Aplastic anemia

Aplastic anemia (AA) is a disease in which the bone marrow, and the blood 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 inability of the stem cells to generate the mature blood cells.

It is most prevalent in people in their teens and twenties, but is also common among the elderly. It can be caused by exposure to chemicals, drugs, radiation, infection, immune disease, and heredity; 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 anemia, these cells are mostly gone and replaced by fat.

First line treatment for aplastic anemia consists of immunosuppressive drugs, typically either anti-lymphocyte globulin or anti-thymocyte globulin, combined with corticosteroids and cyclosporine. Hematopoietic stem cell transplantation is also used, especially for patients under 30 years of age with a related, matched marrow donor. In February 2014, the oral thrombopoietin analog eltrombopag was approved by the FDA for the treatment of patients who are refractory to immunosuppression. This additional treatment option is the first of its class, and represents a significant advancement in the prognosis and treatment of patients with aplastic anemia.

Signs and symptoms

• Anemia with malaise, pallor and associated symptoms such as palpitations
• Thrombocytopenia (low platelet counts), leading to increased risk of hemorrhage, bruising and petechiae
• Leukopenia (low white blood cell count), leading to increased risk of infection
• Reticulocytopenia (low counts of reticulocytes, that is, immature red blood cells)

Causes

Aplastic anemia can be caused by exposure to chemicals, drugs, radiation, infection, immune disease, and heredity; in about half the cases, the cause is unknown.

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 is followed by 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.

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

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.

Diagnosis

The condition needs to be differentiated from pure red cell aplasia. In aplastic anemia, the patient has pancytopenia (i.e., anemia, neutropenia 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:

1. Bone marrow aspirate and biopsy: to rule out other causes of pancytopenia (i.e. neoplastic infiltration or significant myelofibrosis).
2. History of iatrogenic exposure to cytotoxic chemotherapy: can cause transient bone marrow suppression
3. X-rays, computed tomography (CT) scans, or ultrasound imaging tests: enlarged lymph nodes (sign of lymphoma), kidneys and bones in arms and hands (abnormal in Fanconi anemia)
4. Chest X-ray: infections
5. Liver tests: liver diseases
6. Viral studies: viral infections
7. Vitamin B₁₂ and folate levels: vitamin deficiency
8. Blood tests for paroxysmal nocturnal hemoglobinuria
9. Test for antibodies: immune competency

Treatment

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 a cyclosporin 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, 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. New treatment options include eltrombopag, which has shown promise as treatment for both moderate (non-severe) aplastic anemia, as well as severe aplastic anemia that is refractory to traditional immunosuppression.

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.

Follow-up

Regular full blood counts are required 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.

Prognosis

Untreated, severe aplastic anemia has a high risk of death. Treatment, by drugs or stem cell transplant, has a 5-year survival of about 70%, 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 has been shown to be 82% for patients underneath the age of 20, 72% for those 20â€"40 years of age and closer to 50% for patients over the age of 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, who undergo immune suppression have five year survival rates of up to 75%.

Relapses are common. Relapse following ATG/cyclosporin use can sometimes be treated with a repeated course of therapy. In addition, 10-15% of severe aplastic anemia cases evolve into MDS and leukemia.

Milder disease can resolve on its own.