Anemia
From Science Online
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Introduction: What is Aplastic Anemia?
Blood is one of the most important tissues in our body. It performs functions that range from the transport of oxygen and other molecules to cells to fighting infections to clotting wounds. Anemia is a general term referring to a disease in which the body cannot produce cells that carry enough oxygen or function as effectively as is necessary for our bodies to work correctly (). The onset of this rare and serious disease occurs when the stem cells in the bone marrow do not make enough blood cells, leading to a heightened risk for infection or uncontrolled bleeding.
Symptoms of Aplastic Anemia
Some of the symptoms of aplastic anemia can include fatigue, shortness of breath, dizziness and a rapid heart rate due primarily to the fact that there are not enough red blood cells to carry ample oxygen to the cells for them to function. Other symptoms can include prolonged infections, as a result of a low white blood cell count, easy bruising, and extensive and long-lasting bleeding from even minor injuries, which is due to a shortage of platelets to clot the blood (MayoClinic). Many of these symptoms, however, are common to other types of anemia and result from different blood deficiencies. One of the main ways that aplastic anemia is diagnosed is through a blood test. In patients suffering from this disease red, white, and platelet blood cells all have low counts. Many other types of anemia only affect one type of cell, but since aplastic anemia affects the hematopoietic stem cells that will develop into all of the different blood cells, none are produced in high enough quantities. In order to confirm the diagnosis, a bone marrow biopsy must be preformed. The surgery involves the use of a needle to retrieve marrow from one of the larger bones in the body. This sample is then studied under a microscope to check the count of the cells. A distinguishing feature of aplastic anemia is that although few blood cells are present, the cells that are made in the marrow are correctly formed. Patients with blood diseases like leukemia or sickle cell anemia would present with cells that are abnormal in their shape (MayoClinic).
Etiology: The Biochemistry of Anemia
There are several theories as to why this shortage occurs, particularly since it frequently manifests itself years after birth (MayoClinic). Some factors that could damage bone marrow and jeopardize the production of new blood cells are radiation and chemotherapy treatments, exposure to toxic chemicals, or a viral infection; however, the most widely accepted explanation for why patients develop aplastic anemia is an immune disorder. Autoimmune diseases frequently occur when cytotoxic T leukocytes fail to recognize that one of the patient’s own cells belongs in the body. Typically cytotoxic T cells connect to a cell in the body through MHC and check for antigens that would indicate that the cell is infected. Patients with autoimmune disorders have T cells that cause apoptosis of uninfected cells(Campbell, 2005). In aplastic anemia, the disorder would involve an attack on the tissue containing hematopoietic stem cells (HSCs) causing apoptosis of these cells and leading to a reduction in the number of erythrocytes (red blood cells) in the blood stream (Yamaguchi, 2005). Although these factors can cause aplastic anemia, along with many other types of anemia, the etiology about half of the aplastic cases cannot be uncovered (MayoClinic). As a result there has been an increase in the study of the causation of this disease and a promising line of research involves the shortening of chromosomal telomeres in the stem cells of bone marrow. Telomeres are DNA fragments at the end of linear eukaryotic chromosomes. Humans have telomeres because of a phenomenon know as the “end-replication” problem (Fibbe, 2005). DNA polymerase is unable to synthesize DNA in the 3’-to-5’ direction, so the replication of the lagging strand will always be left a little bit short. This will happen every time the DNA is copied for mitosis, so each cell division results in a gradual shortening of the chromosome. Telomeres exist as non-coding regions of DNA that are a safety net so the important coding regions are not lost through the end-replication problem (). After approximately 60 to 80 copies, a cell cannot move into the S phase of the cell cycle and are no longer useful, a process that will eventually lead to apoptosis of the cell. The protein complex that is responsible for synthesizing and maintaining the important telomeres is called telomerase. It is comprised of an RNA component called TERC and a protein component, telomerase reverse transcriptase (TERT) (Yamaguchi, 2005). Telomerase is not found in high quantities in human somatic cells since they do not divide enough for the coding region of the chromosome to be put in jeopardy, but stem cells are dividing much more frequently than typical cells in the body. The TERT catalytic protein is the primary regulator of telomerase activity. HSCs are also maintained by the mechanisms of telomerase, and a mutation of this enzyme could be responsible for the damage done to them, resulting in aplastic anemia (Fibbe, 2005). Hirokoi Yamaguchi and his team have investigated “whether mutations in genes for components of telomerase also occur in aplastic anemia” (Yamaguchi, 2005). They found that patients who presented with symptoms of late-onset aplastic anemia and who had mutations in their TERT enzymes did not respond to typical methods of treatment for aplastic anemia. Willem Fibbe summarized these findings in an editorial, explaining, “prolonged damage to HSCs in aplastic anemia can induce residual, undamaged stem cells to undergo more than the usual cell divisions. As a result an accelerated rate of telomere shortening in circulating blood cells would be expected” (Fibbe, 2005). Basically, the patients who respond to the normal immunosuppressive therapy have functional stem cells, they are simply reduced in number because of an autoimmune attack, however, those patients who do not respond to this therapy are frequently found to have significantly shortened telomeres. These patients have stem cells that are intrinsically flawed (Fibbe, 2005).
Protein Implicated and Its Structure
The only protein that is really implicated in aplastic anemia is telomerase, but it is only involved in cases in which the patient does not respond to normal treatments of immunosuppressive therapy or to bone marrow transfusions. This protein, called TERT, is responsible for maintaining the length of telomeres. When it is damaged or mutated, the HSCs can lose their function as too much coding region is removed by the end-replication problem. The stem cells of the bone marrow are then corrupted and functional erythrocytes are not generated in great enough quantities(Fibbe, 2005).
It has 9 alpha helicies and 3 beta pleated sheets comprising its sencondary protein structure.
Treatment & Prognosis
The primary treatment for patients suffering from aplastic anemia is multiple blood transfusions. While they are not a genuine cure for the disease, they can treat the symptoms by providing the blood cells necessary to survival. The transfusion of red blood cells helps relieve the fatigue associated with anemia and prevents bleeding. Red blood cells will remain functional in the body for about a month. Another possible method of treatment is achieved through the use of immunosuppressants. Since many aplastic cases are caused by autoimmune disorders these drugs will inhibit the activities of immune cells that are attacking the bone marrow. The biggest downside to this type of treatment is that the drugs will further weaken the immune system of the patient and cause them to become even more susceptible to other diseases and infections(MayoClinic). Another very promising method for actually curing aplastic anemia is through a bone marrow transplant. This treatment option is typically reserved for people with very severe anemia. A related, matched donor can give the transplant with a very good chance that the patient will recover from their disease. The procedure is a risky one, however, because there is always a chance that the body will reject the transplant. This type of failure could cause life-threatening complications, but for patients who are candidates for the procedure, a bone marrow transplant can be the most effective way to treat the disease(MayoClinic). The prognosis for most people suffering from aplastic anemia is relatively high. In few cases, all treatments fail and the disease is ultimately fatal. Luckily many patients respond to at least one of the potential ways to treat the symptoms and can lead a fairly normal life. They will still frequently be short of breath and should avoid excessive exercise because mild exertion can cause fatigue and ultimately wear on the heart since it must work harder to keep cells supplied with oxygen. Patients should also avoid contact sports due to an increased risk of internal bleeding as a result of low platelet count. Another method of self-treatment is to avoid infection since the immune system is greatly weakened by the low white blood cell count, meaning that even a minor infection could have serious repercussions if the body cannot fight it (MayoClinic).
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