hematological laboratories for qualitative and quantitative hemoglobin analyses. Currently, four different techniques are routinely used in the lab setting: 1) alkaline and acid gel electrophoresis; 2) isoelectric focusing (IEF); 3) high-pressure liquid chromatography (HPLC); and 4) capillary electrophoresis (CE).

Sebia Electrophoresis provides multiple platforms for the detection of hemoglobinopathies and thalassemias—fully automated capillary electrophoresis systems and a semi-automated agarose gel system to accommodate both alkaline and acid agarose gel electrophoresis.

Alkaline and acid agarose electrophoresis

Because of its simplicity, alkaline gel electrophoresis is one of the most popular methods for Hb screening. Semi-automated agarose gel electrophoresis is also cost-effective for low- to medium-volume laboratories. However, the technique is relatively laborious, requiring manual sample preparation. Red blood cells must be washed in saline to remove plasma proteins and to eliminate non-hemoglobin bands on the gel. Electrophoresis at alkaline pH (8.5) allows for the separation of the major hemoglobins and a number of less common Hb variants. Visualization of the Hb bands is done by automated staining of the gel with amido black. The clear background of the gels enables measuring the concentration of individual fractions by densitometric scanning. However, due to the precision and accuracy of Hb in low concentrations (Hb A2 for example), the College of American Pathologists (CAP) no longer recommends the use of densitometric scanning for quantification of Hb A2. With alkaline agarose gel testing, some common Hb variants comigrate, such as Hb C, Hb E, Hb A2 & Hb O-Arab and Hb S, Hb D and Hb G.

In order to separate some Hb variants that commonly comigrate at alkaline conditions, the sample may also be analyzed on gel at an acidic pH (6.0). In these conditions, molecular charge will differ and migration patterns will change. As a result, Hb S can be differentiated from Hb D, and Hb C can be differentiated from Hb E.

Isoelectric focusing

IEF provides excellent separation of many hemoglobin variants and detects fast-migrating or low concentration hemoglobin variants such as Hb H, Hb Bart’s, and delta chain variants.

IEF gels contain special molecules—ampholytes—that create a pH gradient in an electrical field. When a pH gradient is present, hemoglobin molecules migrate to a position on the gel where the net charge equals zero (0), resulting in very narrow and focalized bands. On IEF gels, Hb C separates from Hb E and Hb O-Arab, and Hb S from Hb D and Hb G. IEF gels, however, are processed manually and require a significant amount of technical time. Additionally, IEF results are qualitative, and interpreting results requires significant experience.

High pressure liquid chromotagraphy

HPLC is a pressure-driven technique. Hemoglobin samples are injected into a resin column and retained based on the charge. The eluting solution that competes for the negatively charged resin is added in increasing concentration. Hemoglobin variants elute from the column and are detected at 415 nm, then at 690 nm to correct the baseline of the result. The hemoglobin retention time (from injection until the maximum point of each peak) is calculated and plotted on a chromatogram.

HPLC instruments are primarily indicated for the measurement of Hb A2 and F, but also provide data (retention times) on many Hb variants. However, HPLC should not be used as the sole method for identification of hemoglobin variants.¹ HPLC is very complementary to CE technology; together these two automated methodologies provide valuable data for result interpretation.^2,3 HPLC techniques result in patterns that are relatively complex and require training and experience for interpretation of results.⁴

Capillary electrophoresis

CE technology utilizes liquid flow electrophoresis—buffer replaces agarose gel as the medium. Hemoglobin variants are separated by electroosmotic flow at an alkaline pH (9.4) using negatively charged silica capillaries and high voltage. Multiple samples undergo an eight-minute high-resolution separation, concurrently. A high-resolution hemoglobin separation is obtained, similar to IEF separation. The ideal wavelength of 415 nm is utilized for hemoglobin detection with CE. The result, or electropherogram, is made up of 300 consecutive readings (dots) and is divided into 15 zones. To facilitate interpretation, results are automatically positioned with regard to the Hb A and Hb A2 fraction in the sample. Hemoglobins (normal and variant) are displayed as peaks, and the zone to which a variant belongs is identified automatically by the system. An on-board hemoglobin library is present in the form of a drop-down list and lists all of the normal and variant hemoglobins that may be present within a particular zone.

With Sebia’s CE systems, packed red blood cell samples are utilized for analysis. Plasma is removed from samples, and the bar-coded primary sample tube is loaded onto the instrument; all other steps in sample processing and separation are performed automatically by the system.

More features of CE technology

In one analysis, separation of Hb S from Hb D, and Hb C from Hb E (and from Hb A2).
Precise, quick quantification of Hb F and Hb A2, even in the presence of Hb S.⁵
Posttranslational Hb variants (such as glycated HbS1c) do not separate from the main fractions.⁶
Delta chain variants, alpha chain variants, and other minor Hb fractions are readily visualized.⁸
Hb H and Hb Bart’s are more readily detected and measured by CE than by the HPLC method .⁴

Multiuse instrument

Sebia systems may be used for other types of analysis, including serum/urine protein electrophoresis, immunotyping (automated immunofixation alternative), and CDT (a marker for chronic alcohol abuse)⁸

CAP requires the use of a second, complementary technique for abnormal hemoglobin results. CE is most complementary with acid gel electrophoresis and HPLC. By combining CE and HPLC methodologies, one can significantly reduce the number of unusual hemoglobin variants that can be confused with normal hemoglobins or common Hb variants (2).

Newborn screening with dried blood spot samples

Sebia’s newest FDA-cleared CE assay for hemoglobinopathy testing is Capillarys Neonat Hb Fast. It is used for the screening of newborn blood samples collected on Guthrie Cards. Newborn dried blood spot samples are screened for the presence of normal hemoglobins (F and A) and common hemoglobin variants to include S, C, D, E, and Bart’s. The system is fully automated and fast, with an instrument throughput of 96 results in two hours. The fast throughput is accomplished due to eight simultaneous analyses taking place; a high-resolution seven-minute migration occurs for each newborn sample with results similar to IEF separation. Result interpretation is aided by automatically color-coded curves (normal or abnormal results) and on-board hemoglobin library by zone. All normal hemoglobins and common variants migrate in different zones—Bart’s, A, F, D, S, E, A2, and C.

The following table lists HPLC migration characteristics in the presence of common variants.

Hb present	Hb A2 result	Hb F result	Comments
S	falsely elevated		coelution of Hb S1c fraction with A2 ⁽⁴⁾
E	falsely elevated		coelution of Hb E with A2 ⁽⁴⁾
D	underestimated		⁽³⁾
G-Philadelphia	falsely elevated		coelution of G-Philadelphia with A2
Lepore	falsely elevated		coelution of Lepore with A2 ⁽³⁾
A1c (elevated)		falsely elevated	⁽³⁾

Poor Eating Habits May Lead to Anemia in Older Women

2011-05-25T16:33:00.000+05:30

Study finds that as nutrient intake declines, risk rises

By robert preidt

FRIDAY, March 25 (HealthDay News) -- A poor diet is associated with a greater risk of developing anemia among postmenopausal women, a new study has found.
Researchers analyzed data from 72,833 older women in the United States and found that deficiencies in more than a single nutrient were associated with a 21 percent increased risk of persistent anemia. Risk increased 44 percent with deficiencies in three nutrients.
Women with anemia consumed less protein, folate, vitamin B12, iron, vitamin C and red meat than did others, the study found. The results are published in the April issue of the Journal of the American Dietetic Association.
Inadequate nutrient intake was less frequent among whites than in other racial or ethnic groups: 7.4 percent, compared with 14.6 percent of Asian/Pacific Islanders, 15.2 percent of Native Americans/Alaskans, 15.3 percent of blacks and 16.3 percent of Hispanics.
The researchers also found that the use of multivitamin and mineral supplements was not associated with lower rates of anemia. Age, body mass index and smoking were associated with anemia.
Anemia has been linked to an increased risk of death and, "anemia, particularly iron deficiency, has been associated with reduced capacity for physical work and physical inactivity, injury related to falls and hospitalizations, making this an important health-care concern in the aging," lead investigator Cynthia A. Thomson, associate professor of nutritional sciences at the University of Arizona in Tucson, said in a journal news release.
"Efforts to identify anemia that may be responsive to modifiable factors, such as diet to improve health outcomes, are needed," the researchers concluded. "Additional efforts to regularly evaluate postmenopausal women for anemia should be considered and should be accompanied by an assessment of dietary intake to determine adequacy of intake of anemia-associated nutrients, including iron, vitamin B12 and folate," they wrote.
"While the type of anemia is often designated by a more comprehensive biochemical assessment than hemoglobin alone, nutritional therapy to improve overall nutrient-density and quality of the diet should also be a clinical focus," Thomson and colleagues said.

4-year-old cured of Thalassemia major with stem cell transplant

2011-05-24T08:02:00.000+05:30

Ahmedabad doctorshave carried out a rare successful stem cell transplant on a four-year-old girl suffering from Thalassemia major, relieving her of life-long blood transfusions.
Isha Gohel from Saurastra, who was diagnosed of suffering from advanced stages of Thalassemia, had started receiving blood transfusions at the age of 18 months.
When she was brought to Apollo hospital in Ahmedabad, doctors after investigations found that she was a case of class 3 Thalassemia Major. Since she did not get good quality blood transfusion, her condition was very poor. She had developed marked enlargement of the spleen leading to further poor response to blood transfusions.
Terming Isha's case as challenging, Dr Chirag A Shah, haematologist, Apollo hospital here, said that they followed the style of treatment of Dr G Lucarelli from the Mediterranean Institute of Haematology - an international centre for transplantation in thalassemia and Sickle Cell Anaemia - in Italy who has successfully treated advanced cases of thalassemia.
Her spleen was removed and stems cells from Isha's two-year-old brother were transplanted. "We followed his (Lucarelli's) formulae for treatment of Isha and we were successful," he said.
"Stemcell transplant in advanced cases of thalassemia results in poor outcome. Such patients are not advised a transplant as they frequently have poor results and have high risk of complications," Shah said.
He said that Isha's case was difficult for them as her spleen had blown out of proportion and her liver too was damaged due to iron deposits.
Giving details of her treatment, he said, "We first surgically removed her spleen in January and the following month we started on a special protocol of medicines to reduce her risk of being Class 3. This continued for over one month until finally she underwent stem cell transplant procedure in April. The stem cells were from her younger brother."
Isha is now on the road to recovery and and will be transfusion free forever as her underlying Thalassemia major is now cured after stem cell transplant.

"Behavioral Strategies for Parents" Webinar Available Online

2011-05-14T17:06:00.001+05:30

Dr. Lauren Mednick's presentation on "Behavioral Strategies for Parents of Children with Thalassemia," CAF's March 2 webinar, is now available for watching.

Lauren Mednick, PhD, is an assistant in Psychology at Children’s Hospital Boston and is on the faculty at Harvard Medical School. She received her B.S. in Psychology from the University of Illinois and both her Master of Philosophy and her PhD in Clinical Child Psychology, with an emphasis on behavioral medicine, from The George Washington University. Her subsequent clinical, teaching and research efforts have focused on helping children and families cope with medical stressors. The majority of her time is spent in direct clinical care, conducting outpatient therapy with children and adolescents diagnosed with acute and chronic medical conditions, including thalassemia. Dr. Mednick also has an interest in how a parent is coping impacts a child’s physical and emotional well-being and focuses much of her work on investigating stress and coping in parents of children diagnosed with various medical conditions. CAF is thrilled to be able to offer the experience and knowledge that Dr. Mednick has learned working with families with thalassemia, as well as with other chronic conditions.

Kolkata conducts unique Thalassemia treatment

2011-05-14T16:54:00.000+05:30

A Kolkata hospital conducted the first successful mixed stem cell (cord blood and bone marrow) transplant surgery to give new life to a child suffering form the HbE-Beta Thalassemia disease.
Dr. Ashish Mukherjee conducted the surgery on Apr 3 to treat a five year old boy named Moinam at the Netaji Subhash Chandra Bose Cancer research Institute in Kolkata.

For conducting this treatment they took the stem cells from the cord blood of the second child (sister of Moinam) of Ashim Pal and Monisha Pal and then preserved it under specified conditions at CordLife, lrgest network of stem cell bank with full processing.

"When stem cells are needed to treat a life threatening disease, doctors ans can effectively predict transplant success by evaluating two factors-HLA compatibility and stem cell count," Prosanto Chowdhury, Medial Director, Cord Life India, said.

"Transplants like these confirm CordLife's technology and our assurance to parents who bank with us their baby's cord blood. HLA matching was undertaken which provided that the tissues of both the children matched and the treatment could proceed. This is the first case of mixed stem cell transplant in India," he said.

Thalassemia is an inherited blood disorder in which the body produces an abnormal form of haemoglobin, the metallo protein in red blood cells that carries oxygen.

However, in case of Thalassemia when an HLA identical sibling marrow donor is available, the chance of cure is currently as high as 90 percent.

Illustrating the complicated treatment, Dr. Ashish Mukherhjee, Director NCRI, said: "The first step was to destroy all the existing bone marrow cells for which the conditioning chemotheraphy was used. Then the donor's stem cells from two different sources were injected into the patient's body."

"Bone marrow stem cell, on the other hand leads to Graft Versus Host Disese which is triggered by the body's defence mechanism while the transfusion is being done. The two therapies can complement, not only increase the Stem Cell count but also reduce the chance of Graft versus Host disease and lead to a complete cure," Mukherjee said.

The stem cells that were transplanted in the young patient came from his sister's cord blood and bone marrow.

"It was Dr. Asish Mukherjee who gave our child a new life. He told us that our child will get cured and that was the assurance on which we were bagging upon," Ashim Kumar Pal, father of Moinam said.

No marriage for Thalassemia couples in Sri Lanka

2011-05-14T16:50:00.002+05:30

The Health Ministry will introduce legal provisions to forbid marriages between two Thalassemia carriers to eradicate the disease from Sri Lanka, Health Minister Maithripala Sirisena said.

Minister Sirisena said the ministry has taken measures to make blood tests mandatory for every young couple before marriage.

“If the blood tests do not bring the desired results, the Health Ministry has no option but to bring legislations forbidding marriages between two Thalassemia carriers as Thalassemia is a hereditary disease. Our aim is to eradicate Thalassemia from Sri Lanka by 2015,” Minister Sirisena stressed.

The government spends around Rs. 1.6 billion to treat Thalassemia patients annually and Rs. 350 million out of it is spent only on drugs. If Thalassemia which is a preventable disease could be eradicated, the government can utilize these funds for a better cause, he said.

Some 250,000 marriages are performed annually in Sri Lanka and offspring of 1,600 parents are born with Thalassemia. Latest data shows that there are 1,600 Thalassemia patients in the country and 160 of them are children.

Thalassemia cured using cord blood stem cells

2011-04-27T08:19:00.000+05:30

R. PRASAD

Cord blood and bone marrow stem cells with a perfect tissue match from her one-year-old brother were used for transplantation

Eight-year-old Thamirabharuni and her one-year-old brother Pugazhendhi share a special kind of bond not commonly seen among siblings. Thanks to her brother, Thamirabharuni no longer suffers from thalassemia disease.
The stem cells transplanted in March helped her get rid of thalassemia. And hundred days after the procedure, one can safely say that her disease has been cured.
The stem cells that were transplanted came from two different sources — her brother’s cord blood, which was harvested during the time of his birth, and his bone marrow. Stem cells from the bone marrow had to be transplanted as there was insufficient number of stem cells in Pugazhendhi’s cord blood.
In the absence of cord blood stem cells, about 200 ml of bone marrow would have been required. It is difficult to get this quantity of bone marrow from a nine-month-old baby.
The cord blood was collected by and stored at Chennai based LifeCell International Pvt. Ltd., a private cord blood bank.
Risk of infection

So is it all over? “One has to be still careful. There is a risk of infection till the end of the first year [after transplantation],” said Dr. Revathy Raj, Consultant Paediatric Haemato Oncologist, Apollo Speciality Hospital, Chennai. Dr. Raj had done the transplantation for Thamirabharuni and two other cord blood transplantations for thalassemia before this.
The fact that patients are on immuno suppressing drugs for one year makes them vulnerable to infections. The risk of rejection of the transplanted stem cells, and the graft versus host disease (GVHD) reduce with time.
Thalassemia arises when red blood corpuscles (RBC) production is defective. A person suffers from the disease only when he inherits a defective gene from both parents. He becomes a carrier when he inherits a defective gene from only one parent. The diseased person has to undergo blood transfusion once every month for the rest of his life.
Gold standard

Though stem cells separated from bone marrow have been used for more than 30 years to treat thalassemia, and is a gold standard in treating the disease, cord blood stem cells are slowly becoming an attractive alternative.
Contrary to what is projected by some cord blood banks, doctors are very reluctant to use cord blood stem cells to treat thalassemia in the absence of a full tissue match.
Perfect match

“We need a 6/6 [perfect match] for thalassemia. Even a 5/6 match is not sufficient,” asserted Dr. Raj. And doctors refrain from using stem cells from unrelated donors, even if there is a perfect match.
Apart from infections, there are two major challenges from transplantation — graft versus host disease (GVHD) and rejection of the donated stem cells. “There is a 30 per cent chance of having graft versus host disease even when it is from a fully matched related (sibling) donor.” This risk increases to 50 per cent when it is from an unrelated donor, even if there is 6/6 tissue match.
Rejection rate becomes an issue even when there is a perfect tissue match. According to her, in the case of thalassemia, the rejection rate can be up to 20 per cent even with related donors, and up to 40 per cent in the case of unrelated donors.
But why should rejection and GVHD be an issue at all when there is a perfect 6/6 tissue match, and why should it be so high when stem cells are from unrelated donors?
Minor HLAs not tested

“There are several minor HLA antigens that are not tested. So if we use stem cells from people belonging to some other ethnic background, there are greater chances of [minor] HLA differences,” Dr. Raj stressed. “And this causes rejection and GVHD.”
In general, greater the tissue match and higher the stem cell count in cord blood, lesser are the chances of rejection and GVHD.
“So why undertake procedures that are risky when thalassemia can be treated through monthly transfusions,” she noted.
Private banking of cord blood for use by the family therefore becomes important when one of the siblings is suffering from a disease that can be cured using it.
Case for public banking

Despite the risk of rejection and GVHD, a less than perfect sample can be used to treat children suffering from life threatening diseases such as leukaemia and aplastic anaemia. This is where public cord blood banking gains significance.
There is a strong case for promoting public banks as depending solely on bone marrow samples will not be wise.
Even if a perfectly matched bone marrow donor is found, chances are that the person may no longer be interested in donating.
Collecting cord blood samples is easy, the number of samples that can be banked is limited only by resources, and samples can be made available at very short notice.

Medical leap gives hope to blood disorder sufferers

2011-02-15T15:16:00.000+05:30

Gene therapy for the blood disorder beta-thalassemia will be carried out in Thailand for the first time by the end of this year.

A team of doctors at Ramathibodi Hospital is studying the gene therapy technology alongside experts in Paris under a collaboration programme between the Mahidol University led by Prof Suthat Fucharoen and French-American researcher Philippe Leboulch of Harvard Medical School and the University of Paris.
The Thai doctors expect to return to Thailand to conduct a trial around December, said Dr Suradej Hongeng, of Ramathibodi Hospital's department of pediatrics.
The collaboration came about after the world's first successful treatment of beta-thalassemia with gene therapy.
A 21-year-old Frenchman treated with the therapy in 2007 now no longer has the need for blood transfusions. He previously had required transfusions every month since birth.
The successful treatment was published in the journal Nature last September.
Beta-thalassemia is caused when a patient cannot produce enough of the beta-globin component of haemoglobin, the protein used by red blood cells to carry oxygen around the body. This can cause life-threatening anaemia, leading to severe damage of the body's major organs.
Gene therapy is generally the insertion, alteration or removal of genes within a patient's cells and biological tissues to treat disease.
"This success justifies the hopes placed in the use of gene therapy to treat blood diseases," said Dr Suradej, a haematology specialist.
"It is also the first time an effective technology has been developed to improve the quality of life for people with thalassemia."
An estimated 20 million Thais are carriers of thalassemia. It is one of the world's most common genetic disorders, putting an enormous financial strain on Thailand and countries located in the "Thalassemia Belt", which stretches from the Mediterranean through the Middle East and Central Asia to Southeast Asia.
About three in 800 children born in Thailand are affected by the severest form of the disorder, beta-thalassemia, requiring regular blood transfusions.
However, blood transfusions carry the risk of contracting HIV and hepatitis B and C from donors, or iron overloading.
The only known cure for the condition is through a bone marrow transplant.
However, this process is dangerous and it can be very difficult to find a matching bone marrow donor, Dr Suradej said.
He hoped the gene therapy for thalassemia treatment would eliminate the problems posed by bone marrow transplants, as well as lead doctors to adapt the technology to treat the symptoms of beta-thalassemia, such as as neurological problems and muscle disabilities.

France's first 'saviour sibling' stirs ethical debate about biotechnology

2011-02-10T15:28:00.000+05:30

The country’s first "saviour sibling", a healthy boy whose discarded umbilical cord will help heal one of his two siblings from a genetic blood disease, has brought complicated ethical issues over biotechnology to the forefront in France.
France’s first so-called "saviour sibling" was born in a hospital in the Parisian suburb of Clamart in late January, doctors announced Tuesday. The baby, whose blood stem cells will help cure one of his siblings from a severe genetic blood disease, has also opened a new front in the bioethics debate in France.
Born to parents of Turkish origin and named Umut Talha (Turkish for "our hope"), the child was conceived under circumstances that would have been unthinkable only a generation ago.
Umut Talha’s parents approached the hospital in Clamart a little more than a year ago with a serious problem: their two young children were both afflicted with an inherited blood disorder, Beta thalassemia, which requires monthly blood transfusions. The parents knew the hospital was one of only three in France that was developing a treatment for their children's illness.
An embryo was screened and genetically selected from an original group of 12 embryos. It was picked to ensure it did not carry the gene for Beta thalassemia, but also based on its compatibility with the sick siblings. Besides selecting an offspring that would be spared from the disorder, the parents hoped the future baby would also become a donor of the right kind of treatment cells.
In the end the boy was born disorder-free, and his cells were confirmed to be compatible with his older sister, now aged two. Doctors feel confident that Umut’s sister will be cured with the cells from his discarded umbilical cord, and her monthly blood transfusions will be discontinued.
The family have since returned to their home in southern France, but they plan to return to Clamart to undergo the same procedure to cure their other child, Umut’s four-year-old brother.

Hopes and hurdles
French newspapers spread “medicine baby” across headlines on Tuesday. But speaking at a press conference René Frydman, a fertility pioneer and father of the first French test-tube baby, who also oversaw Umut’s case, said he preferred the term “double-hope baby”.
“Medicine baby is a media term invented by people who are against this kind of procedure,” Frydman told reporters. In English-speaking countries, the terms “donor baby” and “saviour sibling” have been widely used in the media.
For Frydman, Umut represents a double hope for his parents: the hope of having a new, healthy baby, and the hope of curing one of their sick children. But other scientists, religious groups and parents beg to differ.

The issue of saviour babies has raised complex ethical debates, and renewed fears of a move towards “designer babies”, or babies whose traits – such as intelligence, eye-colour and height – have been predetermined.
The timing of Umut's birth could be significant. The very law that allows for cases like Umut’s is being revised starting today. Observers say that the existing legislation guiding biotechnology in France may be tightened and restrict research in certain fields, including stem cells.
The country’s standing bioethics law allows for cases like Umut’s. In fact, the government has earmarked 800,000 euros per year for Clamart to practice and develop the procedure.
But Frydman and his colleagues say a lot more needs to be done, complaining of endless hurdles to launch further research and access funds. They regret that France has started a decade after the United States and that the government is still reluctant to give them its full backing.

Researchers report gene therapy strategy that improves Beta Thalassemia in mice model

2011-02-10T13:49:00.000+05:30

Researchers at Nationwide Children's Hospital report a gene therapy strategy that improves the condition of a mouse model of an inherited blood disorder, Beta Thalassemia. The gene correction involves using unfertilized eggs from afflicted mice to produce a batch of embryonic stem cell lines. Some of these stem cell lines do not inherit the disease gene and can thus be used for transplantation-based treatments of the same mice. Findings could hold promise for a new treatment strategy for autosomal dominant diseases like certain forms of Beta Thalassemia, tuberous sclerosis or Huntington's disease.
Embryonic stem cells have the potential to produce unlimited quantities of any cell type and are therefore being explored as a new therapeutic option for many diseases. Unfertilized eggs can be cultured to form embryonic stem cells, so-called parthenogenetic embryonic stem cells.
"Parthenogenetic embryonic stem cells can differentiate into multiple tissue types as do stem cells from fertilized embryos," said K. John McLaughlin, PhD, principal investigator in the Center for Molecular and Human Genetics at The Research Institute at Nationwide Children's Hospital. Previously, the group demonstrated that blood cells derived from parthenogenetic cells could provide healthy, long-term blood replacement in mice.
"Advantages of parthenogenetic stem cells are not only that fertilization is not needed, but also that the recipient's immune system may potentially not view them as foreign, minimizing rejection problems. Furthermore, since parthenogenetic embryonic stem cells are derived from reproductive cells which contain only a single set of the genetic information instead of the double set present in body cells, they may not contain certain abnormal genes present in the other copy," said Dr. McLaughlin also one of the study authors.

A single copy of an abnormal gene inherited from one parent can cause so-called autosomal dominant diseases such as tuberous sclerosis or Huntington's disease. The affected person has one defective and one normal copy of the gene, but the abnormal gene overrides the normal gene, causing disease. In normal sexual reproduction, each parent provides one gene copy to offspring via their reproductive cells. Therefore, the reproductive cells of a patient with an autosomal dominant disease could either pass along a defective copy or a normal copy.
"As the donor patient has one defective gene copy and one normal, and only one copy is used for normal reproduction, we can select egg-cell-derived embryonic stem cells with two normal copies," said Dr. McLaughlin. "These single-parent/patient-derived embryonic stem cells can theoretically be used for correction of a diverse number of diseases that occur when one copy of the gene is abnormal," said Dr. McLaughlin.
To test this theory, Dr. McLaughlin and colleagues from the University of Pennsylvania, University of North Carolina and University of Minnesota, examined whether parthenogenetic embryonic stem cells could be used for tissue repair in a mouse model of thalassemia intermedia. Thalassemia intermedia is an inherited blood disorder in which the body lacks sufficient normal hemoglobin, leading to excessive destruction of red blood cells and anemia. They used a mouse model in which one defective gene copy causes anemia.
Using approaches developed from a previous study done by this group, Nationwide Children's Research Fellow Sigrid Eckardt, PhD, derived embryonic stem cells from the unfertilized eggs of female mice with the disease, and identified those stem cell lines that contained only the "healthy" hemoglobin genes. These "genetically clean" embryonic stem cell lines were converted into cells that were transplanted into afflicted mice that were carriers of the disease causing gene. Blood samples drawn five weeks after transplantation revealed that the delivered cells were present in the recipients' blood. Their red blood cells were also corrected to a size similar to normal mice and red blood cell count, hematocrit and hemoglobin levels became normal.
"Overall, we observed long-term improvement of thalassemia in this model," said Dr. Eckardt. "Our findings suggest that using reproductive cells to generate embryonic stem cells that are 'disease-free' may be a solution for genetic diseases involving large, complex or poorly identified deletions in the genome or that are not treatable by current gene therapy approaches." Dr. McLaughlin says that this approach also contrasts with typical gene therapy approaches in that it requires no engineering of the genome, which is currently difficult to achieve in human embryonic and embryonic-like (IPS) stem cells.

Source: Nationwide Children's Hospital

Gene Rx May Fight Severe Blood Disorder

2010-09-21T08:26:00.000+05:30

But far more research is needed to know whether treatment is safe and effective, researcher cautions

By Steven Reinberg - HealthDay Reporter

Patients suffering from a severe, inherited blood disorder may one day benefit from a new gene therapy and no longer need regular blood transfusions, new research suggests.
However, far more study is needed to determine whether the therapy is safe and effective. So far only one patient has received the experimental treatment, and the researchers have followed him for only three years.
The blood disorder -- beta-thalassemia -- occurs when a crucial blood protein known as beta globin is missing from the red blood cells that carry oxygen. Without beta globin, many of the red blood cells die off, causing severe anemia and eventually death if the person goes untreated.
Beta-thalassemia mostly affects people of Mediterranean, Middle Eastern, Southeast Asian and Chinese descent. Some 100,000 children are born with the disease each year around the world, according to the March of Dimes, and untreated, those with the most severe form usually die in childhood.
In those treated, the excess iron building up from the blood transfusions must be removed with chelating drugs, which can cause unpleasant side effects ranging from joint pain and vomiting to vision and hearing problems.
And even though lifesaving treatments have greatly improved prospects for long-term survival, those with the disorder are at risk of heart failure and other life-threatening complications -- some related to the treatments themselves -- as they age.
Among those struggling with this illness -- and often losing -- was a teenager who volunteered for the gene therapy. Like many others, he needed a matched donor for a stem cell transplant, but none was available, the study noted.
"The patient was 18 years old when we first treated him and [had been] transfused monthly for most of his life," said lead researcher Dr. Philippe Leboulch, a professor of medicine and cell biology at the University of Paris in France.
Transfusions continued until a year after the treatment, Leboulch said. "One year after the treatment he became transfusion-independent," he said. "That has been the case for over two years now."
For the study, Leboulch's team worked on a modified virus and removed all the viral genes. They then replaced those genes with a so-called globin gene. In addition, they added factors so the gene would act only on red blood cells, where the iron-rich protein known as hemoglobin normally carries oxygen throughout the body.
This new "gene" was then injected into the patient, where it went on to repair the damaged globin gene and started producing normal hemoglobin, Leboulch said.
"This is one more example of a gene therapy that starts to show a clinical benefit for patients," he said.
However, Leboulch is cautious. "This is the first patient in the trial. Of course we need to do more patients and see what happens," he said.
Leboulch noted another problem with gene therapy: the inability to control all the effects a new gene will have in the body. The globin gene, for example, appears to link to another gene that is involved in cell growth, causing a mild expansion of blood stem cells in the patient's body. This could account for some therapeutic benefits, but might also be a precursor to cancer, the researchers noted.
"So far there is no sign of any abnormality," Leboulch said.
Dr. Francoise Bernaudin, a clinical hematologist who has followed the patient since early childhood, said it was "wonderful to see that this young man is for now free of transfusions and injections for iron chelation.
"He is happy to have a normal life back, and for the first time has a full-time job as a cook in a main restaurant in Paris," said Bernaudin in a news release on behalf of bluebird bio, developer of the LentiGlobin gene therapy treatment that the researchers are using. The trials are sponsored by the Cambridge, Mass.-based bluebird bio.
The report is published in the Sept. 16 issue of Nature.
Based on their initial success with gene therapy, Leboulch's group plans to treat another two patients. If they also respond well, they will enroll "a larger cohort" of patients, he said.
In addition, the researchers plan to treat patients who have sickle cell disease with the gene therapy as well, Leboulch said. The same technique can be used for both diseases, he said.
Leboulch concedes that the treatment is very expensive. But he hopes that if it becomes widely used, the price will drop, eventually costing less than a lifetime of monthly transfusions and chelating drugs.
Dr. Mustafa Tekin, an associate professor at the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine, said that "gene therapy has been long awaited for thalassemia."
"This is the first example of a successful gene therapy for beta-thalassemia," he said. "This brings great hope for patients for the final cure for the disorder."
However, there are possibilities of adverse effects, Tekin said. He joined the researchers in cautioning that treatment to date has been limited to just one patient.
Tekin said that the gene that absorbed the therapeutic gene is associated with certain cancers, such as leukemia. While the patient does not have signs of the cancer, it is important "to follow this patient for the long-term for signs of leukemia," he said.
More trials and patients are needed to really assess the effects and side effects of the treatment, Tekin said. Whether it will treat other forms of thalassemia isn't known, he added.
"One patient is important and a significant achievement, but you still need to see more patients to make sure that it works for many patients and also that it works safely," he said.

Anemia Drugs Could Pose Threat to Some Kidney Patients

2010-09-21T08:12:00.001+05:30

Study finds 'poor responders' to meds like Aranesp at higher risk for heart trouble, death

By Serena GordonHealthDay Reporter

When people with chronic kidney disease and type 2 diabetes take certain anemia drugs, the level of hemoglobin cells in their blood should go up.
But a new study finds that if those levels don't increase by much, these "poor responders" experience a significantly increased risk of heart problems and death.
Reporting in the Sept. 16 issue of the New England Journal of Medicine, a team of international researchers says that those who had the worst response to erythropoiesis-stimulating agents (ESAs) -- drugs that include Aranesp, Epogen and Procrit -- had a 31 percent rise in the risk of cardiovascular complications and a 41 percent increased risk of death.
"For people who have chronic kidney disease, I think this is further evidence that we have to be extremely cautious when we use ESAs. There is a potential for harm. The patients who respond poorly are the ones who get the most drug, and we may be putting them at increased risk," said the study's lead author, Dr. Scott Solomon, director of noninvasive cardiology at Brigham and Women's Hospital and an associate professor of medicine at Harvard Medical School in Boston.
"What we can't determine from this study is if these patients had worse outcomes because they were sicker to begin with, or because they got more of the drug, or some combination of the two," added Solomon.
When someone has kidney disease, the kidneys may not produce enough of the hormone erythropoietin to prevent anemia, a deficiency in red blood cells. Symptoms of anemia include fatigue and pale skin, and it can even contribute to heart disease, according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases.
ESAs were developed to replace the missing erythropoietin in kidney patients and stimulate red blood cell production. But these drugs can cause serious, even life-threatening complications in some patients. Because of this, the U.S. Food and Drug Administration requires manufacturers to include a warning about the risks.
The current study is a secondary analysis of a randomized, double-blind, placebo-controlled study done in 24 countries from 2004 to 2009. All of the study volunteers -- 1,872 in all -- had type 2 diabetes and chronic kidney disease.
The study volunteers were randomly assigned to receive either 0.75 micrograms of darbepoietin alfa (Aranesp) per kilogram of body weight or a placebo. In people who didn't respond well to the initial dose of the drug, the dose was repeated after two weeks. After that, hemoglobin levels were monitored and doses adjusted based on an individual's hemoglobin levels, reported the study.
In the initial analysis of these study volunteers, the researchers found no reduction in the risk of death or of cardiovascular or kidney problems in those taking the drug compared to those on placebo. But they did see a significant increase in the risk of stroke. Solomon said there was only a slight, "unimpressive" increase in quality of life for those taking the ESA.
At the same time, other studies have been finding an increased risk of heart problems in people taking ESAs. Solomon's team wanted to know why some people might be at greater risk than others.
In a sub-analysis of the initial study, they divided the group into four smaller groups based on their response to darbepoietin alfa, which is how they found the increased risk of death and cardiovascular events in people who responded poorly to the drug.
Solomon said he thinks this effect would likely be seen in other ESAs, not just darbepoietin alfa. Amgen, the maker of Aranesp, provided funding for the study.
"This study helps clarify some of the confusion from previous studies. When you isolate who are the people who got into trouble, it was people who wouldn't respond to ESAs. I think it helps clarify how to use ESAs. If I see that you don't respond, there may be something else going on with you, and I need to give you some special attention because you're at greater risk of having a bad outcome," said Dr. Robert Provenzano, chair of the department of nephrology at St. John Providence Health System in Detroit.
But, if you respond normally to ESAs, he said, the drugs may improve your quality of life when the medication is adjusted to keep your hemoglobin levels between 10 and 12.5 mg/dL.
Solomon said he wasn't sure if the modest benefit seen in patients was worth the potential increase in stroke risk. Provenzano countered that such a decision needs to be individualized based on the effects of the anemia, along with other aspects of the patient's life.
If you take this medication, Provenzano suggested asking your doctor where you fall on the continuum of response and whether you're in a high-risk group.

Gene-therapy hope for β-thalassaemia patients

2010-09-17T10:31:00.000+05:30

A defective haemoglobin gene has been successfully replaced with a healthy copy.

Joseph Milton

Gene therapy for a form of β-thalassaemia, a genetic disorder whose sufferers require frequent blood transfusions because they cannot properly produce red blood cells, seems to have been successful in a patient who, three years after treatment, no longer requires transfusions¹. Doubts remain, however, over whether a set of lucky circumstances is behind the success.
Patients with β-thalassaemia carry faulty copies of the genes needed to produce the β-globin chain of haemoglobin, sometimes lacking the genes altogether. This leads to a shortage of red blood cells, the body's oxygen carriers.
Sufferers must have regular blood transfusions throughout their lives, an inconvenient and debilitating regime that ultimately shortens life expectancy. The only known cure is stem-cell transplantation, but few patients are able to find a suitable donor.
Because of the gruelling nature of this treatment, the development of gene therapies for β-thalassaemia is seen by many as an exciting prospect. The subject of the latest trial was an 18-year-old man with β^E/β⁰-thalassaemia — in this form of the disease, one copy of the β–globin gene produces unstable β-globin and the other copy is non-functional.
Around half of the patients with this form of β-thalassaemia are dependent on transfusions, and the patient concerned had received blood transfusions since the age of three.
Philippe Leboulch of Harvard Medical School, part of the team that carried out the study, described the treatment as "life-changing". "Before this treatment, the patient had to be transfused every month. Now he has a full-time job as a cook," he says.

Unrepeatable?

However, Michael Antoniou of King's College London, suggests that this case was "an extremely fortuitous event", and that the positive outcome seen is unlikely to be repeatable in other patients.
The procedure was carried out as follows. In 2007, an international team led by Marina Cavazzana-Calvo of University Paris-Descartes extracted haematopoietic stem cells (HSCs) from the patient's bone marrow. These cells give rise to all blood cell types, including the haemoglobin-containing red cells. The researchers cultured these cells, and mixed them with vectors based on the lentiviruses — a retrovirus subgroup with a long incubation period — into which a functional copy of the β-globin gene had been introduced. These vectors were shown in preclinical trials to be safer than those derived from the retroviruses — which are also replicated in a host cell — that have been used in previous gene-therapy procedures.
Chemotherapy was used to eliminate as many of the patient's faulty HSCs as possible, to prevent dilution of the genetically corrected cells, which were then transplanted. Levels of healthy red blood cells and normal β-globin in the subject's body gradually rose until, around a year after the treatment, he no longer required transfusions. After 33 months he remains mildly anaemic, but the fact that he remains transfusion-free has been hailed as a success.
However, that achievement is tempered by a cautionary note. The researchers have detected overexpression of a protein called HMGA2, which has been linked to cancers, in a high proportion of the genetically modified cells.
Overexpression occurred because the lentivirus vector can randomly integrate into chromosomes. By chance, one transplanted haematopoietic cell clone contains a vector insertion in the HMGA2 gene. A year after the transplant, the researchers noticed that the proportion of genetically modified cells that originated from this particular cell clone was rising until it reached a plateau at around 50%.
The reasons for the over-representation of that particular clone remain unclear, but that could be down to the fact that the patient's haematopoietic system was reconstituted from just a few modified HSCs. Luigi Naldini, a gene-therapy researcher at San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, says that successfully grafting a larger initial population of modified HSCs could potentially prevent the problem from developing.
Looking at the haematopoietic system in its entirety, the researchers found that increased levels of HMGA2 were present in only about 5% of the patient's circulating cells, but overexpression of HMGA2 has led to enlargement of the patient's red blood cells. The researchers say that this enlargement caused by the overexpression of HMGA2 could be partly responsible for the therapeutic benefits, but it could also be a signal of future malignancies.
Antoniou suggests that the HMGA2 effect is "key" to the therapeutic effect, and that without the unintended insertion, combined with the patient's ability to produce some β-globin naturally, transfusions would probably still be required.
But Leboulch says that β-globin production from the modified cells was just as high before the cells containing the insertion reached the 50% mark, so that most of the therapeutic effect must be due to the implanted modified cells, rather than the expansion of the blood cells caused by the HMGA2 insertion. And Naldini says that the fact that β-globin expression by the implanted cells is being seen at all represents a major step forward.

Johns Hopkins Children's Center urges new screening program to improve sickle cell trait

2010-09-16T15:26:00.001+05:30

The Johns Hopkins Children's Center top pediatrician is urging a "rethink" of a new sickle cell screening program, calling it an enlightened but somewhat rushed step toward improving the health of young people who carry the sickle cell mutation.
Beginning this fall, all Division I college athletes will undergo mandatory screening for the sickle cell trait. The program, rolled out by the National Collegiate Athletic Association (NCAA), is an attempt to prevent rare but often-lethal complications triggered by intense exercise in those who carry the genetic mutation yet don't have the disease.
Nationwide, newborns are screened for sickle cell disease, but carriers, or people with one mutant and one normal sickle cell gene, do not have symptoms of the disease and may be unaware that they are carriers.
While the program's goal is laudable, its implementation has been hasty and its consequences poorly thought out, warns Johns Hopkins Children's Center Director George Dover, M.D., in a Sept. 9 commentary for The New England Journal of Medicine.
The program is expected to affect nearly 170,000 college athletes and identify anywhere between 400 to 500 new cases each year. Carriers of the sickle cell trait are asymptomatic but are at higher risk for infarction of the spleen caused by lack of oxygen supply to the organ and exercise-induced rhabdomyolysis, a condition marked by the rapid breakdown of injured muscle followed by the release of proteins in the bloodstream that harm the kidneys and can lead to kidney failure. Research has shown that the risk of sudden death during exercise is between 10 and 30 percent higher among those who have the sickle cell trait than those without it. The program stems from the 2006 death of a 19-year-old freshman who died after football practice from exercise-induced rhabdomyolysis.
Dover and co-authors Vence Bonhaj, J.D., and Lawrence Brody, Ph.D., of the National Human Genome Research Institute, call the program "an enlightened first step by the NCAA toward improving the health of student athletes," but one rife with pitfalls and raising many questions. Such questions include: "Will any positive test results be followed by a second test to eliminate false positives?" and "Who is responsible for counseling students who test positive in order to explain the difference between actual disease and carrier status and the risks associated with each?"
Dover and his co-authors say that the following stipulations should be included in the program:
• Verifying test result accuracy by follow-up testing to eliminate false positives • Post-test counseling • Measures to prevent discrimination based on positive test results • Making athletic practice safer to reduce or eliminate the risk for death among carriers by instituting proper hydration and avoiding workouts during high humidity and peak heat
Students will be allowed to opt out of screening if they show proof of previous testing or sign a waiver releasing their college of any legal liability. These suggest that the program was designed primarily as a legal defense measure, but its medical, social and psychological consequences remain unaddressed, the authors say.
As the most extensive sickle cell screening program in the past 30 years, this initiative will likely pave the way for other mass screening programs among college athletes, including ones aimed at identifying the carriers of cardiac anomalies, the most common cause of sudden death in athletes.
"The precedent-setting nature of this screening program dictates that we proceed with caution because any subsequent genetic screening programs may be modeled after this prototype," says Dover, a pediatric hematologist and expert on sickle cell disease.
Some 100 million people worldwide and 2 million people in the United States are believed to be carriers of the sickle cell mutation (sickle cell trait) but do not have sickle cell anemia. Named for the unusually sickle-shaped red blood cells caused by an inherited abnormality, sickle cell anemia affects nearly 100,000 Americans, most of them African-American. In sickle cell anemia, the red blood cells become rigid, which reduces their oxygen delivery to vital organs and causes them to get stuck in the blood vessels, leading to severe pain and so-called "sickling crises," which require hospitalization.
Source : Johns Hopkins Children's Center

Promising results in mice could prevent fatal iron buildup in humans

2010-09-16T14:32:00.000+05:30

A new study shows that a protein found in blood alleviates anemia, a condition in which the body's tissues don't get enough oxygen from the blood. In this animal study, injections of the protein, known as transferrin, also protected against potentially fatal iron overload in mice with thalassemia, a type of inherited anemia that affects millions of people worldwide.
Implications of the study, published in the January 24 online edition of Nature Medicine, could extend well beyond thalassemia to include other types of anemia including sickle cell anemia and myelodysplastic syndromes (bone marrow disorders that often precede leukemia) if proven in humans. The research was conducted by scientists at Albert Einstein College of Medicine of Yeshiva University.
"People who have thalassemia or other types of anemia need frequent blood transfusions over many years to correct the problem," says Mary E. Fabry, Ph.D., professor of medicine at Einstein and a study author. "But the human body has no way to get rid of the massive amount of iron in the transfused blood, and the resulting iron overload - especially its accumulation in the heart and liver - is often fatal. Our study suggests that treatment with transferrin could prevent this."
It's projected that over the next 20 years, more than 900,000 children with thalassemia will be born each year. Ninety-five percent of thalassemia births are in Asian, Indian, and Middle Eastern regions. However, the U.S. is seeing more cases due to a growing influx of immigrants.
In thalassemia, gene mutations lead to underproduction of the globin protein chains that form hemoglobin, the iron-containing, oxygen-carrying molecule in red blood cells. (Normal hemoglobin consists of four globin protein chains - two alpha chains and two beta chains.) Fewer globin chains mean a shortage of red blood cells, a shorter lifespan for red cells that are produced, and anemia.
Thalassemia is classified as alpha or beta thalassemia, depending on which of the globin protein chains are affected. In a 2009 study involving beta thalassemic mice at Einstein, Dr. Fabry and her colleagues made a paradoxical observation: Despite the rodents' anemia and iron overload, injecting them with more iron improved their anemia by increasing both hemoglobin and the number of red cells.
This finding indicated that "overload" iron wasn't accessible for use in making red cells. And it suggested to Yelena Z. Ginzburg, M.D., a postdoctoral research fellow in Dr. Fabry's lab at the time and a senior author of the present study, that transferrin might be able to tap into that stored iron.
Transferrin is a crucially important protein responsible for transporting iron in the bloodstream and delivering it to cells that need it - particularly the cells that develop into red blood cells. "Yelena [now a researcher at the New York Blood Center in New York City] hypothesized that too little transferrin in the circulation may account for the reduced red cell production and anemia observed in beta thalassemia," says Dr. Fabry. "So she decided to see if injections of transferring - obtainable as a byproduct of blood collection - could help in treating thalassemia."
In the present study, the researchers gave the beta thalassemia mice daily injections of human transferrin for 60 days. The results were impressive.
"The injected transferrin killed three birds with one stone," says Dr. Fabry. "It not only helped in depleting the iron overload that can be so toxic, but it recycled that iron into new red blood cells that ameliorated the anemia. Plus, those red cells survived for a longer time because they had fewer defects."
The Einstein researchers are cautiously optimistic that transferrin could have similar benefits for people.
"Before doing clinical trials, we need to work out a lot of details such as the proper dose of transferrin and the frequency of treatment," says Eric E. Bouhassira, Ph.D., another author of the study who is professor cell biology and of medicine and the Ingeborg and Ira Leon Rennert Professor of Stem Cell Biology and Regenerative Medicine at Einstein. "But transferrin's striking effectiveness in reducing iron overload makes me hopeful that people with anemia could really benefit from it."
The paper, "Transferrin therapy ameliorates disease in beta-thalassemic mice," appears in the January 24 online edition of Nature Medicine.
Source: Albert Einstein College of Medicine

Researchers reveal findings on restricted lineage of iPS cells

2010-09-08T13:26:00.000+05:30

Adult cells that have been reprogrammed into induced pluripotent stem cells (iPS cells) do not completely let go of their past, perhaps limiting their ability to function as a less controversial alternative to embryonic stem cells for basic research and cell replacement therapies, according to researchers at Children's Hospital Boston, John Hopkins University and their colleagues.
The findings, published online July 19 in Nature, highlight a major challenge in developing clinical and scientific applications for the powerful new technique of making iPS cells, which, like embryonic stem cells, have the capacity to differentiate into any type of cell in the body. Similar findings were published simultaneously online in Nature Biotechnology by other Boston researchers.
"iPS cells retain a 'memory' of their tissue of origin," said senior author George Daley, MD, PhD, a Howard Hughes Medical Institute investigator and Director of the Stem Cell Transplantation Program at Children's. "iPS cells made from blood are easier to turn back into blood than, say, iPS cells made from skin cells or brain cells."
In contrast, another technique known as nuclear transfer creates pluripotent stem cells without apparent memory and equally adept at transforming into several tissue types, the paper reports. In iPS cells, the memory of the original donor tissue can be more fully erased with additional steps or drugs, the researchers found, which made those iPS cells as good as the nuclear-transfer stem cells at generating different types of early tissue cells in lab dishes.
The residual cellular memory comes in part from lingering genome-wide epigenetic modifications to the DNA that gives each cell a distinctive identity, such as skin or blood, despite otherwise identical genomes. In the study, the persistent bits of a certain type of epigenetic modification called methylation were so distinctive in iPS cells that their tissues of origin could be identified by their methylation signatures alone.
"We found the iPS cells were not as completely reprogrammed as the nuclear transfer stem cells," said co-senior author Andrew Feinberg, MD, MPH, director of the Center for Epigenetics at Johns Hopkins, whose group did systematic epigenomic analyses of the cells. "Namely, DNA methylation was incompletely reset in iPS cells compared to nuclear transfer stem cells. Further, the residual epigenetic marks in the iPS cells helped to explain the lineage restriction, by leaving an epigenetic memory of the tissue of origin after reprogramming."
Epigenetic memory may be helpful for some applications, such as generating blood cells from iPS cells originally derived from a person's own blood, the researchers said. But the memory may interfere with efforts to engineer other tissues for treatment in diseases such as Parkinson's or diabetes or to use the cells to study the same disease processes in laboratory dishes and test drugs for potential treatments and toxicities.
"These findings cut across all clinical applications people are pursuing and whatever disease they are modeling," said Daley, also a member of the Harvard Stem Cell Institute and professor of biological chemistry and molecular pharmacology at Harvard Medical School. "Our data provide a deeper understanding of the iPS platform. Everyone working with these cells has to think about the tissues of origin and how that affects reprogramming."
iPS cells became a focal point of stem cell biology four years ago when a Japanese team led by Shinya Yamanaka created the functional equivalent of embryonic stem cells from adult mouse skin cells with a cocktail of four molecular factors. A year later, Yamanaka's team, Daley's team and a University of Wisconsin group all independently reported creating human iPS cells from adult skin cells, raising hopes for future clinical and research applications. Earlier this month, Daley's team and two other groups reported making human iPS cells from adult blood cells, a faster and easier source. In that study, iPS cells from blood were also better at differentiating back into blood cells than into other tissue types.
In the current study, first author Kitai Kim, PhD, postdoctoral fellow in the Daley lab, tested mice iPS cells head-to-head with pluripotent cells made through somatic cell nuclear transfer. Best known as the cloning method that created the sheep Dolly fourteen years ago, nuclear transfer reprograms an adult cell by transferring its nucleus into an unfertilized egg cell, or oocyte, whose nucleus has been removed. The process of transferring the nucleus immediately reprograms it epigenetically, replicating the same process that happens to sperm upon fertilization, Kim said.
"Stem cells generated by somatic cell nuclear transfer are on average, closer to bona fide embryonic stem cells than are iPS cells," Daley said. "This has an important political message--we still need to study the mechanisms by which nuclear transfer reprograms cells, because the process seems to work more efficiently and faithfully. Learning the secrets of nuclear transfer may help us make better iPS cells."
Kim began the study with older mice (ages 1 to 2), aiming to emulate the future human clinical scenario, which is likely to involve older people. Older cells are set in their ways and harder to reprogram, Kim said. Kim originally wanted to compare the transplantation success of blood cells made from three different pluripotent sources: iPS cells, embryonic stem cells (the gold standard), and nuclear transfer stem cells.
He did not get as far as transplantation. "Even in vitro we observed strikingly different blood-forming potential," he and his co-authors wrote in the paper. "We focused instead on understanding this phenomenon."
iPS cells from blood were best at making blood, and fibroblasts were best at differentiating into bone, a closely related tissue, Kim and his colleagues found. The researchers could reset the iPS cells more fully by differentiating them first into blood cells and then reprogramming them again, or by treating them with drugs that change their epigenetic profile.
In contrast, nuclear transfer stem cells from the same sources -- blood cells and skin – were equally able to differentiate into blood and bone, Kim and his colleagues found. Like iPS cells, the nuclear transfer technique also creates patient-specific cells, but has not yet proven successful with human cells.
"This paper opens our eyes to the restricted lineage of iPS cells," said Feinberg. "The lineage restriction by tissue of origin is both a blessing and a curse. You might want lineage restriction in some cases, but you may also have to do more work to make the iPS cells more totally pluripotent."
SOURCE Children's Hospital Boston

Common types of anemias to occur during pregnancy

2010-09-06T16:24:00.000+05:30

What are the most common types of anemias to occur during pregnancy?
There are several types of anemias that may occur in pregnancy. These include:
•   anemia of pregnancy
In pregnancy, a woman's blood volume increases by as much as 50 percent. This causes the concentration of red blood cells in her body to become diluted. This is sometimes called anemia of pregnancy and is not considered abnormal unless the levels fall too low.
Studies of Anemia in Pregnancy. II. The Relationship of Dietary Deficiency and Gastric Secretion to Blood Formation During Pregnancy.
•   iron deficiency anemia
During pregnancy, the fetus uses the mother's red blood cells for growth and development, especially in the last three months of pregnancy. If a mother has excess red blood cells stored in her bone marrow before she becomes pregnant, she can use those stores during pregnancy to help meet her baby's needs. Women who do not have adequate iron stores can develop iron deficiency anemia. This is the most common type of anemia in pregnancy. It is the lack of iron in the blood, which is necessary to make hemoglobin - the part of blood that distributes oxygen from the lungs to tissues in the body. Good nutrition before becoming pregnant is important to help build up these stores and prevent iron deficiency anemia.
•   vitamin B12 deficiency
Vitamin B12 is important in forming red blood cells and in protein synthesis. Women who are vegans (who eat no animal products) are most likely to develop vitamin B12 deficiency. Including animal foods in the diet such as milk, meats, eggs, and poultry can prevent vitamin B12 deficiency. Strict vegans usually need supplemental vitamin B12 by injection during pregnancy.
•   blood loss
Blood loss at delivery and postpartum (after delivery) can also cause anemia. The average blood loss with a vaginal birth is about 500 milliliters, and about 1,000 milliliters with a cesarean delivery. Adequate iron stores can help a woman replace lost red blood cells.
•   folate deficiency
Folate, also called folic acid, is a B-vitamin that works with iron to help with cell growth. Folate deficiency in pregnancy is often associated with iron deficiency since both folic acid and iron are found in the same types of foods. Research shows that folic acid may help reduce the risk of having a baby with certain birth defects of the brain and spinal cord if taken before conception and in early pregnancy.
What are the symptoms of anemia?
Women with anemia of pregnancy may not have obvious symptoms unless the cell counts are very low. The following are the most common symptoms of anemia. However, each woman may experience symptoms differently. Symptoms may include:
•   pale skin, lips, nails, palms of hands, or underside of the eyelids
•   fatigue
•   vertigo or dizziness
•   labored breathing
•   rapid heartbeat (tachycardia)
The symptoms of anemia may resemble other conditions or medical problems. Always consult your physician for a diagnosis.
How is anemia diagnosed?
Anemia is usually discovered during a prenatal examination through a routine blood test for hemoglobin or hematocrit levels. Diagnostic procedures for anemia may include additional blood tests and other evaluation procedures.
•   hemoglobin - the part of blood that distributes oxygen from the lungs to tissues in the body.
•   hematocrit - the measurement of the percentage of red blood cells found in a specific volume of blood.
Treatment for anemia:
Specific treatment for anemia will be determined by your physician based on:
•   your pregnancy, overall health, and medical history
•   extent of the disease
•   your tolerance for specific medications, procedures, or therapies
•   expectations for the course of the disease
•   your opinion or preference
Treatment depends on the type and severity of anemia. Treatment for iron deficiency anemia includes iron supplements. Some forms are time-released, while others must be taken several times each day. Taking iron with a citrus juice can help with the absorption into the body. Antacids may decrease absorption of iron. Iron supplements may cause nausea and cause stools to become dark greenish or black in color. Constipation may also occur with iron supplements.
Prevention of anemia:
Good pre-pregnancy nutrition not only helps prevent anemia, but also helps build other nutritional stores in the mother's body. Eating a healthy and balanced diet during pregnancy helps maintain the levels of iron and other important nutrients needed for the health of the mother and growing baby.
Good food sources of iron include the following:
•   meats - beef, pork, lamb, liver, and other organ meats
•   poultry - chicken, duck, turkey, liver (especially dark meat)
•   fish - shellfish, including clams, mussels, oysters, sardines, and anchovies
•   leafy greens of the cabbage family, such as broccoli, kale, turnip greens, and collards
•   legumes, such as lima beans and green peas; dry beans and peas, such as pinto beans, black-eyed peas, and canned baked beans
•   yeast-leavened whole-wheat bread and rolls
•   iron-enriched white bread, pasta, rice, and cereals
The following is a list of foods that are a good source of iron. Always consult your physician regarding the recommended daily iron requirements.
Iron-Rich Foods   Quantity   Approximate Iron
                                                  Content (milligrams)
Oysters         3 ounces         13.2
Beef liver 3 ounces           7.5
Prune juice   1/2 cup            5.2
Clams      2 ounces         4.2
Walnuts    1/2 cup      3.75
Ground beef          3 ounces 3.0
Chickpeas   1/2 cup            3.0
Bran flakes 1/2 cup    2.8
Pork roast             3 ounces      2.7
Cashew nuts       1/2 cup      2.65
Shrimp                  3 ounces    2.6
Raisins      1/2 cup            2.55
Sardines                3 ounces      2.5
Spinach                 1/2 cup    2.4
Lima beans   1/2 cup            2.3
Kidney beans             1/2 cup            2.2
Turkey, dark meat    3 ounces      2.0
Prunes         1/2 cup      1.9
Roast beef   3 ounces         1.8
Green peas   1/2 cup    1.5
Peanuts      1/2 cup 1.5
Potato      1   1.1
Sweet potato 1/2 cup 1.0
Green beans      1/2 cup      1.0
Egg                          1   1.0
Vitamin supplements containing 400 micrograms of folic acid are now recommended for all women of childbearing age and during pregnancy. These supplements are needed because natural food sources of folate are poorly absorbed and much of the vitamin is destroyed in cooking. Food sources of folate include the following:
•   leafy, dark green vegetables
•   dried beans and peas
•   citrus fruits and juices and most berries
•   fortified breakfast cereals
•   enriched grain products

H1N1 flu increases complication in children with sickle cell anemia: Study

2010-08-27T16:16:00.001+05:30

Children with sickle cell disease are especially hard-hit by the H1N1 flu strain, causing more life-threatening complications than the seasonal flu, according to a study from Johns Hopkins Children's Center.

The study's findings, published online July 23 in an early edition of the journal Blood, should be heeded as a warning call by parents and pediatricians that children with sickle cell anemia are more likely to need emergency treatment and to be hospitalized if they contract the H1N1 flu.

While H1N1 flu in the general population turned out to be much less severe than feared at the start of the 2009 pandemic, children with sickle cell disease remain at greater risk for complications from it, as well as other strains of the flu. A 2009 Hopkins Children's study found that children with sickle cell disease are hospitalized with seasonal flu nearly 80 times more often than other children.

Lead investigator John Strouse, M.D., Ph.D., a hematologist at Hopkins Children's says the study underscores the importance of timely immunization against both the H1N1 and the seasonal flu strains, which this year will be given in a single vaccine.
The Hopkins team analyzed the records of 123 children with sickle cell disease treated for any kind of flu at Hopkins Children's between September 1993 and December 10, 2009. Of them, 29 were infected with the H1N1 virus, a new strain that emerged for the first time in April of 2009.

While both the seasonal flu and the H1N1 virus caused most of the typical flu symptoms — fever, cough and a runny nose — in most of the children, sickle cell patients infected with H1N1 were nearly three times more likely to develop acute chest syndrome, a leading cause of death among such patients, marked by inflammation of the lungs, reduced ability to absorb oxygen and shortness of breath.

H1N1-infected children also were more than five times more likely to end up in the intensive-care unit than those with the regular flu, and they were overall more likely to need a ventilator for breathing.
Named for the unusually sickle-shaped red blood cells caused by an inherited abnormality, sickle cell anemia affects nearly 100,000 Americans, most of them African-American. The cells' abnormal structure reduces their oxygen delivery to vital organs and causes them to get stuck in the blood vessels, leading to severe pain and so-called "sickling crises," which require hospitalization.

The CDC estimates that up to one-fifth of Americans get the flu each year, resulting in 200,000 hospitalizations and 36,000 deaths.
Source : Johns Hopkins Children's Center

New Medicare Rules May Curb Use of Anemia Drugs for Dialysis

2010-08-23T15:19:00.001+05:30

By ANDREW POLLACK

Yet more restrictions in the use of anemia drugs are on the way.
Medicare issued final rules Monday that are expected to sharply curtail the use of anemia drugs, particularly Amgen’s Epogen, in the treatment of patients undergoing kidney dialysis.
However, after getting lots of protest, Medicare decided to exempt certain oral drugs from the new system until 2014, which could be good news for Genzyme.
Under the new system, the Centers for Medicare and Medicaid Services will pay a set fee for each dialysis treatment. That so-called bundled payment is supposed to cover both the dialysis service, in which wastes are removed from the body, and the drugs and laboratory tests that accompany it. The new system starts phasing in on Jan. 1.
The new system somewhat resembles concepts in the new health care law, but the dialysis system reform was initiated earlier by Congress, under different legislation.
Until now, Medicare has paid a set fee for the service but certain drugs, like Epogen, are reimbursed separately.
Critics say that gave hospitals and dialysis clinics financial incentives to use a lot of Epogen, which dominates the dialysis market because of Amgen’s patent position. Amgen sells about $2.5 billion of Epogen a year, virtually all for use in dialysis in the United States, and the drug is one of the biggest pharmaceutical expenses for Medicare.

Concern about this system grew stronger when some clinical trials revealed that overuse of Epogen might harm patients, increasing their risk of heart attacks and strokes.
“When drugs remain outside the payment bundle, financial issues can influence both facility and patient behavior, as the over-utilization of EPO to the detriment of patient care in the past has demonstrated,’’ Medicare said in its ruling Monday.
Of course, the new system could have the opposite effect. Epogen will go from being a potential profit source for dialysis clinics to an expense that detracts from profit. So now there will be an incentive to under-use the drug, perhaps subjecting dialysis patients to more anemia and fatigue.
But clinics will have to meet certain standards for quality of care, which Medicare hopes will deter under-use. Medicare said it expects less costly alternatives might be used.
One approach would be to give Epogen by separate injections under the skin. Less of the drug is needed that way than when it is given through the intravenous line now used to deliver dialysis.
When they had a financial incentive to use more Epogen, dialysis clinics resisted giving such separate injections, saying they added to the pain and discomfort for patients. Now, however, many clinics are expected to switch.
Analysts have been expecting the final rules since Medicare first proposed the changes last year, and they have by and large already factored in a reduction in sales of Epogen of as much as 40 percent.
In a note to clients Monday afternoon, however, Jim Birchenough, an analyst at Barclays Capital, said such estimates might be too high and that the transition to giving patients separate injections will occur gradually.
The big suspense in the final rules would be whether Medicare would stick with its original proposal to include certain oral drugs, like Amgen’s Sensipar and Genzyme’s Renvela, in the bundle. These drugs are used to control calcium and phosphorus levels in the patient’s blood.
Opponents of inclusion of the oral drugs argued Medicare had no right to do so, because the drugs typically are not given at the dialysis clinic. Like most other pills, patients get a prescription and Medicare pays for the drugs under its prescription coverage, known as Part D, not under its dialysis program.
The opponents also said that because the drugs were expensive, inclusion in the bundle would curtail their use, to the detriment of patients.
In the final rules issued Monday, Medicare defended its position to include the drugs, but postponed the starting date by three years, until Jan. 1, 2014, to allow time for the study of “operational and safety issues.’’

Anemia and Thrombocytopenia in Pregnancy

2010-08-20T11:39:00.006+05:30

Author: Diana Curran, MD, FACOG, Assistant Professor, Residency Program Director, Department of Obstetrics and Gynecology, University of Michigan Health Systems

Thrombocytopenia

Thrombocytopenia in pregnancy is common and is diagnosed in approximately 7% of pregnancies. It is typically defined as a platelet count of less than 150,000/µL. The most common cause of thrombocytopenia during pregnancy is gestational thrombocytopenia, which is a mild thrombocytopenia with platelet levels remaining greater than 70,000/µL.

Patients who are affected usually are asymptomatic and have no history of thrombocytopenia prior to pregnancy. Their platelet levels should return to normal within several weeks following delivery. An extremely low risk of fetal or neonatal thrombocytopenia is associated with gestational thrombocytopenia. Gestational thrombocytopenia may result from increased platelet consumption and can be associated with antiplatelet antibodies. Gestational thrombocytopenia can be hard to distinguish from immune thrombocytopenia purpura (ITP) presenting during pregnancy.

Immune thrombocytopenia purpura
Acute ITP is a disorder occurring in childhood with little implication for women who are pregnant because it resolves spontaneously. Chronic ITP may occur in the second or third decade of life, affecting females 3 times as frequently as males. This condition is characterized by immunologically mediated platelet destruction. Antiplatelet antibodies (immunoglobulin G) attack platelet membrane glycoproteins and destroy platelets at a rate that cannot be compensated by the bone marrow. ITP is usually associated with persistent thrombocytopenia (<100,000/µL), normal or increased megakaryocytes on bone marrow aspirate, exclusion of other disorders associated with thrombocytopenia, and the absence of splenomegaly. Patients may report a history of easy bruising and petechiae or epistaxis and gingival bleeding preceding the pregnancy.
Although worsening of the disease is not typical during pregnancy, when it occurs, the mother is at risk for bleeding complications at the time of delivery. Therapies aimed at improving the maternal platelet count in anticipation of delivery include intravenous immunoglobulin (IVIg) and steroids. The patient may require platelet transfusion during delivery if the platelet count drops below 20,000/µL. Splenectomy is reserved for severe cases only.
Some controversy exists regarding the threat of intracranial hemorrhage (ICH) in neonates born to mothers with ITP. Although as many as 12-15% of infants born to mothers with ITP may develop platelet counts less than 50,000/µL, the risk of ICH is estimated at less than 1% in 2 recent prospective studies.

Neonatal alloimmune thrombocytopenia
In contrast to ITP, neonatal alloimmune thrombocytopenia may pose a serious risk to the newborn. It may occur in 1 in 1000 live births and often is unanticipated when it occurs in first pregnancies. The presentation may be in the setting of an unremarkable pregnancy and delivery. Clinical manifestations in the neonate include generalized petechiae, ecchymoses, hemorrhage into viscera, increased bleeding at the time of circumcision or venipuncture, or, most gravely, ICH. ICH may occur in utero in as many as 25% of cases. Like Rhesus (Rh) disease, neonatal alloimmune thrombocytopenia results from maternal alloimmunization against fetal platelet antigens. The most severely affected antigen is human platelet antigen-1a, which has been described in approximately 50% of cases in white persons. A high risk of recurrence of neonatal alloimmune thrombocytopenia exists, and it tends to worsen with subsequent gestations in a manner similar to Rh disease.
For patients who have a history of the disease and are experiencing their first pregnancy, referral to a maternal-fetal medicine specialist skilled in cordocentesis may be warranted because the fetus may need to have platelet counts or a transfusion while in utero. IVIg has been shown to improve fetal thrombocytopenia. Cesarean delivery is the preferred route of delivery for infants with platelet counts less than 50,000/µL to reduce the risk of ICH secondary to trauma incurred during labor.

Anemia

With normal pregnancy, blood volume increases, which results in a concomitant hemodilution. Although red blood cell mass increases during pregnancy, plasma volume increases more, resulting in a relative anemia. This results in a physiologically lowered hemoglobin (Hb) level, hematocrit (Hct) value, and red blood cell (RBC) count, but it has no effect on the mean corpuscular volume (MCV). Many centers define anemia in a patient who is pregnant as an Hb value less than 10.5 g/dL, as opposed to the reference range of 14 g/dL in a patient who is not pregnant. Treatment with 1 mg folic acid and daily iron is helpful when deficiencies are noted.
Iron deficiency anemia
Iron deficiency anemia accounts for 75-95% of the cases of anemia in pregnant women. A woman who is pregnant often has insufficient iron stores to meet the demands of pregnancy. Encourage pregnant women to supplement their diet with 60 mg/d of elemental iron. An MCV less than 80 mg/dL and hypochromia of the RBCs should prompt further studies, including total iron-binding capacity, ferritin levels, and Hb electrophoresis if iron deficiency is excluded.

Clinical symptoms of iron deficiency anemia include fatigue, headache, restless legs syndrome, and pica (in extreme situations). Treatment is additional supplementation with oral iron sulfate (320 mg, 1-3 times daily). Iron is preferable once daily because more frequent iron supplementation can cause constipation. The clinical consequences of iron deficiency anemia include preterm delivery, perinatal mortality, and postpartum depression. Fetal and neonatal consequences include low birth weight and poor mental and psychomotor performance.1
Folate and vitamin B-12 deficiency
Folate deficiency is much less common than iron deficiency; however, taking 0.4 mg/d to reduce the risk of neural tube defects is recommended to all women contemplating pregnancy. Patients with a history of neural tube defect should take 4 mg/d. An increased MCV can be suggestive of folate deficiency; in this case, determine serum levels of vitamin B-12 and folate. If the levels are low, the patient may require oral folate at a dose of 1 mg 3 times daily. Patients with vitamin B-12 deficiency need further workup to determine the level of intrinsic factor to exclude pernicious anemia. The Schilling test is not recommended during pregnancy because of the radionuclide used in testing. Treatment of vitamin B-12 deficiency includes 0.1 mg/d for 1 week, followed by 6 weeks of continued therapy to reach a total administration of 2 mg.
Infectious causes of anemia
Although rare, anemia can be caused by infections such as parvovirus B-19, CMV, HIV, hepatitis viruses, EBV, malaria, babesiosis, bartonellosis, and clostridium toxin. If the patient's history suggests exposure to any of these infectious agents, appropriate laboratory studies should be performed.

Diamond-Blackfan anemia

This is a rare (7 per 1 million) autosomal dominant disorder of pure red cell aplasia requiring life-long transfusion. Women who are contemplating or who are pregnant require the consultation and care of a hematologist in conjunction with a Maternal Fetal Medicine specialist. Concerns during pregnancy include maintaining adequate hemoglobin while decreasing the risk of fetal exposure to the iron chelating agent (Deferoxamine) used during transfusions.1