Aplastic anemia

Editor-In-Chief: Aric Hall, M.D., Beth Israel Deaconess Medical Center, Boston, MA[mailto:achall@bidmc.harvard.edu]

Overview
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells.

The term 'aplastic' means the marrow suffers from an aplasia that renders it unable to function properly. Anemia is the condition of having fewer red blood cells than normal, or fewer than needed to function properly. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types: red blood cells, white blood cells, and platelets.

Causes
Aplastic anemia is a rare condition with incidence of two cases per million individuals per year in Western countries with rates two to three times as high in Asia. This low incidence leads to difficulties in forming clear associations with causal factors.

One known cause is an autoimmune disorder, where the white blood cells attack the bone marrow.

In many cases, the etiology is impossible to determine, but aplastic anemia is sometimes associated with exposure to substances such as benzene, radiation, or to the use of certain drugs, including chloramphenicol, carbamazepine, phenytoin, quinine, and phenylbutazone. Many drugs are associated with aplasia mainly in the base of case reports but at a very low probability, As an example, chloramphenicol treatment is followed by aplasia in less than 1 in 40,000 treatment courses,and carbamazepine aplasia is even more rare.

Aplastic anaemia is present in up to 2% of patients with acute viral hepatitis.

Signs and symptoms

 * Anemia with malaise, pallor and associated symptoms
 * Thrombocytopenia (low platelet counts), leading to increased risk of hemorrhage and bruising
 * Leukopenia (low white blood cell count), leading to increased risk of infection

Diagnosis
The diagnosis can only be made on bone marrow examination. This will reveal a hypocellular bone marrow with fatty replacement of the normal hematopoetic precursors. The primary diagnostic dilemma is differentiating aplastic anemia from a hypocellular myelodysplastic syndrome. Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a full blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.

Treatment
Treating 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 but a risky procedure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The pluripotent 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").

Medical therapy of aplastic anemia often includes a short course of anti-thymocyte globulin (ATG or anti-lymphocyte globulin) and several months of treatment with cyclosporin to modulate the immune system. Mild chemotherapy with agents such as cyclophosphamide and vincristine may also be effective. Antibodies therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Steroids are generally ineffective.

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 famed case of Ted DeVita.

Prognosis
Untreated aplastic anemia is an illness that leads to rapid death, typically within six months. If the disease is diagnosed correctly and initial treatment is begun promptly, then the survival rate for the next five to ten years is substantially improved, and many patients live well beyond that length of time.

Occasionally, milder cases of the disease resolve on their own. Relapses of previously controlled disease are, however, much more common.

Well-matched bone marrow transplants from siblings have been successful in young, otherwise healthy people, with a long-term survival rate of 80%-90%. Most successful BMT recipients eventually reach a point where they consider themselves cured for all practical purposes, although they need to be compliant with follow-up care permanently.

Older people (who are generally too frail to undergo bone marrow transplants) and people who are unable to find a good bone marrow match have five year survival rate of up to 75%.

Follow-up
Regular full blood counts are required to determine whether the patient is still in a state of remission.

10-33% of all patients develop the rare disease paroxysmal nocturnal hemoglobinuria (PNH, anemia with thrombopenia and/or thrombosis), which has been explained as an escape mechanism by the bone marrow against destruction by the immune system. Flow cytometry testing is probably warranted in all PNH patients with recurrent aplasia.