Aplastic Anemia

Aplastic anemia, or hypoplastic anemia, results from conditions in which blood cell production in the bone marrow or erythrocyte stem cells are underdeveloped, defective, or absent.

There is a great decrease in all blood cells produced in the bone marrow – red cells (which contain hemoglobin and deliver oxygen throughout the body), white cells (vital for immune protection), and platelets (which help clot the blood during bleeding).

Any injury to, or destruction of, all of the blood’s formed elements in bone marrow or the bone marrow matrix, causes life-threatening pancytopenia (anemia, granulocytopenia, or thrombocytopenia) and results from the decreased functional capacity of a hypoplastic, fatty bone marrow. These disorders generally produce bleeding or infection, particularly when they stem from toxins or infections.

Many disease processes interfere temporarily or permanently with the viability of the pluripotential stem cell. Reduction in their numbers or their ability to become committed stem cells causes a reduction in the formation and development of blood cells (hematopoiesis).

If all the cell lines are affected, all cellular components of circulating blood are reduced, resulting in the abnormal depression of all the blood elements (pancytopenia). If only the erythrocyte stem cells are affected, the condition in the marrow is termed “pure red cell aplasia” but in the circulation, it is called “aplastic anemia.”

Pure red cell aplasia has many possible causes: infiltrative disorders of the bone marrow (myelofibrosis, leukemia, myeloma, or carcinoma); autoimmune diseases; renal failure; splenic dysfunction; cobalamin or folate deficiency; infection; and exposure to radiation, drugs, and toxins. The exact mechanism that halts erythropoiesis is not known, but two theories have been proposed.

• The first is called the “seed or stem cell-deficiency theory”. It proposes that a common stem cell population is irreversibly altered, rendering it incapable of proliferation and differentiation.
• The second theory is the “microenvironmental deficiency theory”, which proposes that the stem cell environment (i.e., the marrow) is altered so as to inhibit erythropoiesis. If the erythrocyte stem cells or the marrow is unable to recover from the insult within months, bone marrow aplasia leads to death from anemia, infection, or hemorrhage. If the insult is mild, causing bone marrow hypoplasia, anemia is less severe and the individual may live for years.

Aplastic anemia refers to a condition in which all formed elements of the blood are simultaneously depressed. Although there is a profound depression of erythrocytes, there are normal or slightly decreased WBCs and platelets. Pure red cell aplasia is a type of hypoplastic anemia. It is a congenital condition marked by complete or near-complete absence of all cells of the erythroid series, but with normal production of the other myeloid cells. Consequently, all the complications of anemia occur, as well as hemorrhages resulting from the lack of platelets needed for clotting.

Roughly half of all aplastic anemias occur as a result of drugs (such antibiotics as chloramphenicol, sulfonamides, phenylbutazone [Butazolidin], and such anticonvulsant agents as mephenytoin), such toxic agents as benzene, such insecticides as DDT, or radiation.

The rest may result from immunologic factors, severe disease (especially hepatitis, Epstein-Barr virus, cytomegalovirus, and miliary tuberculosis), or preleukemic and neoplastic infiltration of the bone marrow. Mortality for aplastic anemias with severe pancytopenia is 80% to 90%. Death usually results from bleeding or infection.

Doctors have classified aplastic anemia into three categories: moderate, severe, and very severe. Although basic symptoms and treatments are similar for all three, the time frame for administering treatments will vary according to the severity. Two forms of idiopathic aplastic anemia are known:

• congenital hypoplastic anemia (anemia of Blackfan and Diamond), which develops between the ages of two and three months, and
• Fanconi’s syndrome, which develops between birth and age ten, and where chromosomal abnormalities are usually associated with such multiple congenital anomalies as dwarfism and hypoplasia of the kidneys and spleen. There has been a reported linkage of the disorder to chromosome 15q15.3.

In the absence of a consistent familial or genetic history of aplastic anemia, researchers suspect that these congenital abnormalities result from an induced change in the development of the fetus.

Clinical signs and symptoms of aplastic anemias vary with the severity of pancytopenia, but often develop gradually. Anemic symptoms include the following:

• a progressive weakness and fatigue;
• shortness of breath;
• headache;
• pallor,; and ultimately,
• tachycardia and congestive heart failure.

Aplastic anemia causes the classic cardiovascular and respiratory manifestations of anemia. If the stem cells of platelets and leukocytes also are damaged or deficient, anemia is accompanied by platelet deficiency (thrombocytopenia), which results in hemorrhage into the tissues, leukocyte deficiency (leukopenia) and neutrophil deficiency (neutropenia), and infection. Bone marrow biopsy is necessary to determine whether the anemia is caused by pure red cell aplasia or hypoplasia.

Thrombocytopenia is a lower-than-normal number of circulating platelets resulting from a decreased platelet production, decreased platelet survival, increased platelet destruction (the most common form), or sequestration of blood in the spleen. Secondary thrombocytopenia results from aplastic anemia, acute leukemia, and conditions causing splenomegaly, as cirrhosis or lymphomas, that lead to sequestration of blood in the spleen. Symptoms lead to ecchymosis, petechiae, and hemorrhage, especially from the mucous membranes (nose, gums, rectum, and vagina) or into the retina or central nervous system.

Neutropenia is a diminished number of neutrophils in the blood. This can be a chronic, periodic condition, one of severity (Kostmann’s), or one resulting from a malignancy. Symptoms lead to infection (fever, oral and rectal ulcers, sore throat), but without characteristic inflammation.

Leukemia is a progressive, malignant disease of the blood-forming organs and marked by distorted prolific development of leukocytes in the bone marrow. It is accompanied by a reduced number of erythrocytes and blood platelets resulting in anemia and an increased susceptibility to infection and hemorrhage.

Initially, anemia may be profound from complete replacement of the bone marrow by cancer cells. Since anemia is also a consequence of drug-induced myelopsuppression, the risk of anemia is quite high for cancer patients. Symptoms of leukemia often include fever, pain in the joints and bones, and swelling of the lymph nodes, spleen, and liver.

Diagnosis comes after confirmation through the following tests:

• RBCs are usually normochromic and normocytic, although macrocytosis (larger than normal erythrocytes) and anisocytosis (excessive variation in erythrocyte size) may exist, with a total count of one million or less.
• Absolute reticulocyte count is very low.
• Serum iron is elevated (unless bleeding occurs), but total iron-binding capacity is normal or slightly reduced. Hemosiderin is present and tissue iron storage is visible microscopically
• Platelet, neutrophil, and WBC counts fall.
• Coagulation tests (bleeding time), reflecting decreased platelet count, are abnormal.
• Bone marrow aspiration from several sites may yield a “dry tap”; and a biopsy will show severely hypocellular or aplastic marrow, with varied amounts of fat, fibrous tissue, or gelatinous replacement; an absence of tagged iron (since iron is deposited in the liver rather than the bone marrow) and megakaryocytes; and depression of erythroid elements.

Differential diagnosis must rule out paroxysmal nocturnal hemoglobinuria and other diseases where pancytopenia is common.

There are no known cures, but gradual recovery can occur if the causative factor is eliminated. Patients can be maintained with blood transfusions. There have been some successful bone marrow transplants from close relatives.

Treatment generally involves the following:

• Removing any identifiable cause and preventing further exposure to the causal agent is the most important aspect. However, even after elimination of the cause, recovery can take months.
• Using such vigorous measures as the administration of packed red cells, platelets, and experimental HLA-matched leukocyte transfusions have proven successful.
• Blood transfusions can temporarily improve hemoglobin levels. Splenectomy is considered if transfused erythrocytes are being destroyed in the spleen.
• Bone marrow transplantation is the treatment of choice for severe aplasia and for those who need constant RBC replacement.
• Sometimes, pharmacologic stimulation of the marrow function is tried; but these immunosuppressive drugs have some serious side effects.
• Patients with low leukocyte counts (WBCs) need special measures to prevent infection. Antibiotics are not given prophylactically because they tend to encourage resistant strains of organisms.
• Growth factors have been successfully used to increase the production of WBCs. To date, the use of growth factors like erythropoietin to increase RBCs and platelets have not been particularly successful.
• If platelet count is low (less than 20,000/mm3), preventing hemorrhages is vital and includes such measures as avoiding IM injections, using an electric razor and a soft toothbrush, and using humidifying oxygen to prevent drying of the mucous membranes.

Other treatments are sometimes used if none of the above has been successful. These include such other immunosuppressive drugs and marrow stimulants (cytokines) as stem cell factor and hormones (androgens). Many of these are considered experimental and available only at university-affiliated medical centers conducting clinical trials using these treatments. Certain types of bone marrow transplants are also under investigation.

Peripheral blood stem cell transplantation is being used more often in such hematologic disorders, including aplastic anemia, but research is still being done to determine its effectiveness. In this procedure, stem cells are harvested from the bloodstream of the donor rather than from the bone marrow and recently, stem cells from fetal cord blood have also been used.