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Aplastic anaemiais a rare disease in which the bone marrow and the hematopoietic stem cells that reside there are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). Aplastic refers to the inability of stem cells to generate mature blood cells.
Bone marrow is a semi-solid tissue which may be found within the spongy or cancellous portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production or hematopoiesis. It is composed of hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of the pelvis. On average, bone marrow constitutes 4% of the total body mass of humans; in an adult having 65 kilograms of mass, bone marrow typically accounts for approximately 2.6 kilograms (5.7 lb).
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. This process occurs in the red bone marrow, in the core of most bones. In embryonic development, the red bone marrow is derived from the layer of the embryo called the mesoderm.
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.
It is more frequent in people in their teens and twenties, but is also common among the elderly. It can be caused by heredity, immune disease, or exposure to chemicals, drugs, or radiation. However, in about half the cases, the cause is unknown.
The definitive diagnosis is by bone marrow biopsy; normal bone marrow has 30–70% blood stem cells, but in aplastic anaemia, these cells are mostly gone and replaced by fat.
First line treatment for aplastic anaemia consists of immunosuppressive drugs, typically either anti-lymphocyte globulin or anti-thymocyte globulin, combined with corticosteroids and ciclosporin. Hematopoietic stem cell transplantation is also used, especially for patients under 30 years of age with a related matched marrow donor.
Immunosuppressive drugs or immunosuppressive agents or antirejection medications are drugs that inhibit or prevent activity of the immune system.
Anti-lymphocyte globulin (ALG) is an infusion of animal- antibodies against human T cells which is used in the treatment of acute rejection in organ transplantation. Its use was first reported by Thomas Starzl in 1966. Its use in transplant was supplanted by thymoglobulin between 1984 and 1999.
Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells, which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia.
The disease is also known as the cause of death of Eleanor Roosevelt and Marie Curie.
Anna Eleanor Roosevelt was an American political figure, diplomat and activist. She served as the First Lady of the United States from March 4, 1933 to April 12, 1945 during her husband President Franklin D. Roosevelt's four terms in office, making her the longest serving First Lady of the United States. Roosevelt served as United States Delegate to the United Nations General Assembly from 1945 to 1952. President Harry S. Truman later called her the "First Lady of the World" in tribute to her human rights achievements.
Marie Skłodowska Curie was a Polish and naturalized-French physicist and chemist who conducted pioneering research on radioactivity. She was the first woman to win a Nobel Prize, the first person and only woman to win twice, and the only person to win a Nobel Prize in two different sciences. She was part of the Curie family legacy of five Nobel Prizes. She was also the first woman to become a professor at the University of Paris, and in 1995 became the first woman to be entombed on her own merits in the Panthéon in Paris.
Anemia may lead to feeling tired, pale skin and a fast heart beat.
Anemia is a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood, or a lowered ability of the blood to carry oxygen. When anemia comes on slowly, the symptoms are often vague and may include feeling tired, weakness, shortness of breath or a poor ability to exercise. Anemia that comes on quickly often has greater symptoms, which may include confusion, feeling like one is going to pass out, loss of consciousness, or increased thirst. Anemia must be significant before a person becomes noticeably pale. Additional symptoms may occur depending on the underlying cause.
Malaise is a feeling of general discomfort, uneasiness or pain, often the first sign of an infection or other disease. The word has existed in the French language since at least the 12th century.
Pallor is a pale color of the skin that can be caused by illness, emotional shock or stress, stimulant use, or anemia, and is the result of a reduced amount of oxyhaemoglobin and is visible in skin conjuctivae or mucous membrane.
Low platelets are associated with an increased risk of bleeding, bruising and petechiae. Low white blood cells increase the risk of infections.
Aplastic anemia can be caused by exposure to certain chemicals, drugs, radiation, infection, immune disease; in about half the cases, a definitive cause is unknown. It is not a familial line hereditary condition, nor is it contagious. It can be acquired due to exposure to other conditions but if a person develops the condition, their offspring would not develop it by virtue of their genetic relationship.
Aplastic anemia is also sometimes associated with exposure to toxins such as benzene, or with the use of certain drugs, including chloramphenicol, carbamazepine, felbamate, phenytoin, quinine, and phenylbutazone. Many drugs are associated with aplasia mainly according to case reports, but at a very low probability. As an example, chloramphenicol treatment associated with aplasia in less than one in 40,000 treatment courses, and carbamazepine aplasia is even rarer.
Exposure to ionizing radiation from radioactive materials or radiation-producing devices is also associated with the development of aplastic anemia. Marie Curie, famous for her pioneering work in the field of radioactivity, died of aplastic anemia after working unprotected with radioactive materials for a long period of time; the damaging effects of ionizing radiation were not then known.
Aplastic anemia is present in up to 2% of patients with acute viral hepatitis.
One known cause is an autoimmune disorder in which white blood cells attack the bone marrow. [ citation needed ]
Short-lived aplastic anemia can also be a result of parvovirus infection. [ citation needed ]In humans, the P antigen (also known as globoside), one of the many cellular receptors that contribute to a person's blood type, is the cellular receptor for parvovirus B19 virus that causes erythema infectiosum (fifth disease) in children. Because it infects red blood cells as a result of the affinity for the P antigen, parvovirus causes complete cessation of red blood cell production. In most cases, this goes unnoticed, as red blood cells live on average 120 days, and the drop in production does not significantly affect the total number of circulating red blood cells. In people with conditions where the cells die early (such as sickle cell disease), however, parvovirus infection can lead to severe anemia.
More frequently parvovirus B19 is associated with aplastic crisis which involves only the red blood cells (despite the name). Aplastic anemia involves all different cell lines.
Viruses that have been linked to the development of aplastic anemia include hepatitis, Epstein-Barr, cytomegalovirus, parvovirus B19 and HIV.
In some animals, aplastic anemia may have other causes. For example, in the ferret (Mustela putorius furo), it is caused by estrogen toxicity, because female ferrets are induced ovulators, so mating is required to bring the female out of heat. Intact females, if not mated, will remain in heat, and after some time the high levels of estrogen will cause the bone marrow to stop producing red blood cells.[ citation needed ]
The condition needs to be differentiated from pure red cell aplasia. In aplastic anemia, the patient has pancytopenia (i.e., leukopenia and thrombocytopenia) resulting in decrease of all formed elements. In contrast, pure red cell aplasia is characterized by reduction in red cells only. The diagnosis can only be confirmed on bone marrow examination. Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a complete blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.
The following tests aid in determining differential diagnosis for aplastic anemia:
Treating immune-mediated aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine intake, or, in more severe cases, a bone marrow transplant, a potential cure.The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body ("graft-versus-host disease"). In young patients with an HLA matched sibling donor, bone marrow transplant can be considered as first-line treatment, patients lacking a matched sibling donor typically pursue immunosuppression as a first-line treatment, and matched unrelated donor transplants are considered a second-line therapy.
Medical therapy of aplastic anemia often includes a course of antithymocyte globulin (ATG) and several months of treatment with cyclosporine to modulate the immune system. Chemotherapy with agents such as cyclophosphamide may also be effective but has more toxicity than ATG. Antibody therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Corticosteroids are generally ineffective,[ citation needed ] though they are used to ameliorate serum sickness caused by ATG. Normally, success is judged by bone marrow biopsy 6 months after initial treatment with ATG.
One prospective study involving cyclophosphamide was terminated early due to a high incidence of mortality, due to severe infections as a result of prolonged neutropenia.
In the past, before the above treatments became available, patients with low leukocyte counts were often confined to a sterile room or bubble (to reduce risk of infections), as in the case of Ted DeVita.
Full blood counts are required on a regular basis to determine whether the patient is still in a state of remission.
Many patients with aplastic anemia also have clones of cells characteristic of the rare disease paroxysmal nocturnal hemoglobinuria (PNH, anemia with thrombopenia and/or thrombosis), sometimes referred to as AA/PNH. Occasionally PNH dominates over time, with the major manifestation intravascular hemolysis. The overlap of AA and PNH has been speculated to be an escape mechanism by the bone marrow against destruction by the immune system. Flow cytometry testing is performed regularly in people with previous aplastic anemia to monitor for the development of PNH.[ citation needed ]
Untreated, severe aplastic anemia has a high risk of death. Modern treatment, by drugs or stem cell transplant, has a five-year survival rate that exceeds 85%, with younger age associated with higher survival.
Survival rates for stem cell transplant vary depending on age and availability of a well-matched donor. Five-year survival rates for patients who receive transplants have been shown to be 82% for patients under age 20, 72% for those 20–40 years old, and closer to 50% for patients over age 40. Success rates are better for patients who have donors that are matched siblings and worse for patients who receive their marrow from unrelated donors.
Older people (who are generally too frail to undergo bone marrow transplants), and people who are unable to find a good bone marrow match, undergoing immune suppression have five-year survival rates of up to 75%.[ citation needed ]
Relapses are common. Relapse following ATG/ciclosporin use can sometimes be treated with a repeated course of therapy. In addition, 10-15% of severe aplastic anemia cases evolve into myelodysplastic syndrome and leukemia.[ citation needed ] According to a study, for children who underwent immunosuppressive therapy, about 15.9% of children who responded to immunosuppressive therapy encountered relapse.
Milder disease can resolve on its own.[ citation needed ]
Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia, and 90% develop bone marrow failure by age 40. About 60–75% of people have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% of people have some form of endocrine problems, with varying degrees of severity.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to the presence of defective surface protein DAF on the red blood cell, which normally functions to inhibit such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. Other key features of the disease, such as the high incidence of blood clot formation, are incompletely understood.
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes). Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine. The risk is especially high in cytotoxic chemotherapy for leukemia.
Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous, allogeneic or syngeneic.
Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person. GvHD is commonly associated with stem cell transplants such as those that occur with bone marrow transplants. GvHD also applies to other forms of transplanted tissues such as solid organ transplants.
Primate erythroparvovirus 1, generally referred to as B19 virus, parvovirus B19 or sometimes erythrovirus B19, was the first known human virus in the family Parvoviridae, genus Erythroparvovirus; it measures only 23–26 nm in diameter. The name is derived from Latin, parvum meaning small, reflecting the fact that B19 ranks among the smallest DNA viruses. B19 virus is most known for causing disease in the pediatric population; however, it can also affect adults. It is the classic cause of the childhood rash called fifth disease or erythema infectiosum, or "slapped cheek syndrome".
Cytopenia is a reduction in the number of mature blood cells caused by antibodies that destroy them. This results in a reduction of mature blood cells in the body. It is common in cancer patients being treated with radiation and/or chemotherapy.
Pure red cell aplasia (PRCA) or erythroblastopenia refers to a type of anemia affecting the precursors to red blood cells but not to white blood cells. In PRCA, the bone marrow ceases to produce red blood cells. There are multiple etiologies that can cause PRCA. The condition has been first described by Paul Kaznelson in 1922.
Transient erythroblastopenia of childhood (TEC) is a slowly developing anemia of early childhood characterized by gradual onset of pallor.
Transfusion-associated graft-versus-host disease (TA-GvHD) is a rare complication of blood transfusion, in which the immunologically competent donor T lymphocytes mount an immune response against the recipient's lymphoid tissue. These donor lymphocytes engraft, recognize recipient cells as foreign and mount an immune response against recipient tissues. Donor lymphocytes are usually identified as foreign and destroyed by the recipient's immune system. However, in situations where the recipient is severely immunocompromised, or when the donor and recipient HLA type is similar, the recipient's immune system is not able to destroy the donor lymphocytes. This can result in transfusion associated graft-versus-host disease.
Donor lymphocyte infusion (DLI) or buffy coat infusion is a form of adoptive immunotherapy used after hematopoietic stem cell transplantation.
Timothy Ray Brown is an American considered to be the first person cured of HIV/AIDS. Brown was called "The Berlin Patient" at the 2008 Conference on Retroviruses and Opportunistic Infections, where his cure was first announced, in order to preserve his anonymity, and because he lived in, and was treated in Berlin. He chose to come forward in late 2010. “I didn’t want to be the only person cured,” he said. “I wanted to do what I could to make [a cure] possible. My first step was releasing my name and image to the public.”
Bone marrow failure occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets. Red blood cells transport oxygen to be distributed throughout the body’s tissue. White blood cells fight off infections that enter the body. Bone marrow also contains platelets, which trigger clotting, and thus help stop the blood flow when a wound occurs.
Neal Stuart Young is an American physician and researcher, chief of the Hematology Branch of the National Institutes of Health (NIH), and Director of the Center for Human Immunology at the NIH in Bethesda, Maryland. He is primarily known for work in the pathophysiology and treatment of aplastic anemia, and is also known for his contributions to the pathophysiology of parvovirus B19 infection.
Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.
Thymoglobulin is an anti-human thymocyte immunoglobulin preparation made of purified polyclonal antibodies derived from rabbits. While these antibodies have a variety of specificities, their main mechanism of immunosuppression is through depletion of T cells. Thymoglobulin is currently approved for clinical use in Europe and the United States for renal allograft rejection, prevention of graft-vs.-host disease, and conditions involving bone marrow failure, including aplastic anemia and has additional off-label uses.
Aplastic anaemia (AA) is a rare bone marrow failure disorder with high mortality rate, which is characterized by pancytopenia and an associated increase in the risk of hemorrhage, infection, organ dysfunction and death.
In the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia.