Beta Thalassemia Major The Problem Biology Essay

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Beta Thalassemia is the one most common genetic disorder in the world. There is a probability of 0.25 with each pregnancy that a child will be born with Thalassemia if both parents carry the Thalassemia gene. β-Thalassemia is caused by an alteration in the beta globin gene of hemoglobin in chromosome 11.1 A person will only be diagnosed with Thalassemia after about 1 years old. β-Thalassemia can causes anemia ranging from moderate to severe and can also inhibit the growth and development of a child. In certain cases it can causes other physical complications that can lead to a significantly decreased life-span.

Majority of stem cell transplantations in β-Thalassemias were performed by using human leukocyte antigen HLAcompatible sibling donor bone marrow5.Bone Marrow Transplant can cure β-Thalassemia by replacing your child's defective bone marrow where red blood cells are made, with those attained from a compatible donor. This procedure should be done when the child is young to have a more optimistic result.

The stem cells are collected from the donor's bone marrow in the process call "harvesting". The donor is give general anesthesia or regional anesthesia to make the donor unconscious or cause loss of feeling below the waist.7 Needles are then inserted into the pelvic bone to collect the stem cells. After the stem cells being processed it is received by the recipient through a intravenous (IV) line just like a blood transfusion. However recently, modern HLA typing has enabled transplant to be done from unrelated volunteer donors, with outcome as good as with those obtained from HLA-identical sibling.2 Peripheral Blood Stem Cell transplant is now most commonly used for clinical practise as a treatment for β-Thalassemia replacing BMT for allogeneic stem cell transplantation. PBSCs are collected by a apheresis. In this process, a needle is inserted in the vein of one arm of a donor to withdraw blood which then circulates through a special cell separation machine and automatically separates the stem cells from the blood. The remaining blood and plasma is then circulated back to the donor through another needle inserted into the other arm. This process is repeated so that sufficient stem cells can be collected to guarantee a chance of successful engraftment in the recipient. One week before apheresis, the donor is required to take some medicines to help stimulate the bone marrow to enhance production of new stem cells. These new stem cells will cause the marrow to make proper blood cells which then circulates in the blood system.6

When the stem cells enter the bloodstream after transplantation, it will travel to the bone marrow. Here, a process called "engraftment" takes place where the recipient's bone marrow starts to produce new blood cells such as white blood cells, red blood cells, and platelets.7 Engraftment usually take place within 2 to 4 weeks after transplantation. Doctors monitor it by checking blood counts on a frequent basis. Complete recovery of immune function takes much longer - 1 to 2 years for patients receiving allogeneic transplants.7 Doctors assess the results of several blood tests to confirm that new and normal blood cells are being produced. 

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http://www.makna.org.my/images/Allogenic.gif

Diggram 2: http://www.google.com.my/images?um=1&hl=en&biw=1280&bih=683&tbs=isch:1&aq=f&aqi=&oq=&gs_rfai=&q=Allogeneic%20Hematopoietic%20Stem%20Cells%20Transplant

Diagram 2 shows steps of allogeneic stem cell transplant. However for Thalassemia patients, chemotherapy is not done. Chemotherapy is only done on cancer patients.

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Effectiveness

"Fifteen patients with Beta-Thalassemia under-go an allogeneic peripheral blood stem cell transplant. Median age was 3.5 years (1-15 years). All the donors were HLA- identical (13 siblings and two parents). The median neutrophil and platelet engraftment times were day 12 and day 16, respectively8. Chronic Graft-Versus-Host Disease (GVHD) was observed in three patients. Two patients died. Thirteen patients are healthy, and are transfusion-independent 2-30 months after PSCT. No recurrences of thalassemia have been seen. Overall and event-free survival were 86.6%. In conclusion, we suggest that PSCT can be considered a safe and effective treatment for children with beta- thalassemia.8 "  http://www.nature.com/bmt/journal/v28/n11/full/1703284a.html (8)

"Graph 3. Numbers of hemopoietic stem cell transplants performed for β-Thalassemia through the years." http://www.haematologica.org/cgi/content/full/93/12/1780Figure 2931780

The graf clearly shows that hemopoietic stem cell transplant is done more frequently now compared to the past.

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Figure 2

Graf 2. Proportion of donor engraftment after BMT.

Graf 4: http://bloodjournal.hematologylibrary.org/cgi/content/full/115/6/1296

The graf shows BMT provides about 90% chance of survival and 61% will be Thalassemia-free. Meanwhile, there is a 29% chance or rejection and 14% chance of mortality rate. However the chance of survival and being Thalassemia-free is far higher compared to the chances of rejection and mortality. And this is definitely a recomemded procedure.

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Benefits of Allogeneic Stem Cell Transplantation

"From January 1998-July 2006, 62 stem cell transplantation (SCT) were performed on 60 patients with Beta-thalassemia from HLA-related match donors. The overall survival (OS) and event free survival (EFS) for all patients were 94 and 77%. The outcome of allogeneic SCT in our experience is satisfactory with OS 92% and EFS 77%. Transplantation at a young age and when the disease is mild offers the best outcome" (18) http://www.ncbi.nlm.nih.gov/pubmed/20001624

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Allogeneic stem cell transplant is the only available cure for Beta-Thalassemia. If successful, the healthy stem cells will combine with the body to produce normal blood cells and carry out their role as a specific tissue properly. I think this is the best way as the patients will not require blood transfusion and taking chelation therapy life-long which has many side effects. Besides, the person can carry out normal activities like normal people without getting tired easily. The percentage or cure is also very satisfactory as it has high success rate.

Risks of Allogeneic Stem Cell Transplantation

"Doctors can reduce your chances of getting GVHD by making sure the donor and the patient's stem cells are matched HLA tissue typing, taking medication taken to suppress the patient's immune system, removing some types of T cells from donor cells as T cells attack your body in GVHD and using umbilical cord blood is as the source of donor cells." (13) http://www.nhlbi.nih.gov/health/dci/Diseases/Thalassemia/Thalassemia_Treatments.html

BMT has risks involved, some of which are life threatening. Patients can easily get infection as the immune system will be low, but its control by antibiotics. Those who undergo allogeneic stem cell transplant which uses stem cells from a donor has a higher chance of being affected by Graft-versus-host disease (GVHD). GVHD occurs when the donor's immune system reacts against the recipient's tissue12. This is because the body does not recognize these new cells of tissues. GVDH mainly affects the GI tract, liver, skin, and lungs. GVHD also increases a patient's vulnerability to infection as the immune system is low. In chronic cases, it can cause death. There is a 5% mortility rate in low-risk cases.3

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Economic and Ethical Implications

Since most people cannot afford such operations, the burden falls on society in the form of higher insurance premiums and government subsidies10.

Allogeneic stem cell transplant is a very pricey procedure. The cost for allogeneic transplant is around $150,000 to $200,000 . This brings a large economic burden for the poor families.

However, some people say that the government should not spend this huge amount of money for just this procedure. Instead, they should be focusing on improving the health of the public in general.

Even after the surgery, it can cost more than thousand dollars a year excluding those covered by the insurance to keep the person alive due to the high cost of anti-rejection drugs, follow-up care, home care and medical prescriptions.

As a result of these issues, patient autonomy is severely compromised, access is not based on equality, much less on beneficence and sometimes dangerous procedures with low benefit potential.9

The major ethical issue correlated with transplant is the serious short of donors. It is very hard to find a compatible donor with same HLA-typing because only around 25-30% of thalassemic patients would have a matched sibling donor with same genetic typing and blood group. However recently, modern HLA typing has enabled transplant to be done from unrelated volunteer donors, with outcome as good as with those obtained from HLA-identical sibling.2 Moreover, PSCT can be a dangerous procedure which has life-threatening risks. So, I think that the patient should know the pros and cons of this procedure before it is being done.

Although there may be some ethical issues on allogeneic stem cell transplantation, I think this should not stop β-Thalassemia patients from undergoing this procedure as it is the only way they can lead a normal and healthy lifestyle.

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Alternative Solutions

Blood Transfusions as Treatments for Thalassemia

Transfusion therapy can help β-Thalassemia patient to feel better, able to carry out normal lifestyle, and increase life-span. However, regular blood transfusions and proper medical follow-up cannot cure the disease, but may allow them to live up to 40 or 50 years with a good quality of life3. Blood transfusion is when blood containing healthy red blood cells is transfused into the patient using a needle inserted into the vein. To maintain a normal account of healthy RBCs and hemoglobin in the blood, transfusion has to be carried out regularly which is usually once a month. Blood transfusions are lifesaving. Despite this fact, they're also expensive and has a chance of transmitting infectious disease like HIV and Hepatitis. Besides, transfusion therapy causes iron concentration in the blood to increase which can damage organs like the liver and heart. To prevent this, iron chelation therapy is needed to bring back iron concentration to normal.

"However, regular transfusions can cause iron to accumulate in the patient's body. Therefore, they need treatment to remove excess iron from their bodies as well."

(Thalassaemia at a glance. (n.d.). The Star Online. Retrieved September 13, 2010, from http://thestar.com.my/health/story.asp?file=/2010/6/6/health/6326564&sec=health

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Iron Chelation Therapy as Treatment for Thalassemia

"As early diagnosis and treatment of thalassemia are improving the prognosis of pediatric and young adult thalassemia patients, the major cause of illness and mortality has shifted from the problems of hemoglobin-deficient anemia to iron overload associated with chronic blood transfusion therapy." http://www.thalassemia.com/chelation.html

After about 15-20 transfusions, iron concentration begin to build up due to blood transfusion and may affect organs like the heart and liver. This iron load is known by measuring ferritin blood levels. When ferritin level is above 1,000 ng/mL iron chelation therapy has to be done3. Iron overload in the body is fatal if not treated.

"Since each unit of blood deposits about 230 mg of iron, most patients who require, for instance, 2 units of blood per month will have at most a very slightly negative iron balance with chelation therapy"15 http://sickle.bwh.harvard.edu/index.html

In general the iron accumulating from multiple transfusions can be removed from the body quite effectively with chelation therapy drugs like deferoxamine (Desferal), deferiprone or desferasirox.3 Deferoxamine is in a liquid form and its given slowly under the skin, using a small pump used overnight. Deferoxamine is the most commonly used iron chelator which take away around 30 to 70 mg of iron . The other is Deferasirox which is a capsule taken once a day. Side effects of this medications include headache, nausea, diarrhea and feeling weak. Chelation therapy which is given 5 to 7 days a week and has been proven to avoid liver and heart damage from iron overload. Besides, it allows normal growth and sexual development in children with Thalassemia and also can increase life span.

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http://bloodjournal.hematologylibrary.org/content/vol89/issue3/images/small/bl.0043f2.gif

"Graph 5. Compares the amount of hepatic iron and serum ferritin in patients with thalassemia major. Iron load in the body can be roughly known, based on serum ferritin concentration, which is different with the reference technique, direct measurement of hepatic iron concentration in patients with thalassemia major treated with deferiprone. Open circles indicate the amount determined before deferiprone therapy started and solid circles are at the time of final analysis after 1 to 5 years of treatment. The diagonal line denotes the simple linear least-squares regression between the two variables. (Reprinted by permission of The New England Journal of Medicine, Olivieri NF, Brittenham GM, Matsui D, et al. Volume 332, pp 918-922, 1995. Copyright 1995. Massachusetts Medical Society."

http://bloodjournal.hematologylibrary.org/cgi/content/short/89/3/739 (16)

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Evaluation

SCT still remains the only cure currently available for patients with thalassemia.(5)

This extract is from reference http://www.nature.com/bmt/journal/v42/n1s/full/bmt2008112a.html (5) and this source is reliable as it is agreed by many other source like http://medical-dictionary.thefreedictionary.com/Thalasemia (1) which states "Another promising new treatment is bone marrow transplantation" . Besides, this (1) http://medical-dictionary.thefreedictionary.com/Thalasemia provides many information regarding Thalassemia and its very reliable and factual as it is from the Medical Dictionary, Thesaurus and Encyclopedia and thus is very trustable as written by professionals. This website is a summary of definition, causes and treatment for Thalassemia.

I evaluate another source which is http://bloodjournal.hematologylibrary.org/cgi/content/short/89/3/739 (4) a journel from the American Society Of Hematology weather that blood transfusion and iron-chelation therapy are treatment for β-Thalassemia. It is proven in reference such as http://www.nhlbi.nih.gov/health/dci/Diseases/Thalassemia/Thalassemia_Treatments.html (13) publish by National Heart, Lung and Blood Institute that those two are also treatments for Thalassemia. This source (13) is reliable as the results gone through many stages to ensure its validity before being published.

(2381 words)

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