(Aplastic anemia) Its causes and treatment

(Aplastic anemia) Its causes and treatment

Aplastic anemia is a condition in which the body is unable to produce enough red blood cells. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia is characterized by a lack of all three components of the blood cell spectrum: red blood cells, white blood cells, and platelets.

It occurs most frequently 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. About half of the time, the cause remains a mystery.

Aplastic anemia can be definitively diagnosed by bone marrow biopsy. Aplastic anemia is characterized by the absence of blood stem cells, which normally make up 30–70% of the bone marrow’s mass, and their replacement by fat.

First-line treatment for aplastic anemia consists of immunosuppressive drugs—typically either anti-lymphocyte globulin or anti-thymocyte globulin—combined with corticosteroids, chemotherapy, and ciclosporin. Patients under the age of 30 who have a related, matched bone marrow donor can benefit from hematopoietic stem cell transplantation.

Eleanor Roosevelt and Marie Curie both died of aplastic anemia.

Signs & Symptoms

The symptoms of acquired aplastic anemia occur as a consequence of the bone marrow failing to produce enough blood cells. The specific signs and symptoms of each case are unique. Mild symptoms may persist for many years in some people, while severe symptoms may lead to life-threatening consequences.

To make red and white blood cells as well as platelets, the bone marrow needs to be stimulated. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body’s organs, white blood cells help in fighting infections, and platelets form clots to stop bleeding.

A low level of circulating red blood cells is called anemia. A low level of white blood cells is known as leukopenia. Thrombocytopenia is the medical term for a low platelet count.

Blood sugar levels may drop too low, resulting in tiredness and an increased need for sleep. Other symptoms of anemia include pale skin and a runny nose as well as an increased risk of heart problems like heart palpitations and chest pain. Infections caused by bacteria and fungi are more likely to strike those with leukopenia.

Patients with thrombocytopenia are more prone to bruising and bleeding from the gums and nose even after minor injuries. Menstrual blood loss may be increased in some women. The severity of anemia, leukopenia, and thrombocytopenia affects the symptoms.

Some individuals with acquired aplastic anemia also have another disorder at the same time, called paroxysmal nocturnal hemoglobinuria (PNH). Acquired aplastic and PNH have a close relationship that is not fully understood by researchers. PNH may develop as a result of bone marrow failure and autoimmune acquired aplastic anemia. Individuals affected with acquired aplastic anemia are also at risk that it will evolve into another similar disorder known as myelodysplasia.

In a minority of cases, acquired aplastic anemia may eventually develop leukemia. The PIGA gene, which is only found in the stem cells of the bone marrow, is the culprit in the development of PNH. The PIGA gene mutations cause blood cells to become sensitive to increased destruction by complement, a blood immunity protein. About half patients with aplastic anemia have evidence of PNH at presentation, as detected by flow cytometry.

Furthermore, patients who respond following immunosuppressive therapy may recover with PNH. There are a minority of MDS patients with hypoplastic or low cellularity bone marrow, as seen in acquired aplastic anemia. These conditions are often mistaken for each other, so whether one is transformed to another is uncertain.

Causes (Aplastic anemia)

Aplastic anemia can be caused by immune disease or exposure to certain chemicals, drugs, radiation, or infection; in about half the cases, a definitive cause is unknown. It is not a hereditary condition, nor is it contagious.

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. However, the probability that these drugs will lead to aplastic anemia in a given patient is very low.

Fewer than one in every 40,000 courses of chloramphenicol treatment results in aplasia, and carbamazepine aplasia is even more rare.

Exposure to ionizing radiation from radioactive materials or radiation-producing devices is also associated with the development of aplastic anemia. As a result of working with radioactive materials for so long without protection — and because the dangers of ionizing radiation were not yet known — Marie Curie died of aplastic anemia.
Up to 2% of patients with acute viral hepatitis have aplastic anemia.

One known cause is an autoimmune disorder in which white blood cells attack the bone marrow. Acquired aplastic anemia is a T-cell mediated autoimmune disease, in which regulatory T cells are decreased and T-bet, a transcription factor and key regulator of Th1 development and function, is upregulated in affected T-cells.

As a result of active transcription of the interferon gamma (IFN-gamma) gene by T-bet, IFN-gamma levels are increased, which reduces colony formation of hematopoietic progenitor cells in vitro by inducing apoptosis of CD34+ cells in the bone marrow.

Short-lived aplastic anemia can also be a result of parvovirus infection.

An important cellular receptor for the parvovirus B19 that causes erythema infectiosum (the “fifth disease”) in young children is the P antigen (also known as globoside), one of many blood type-determining molecules in people.

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. Red blood cells have a lifespan of 120 days on average, so a decrease in production has little effect on the overall number of circulating cells, so this rarely becomes an issue. People with conditions that cause the cells to die early (such as sickle cell disease) may experience severe anemia as a result of parvovirus infection.

Aplastic crisis, which affects only red blood cells, is more frequently linked to parvovirus B19 (despite the name). Aplastic anemia involves all cell lines.

Other viruses that have been linked to the development of aplastic anemia include hepatitis, Epstein-Barr, cytomegalovirus, 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. If not mated, intact females will remain in heat, and the high levels of estrogen in the bone marrow will eventually cause it to stop producing red blood cells.

Affected Populations (Aplastic anemia)

Acquired aplastic anemia affects males and females in about equal numbers. The majority of cases involve adolescents or young adults in their late teens or early twenties. Aplastic anemia affects two people out of every million in Europe and Israel.

The incidence rate is two or three times greater in Asia. The exact incidence rates exist for the United States is unknown although some sources say that approximately 500-1,000 new cases of aplastic anemia are diagnosed each year.

There are a number of conditions that share symptoms with aplastic anemia. Comparisons may be useful for a differential diagnosis:

Misdevelopment of blood cells in the bone marrow is the cause of a rare group of blood disorders known as the “myelodysplastic syndromes” (also known as “MDS”). The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. To keep the body’s supply of oxygen flowing, red blood cells carry oxygen throughout the body, white blood cells fight infection, and platelets aid in blood clotting.

Inadequately formed red blood cells enter the bloodstream and fail to develop normally. This results in abnormally low blood cell levels in people with MDS (low blood counts). Acquired aplastic anemia can be difficult to tell apart from MDS. When the bone marrow fails to produce enough blood cells, patients with MDS are at risk of developing acute leukemia.

Hematopoietic stem cells in MDS frequently have chromosomal abnormalities or harmful mutations in specific genes. (For more information on this disorder, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)

It is an acquired stem cell disorder known as paroxysmal nocturnal hemoglobinuria (PNH). Premature destruction of red blood cells (hemolysis) is the classic finding, resulting in repeated episodes of hemoglobin in the urine as a result of this condition (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood.

Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. Patients with PNH are at risk for hemolysis as well as recurrent, life-threatening blood clots (thromboses).

Some degree of bone marrow dysfunction is also present in those who are affected. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder.

Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective “PNH” blood cells, and a predisposition to the multiplication and expansion of these defective stem cells.

PNH occurs when the bone marrow suffers from autoimmune destruction. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH.

Aplastic anemia may also occur as part of an inherited disorder such as Fanconi anemia, the telomere diseases, Schwachman-Diamond syndrome, ataxia-pancytopenia syndrome, and others.

Fanconi anemia is a rare genetic disorder that can manifest as early as infancy or as late as adolescence for some individuals. There are instances where a patient has been diagnosed with Fanconi’s anemia in adulthood. Many different genes have been identified as mutated in Fanconi anemia, and they generally cells ability to repair chromosome damage, and predisposes to damage to stem cells and eventually to leukemic transformation.

The disorder is characterized by deficiency of all bone marrow elements including red blood cells, white blood cells, and platelets (pancytopenia) (pancytopenia). Other symptoms of Fanconi anemia include heart (cardiac), kidney (renal), or skeletal abnormalities, as well as brown patches on the skin (skin pigmentation changes). It is thought that the various Fanconi’s anemia subtypes (complementation groups) are caused by abnormal changes (mutations) to different genes.

Each subtype appears to share the same characteristic symptoms and findings (phenotype) (phenotype). Inheritance of Fanconi’s anemia is via autosomal recessive genes.

The telomere diseases or telomeropathies can also lead to aplastic anemia. In these inherited conditions, there are inherited mutations in genes that maintain the ends of the chromosomes, called telomeres. Telomere diseases speed up the natural deterioration of chromosome ends that occurs as cells and organisms age.

As with Fanconi anemia, patients may not show signs of disease until adulthood. Telomeropathies can cause bone marrow failure as well as pulmonary and liver cirrhosis. Symptoms can be mild or severe, affecting different organs or multiple organs in the family.

Aplastic anemia
Equal division of blood cells


A diagnosis of acquired aplastic anemia may be suspected when an otherwise healthy individual has low levels of all three blood cell types (pancytopenia) (pancytopenia). Patients’ medical histories and various specialized tests, such as bone marrow biopsy, can help confirm the diagnosis.

During this procedure, a small specimen of bone marrow tissue is surgically removed, usually from the hip or pelvis, and studied under a microscope. In acquired aplastic anemia this sample will show a dramatic reduction or complete lack of cells. Additional tests may be necessary to rule out other disorders such as leukemia and to determine if there is an inherited or genetic cause.

Standard Therapies 

Treatment (Aplastic anemia)

Treatment of acquired aplastic anemia varies, depending upon the individual’s age, general health, and the severity of aplastic anemia. Treatment aims to correct the bone marrow failure, as well as to treat the patient’s immediate signs and symptoms. The two main forms of specific treatment are bone marrow transplantation and immunosuppressive therapies.

In the case of acquired aplastic anemia, treating the symptoms of low blood counts may be the primary goal of treatment. Anemia can be treated with transfusions of red blood cells, platelet transfusions can be used to treat or prevent major bleeding, and antibiotics can be used to treat or prevent infections.

Bone marrow transplantation, specifically an allogeneic transplant, is the treatment of choice in children and younger adults. Chemotherapy is used to eradicate or destroy the abnormal bone marrow cells in the patient and replace them with healthy marrow obtained from a donor during an allogeneic bone marrow transplant.

The donor marrow is transplanted by injecting the cells of the donor intravenously into the patient’s body, where it travels to the patient’s bone marrow and eventually begins producing new blood cells.

The best match for a bone marrow transplant is an identical twin, sibling or close relative who shares most of the same genetic makeup as the patient. However, in many cases, a search for an unrelated, matched donor is necessary, or more recently a partly matched family member is the donor.

Graft rejection and graft-versus-host disease are potential complications with any transplant procedures, including bone marrow transplant. The risks of graft-versus-host disease after a bone marrow transplant are wide-ranging, ranging from minor inconveniences to serious health issues.

Graft rejection or graft-versus-host disease can be prevented or treated with medications. 

Individuals who are not candidates for a bone marrow transplant, either because of advanced age or lack of a suitable donor, are usually treated with immunosuppressive treatment. The immune system is suppressed using drugs in this case.

Since many cases of acquired aplastic anemia are believed to result from an individual’s immune system mistakenly attacking bone marrow, suppressing the activity of the immune system often allows the bone marrow to recover and eventually to begin producing new blood cells. The two most commonly used immunosuppressive agents, given alone or in combination, are antithymocyte globulin (ATG) and cyclosporine. Horse ATG is more effective than rabbit ATG in the treatment of aplastic anemia.

Immunosuppressive therapy can restore an affected individual’s blood count to normal or near normal levels for prolonged periods. Nevertheless, relapses of aplastic anemia may necessitate repeating the treatment in order to ensure a long-term benefit. Aside from that, even those who have responded well to immunosuppressive therapy may still be at risk of developing PNH, myelodysplasia, or leukemia in the long term.

Approximately one-third of individuals treated with immunosuppressive drugs do not respond to therapy (refractory aplastic anemia) (refractory aplastic anemia). It is possible to treat these patients with hematopoietic stem cell transplants. Immunosuppression can be repeated in refractory aplastic anemia and also for patients who have relapsed.

Erythropoietin and neupogen, which are hematopoietic growth factors, are ineffective in aplastic anemia, but the platelet stimulator eltrombopag, which increases the production of platelets, was successful in increasing blood counts in patients with refractory aplastic anemia.

For patients with severe aplastic anemia who have had an inadequate response to immunosuppressive therapy and are not candidates for a hematopoietic stem cell transplant, the drug Promacta was approved by the FDA in 2014. 

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