Aplastic Anemia Specialist Hospitals in Hyderabad
Aplastic anemia develops as a result of bone marrow damage. The damage may be present at birth or occur after exposure to radiation, chemotherapy, toxic chemicals, some drugs or infection. Symptoms may develop slowly or suddenly. Fatigue, frequent infections, rapid heart rate and bleeding may occur. If necessary, treatment can include medication, blood transfusions and stem-cell transplants.
What is aplastic anemia?
Aplastic anemia is a rare acquired disorder in which there is a failure of the bone marrow to produce sufficient blood cells for the circulation. Acquired means that the condition is neither present at birth nor inherited but has developed during the patient’s life. Blood cells come from special cells in the bone marrow, called stem cells. Less than 1 in 5,000 of the
marrow cells is a stem cell. The stem cells give rise to a progressively maturing series of different cell types which eventually lead to all the functional blood cells found in the circulation. In aplastic anemia blood production by stem cells fails resulting in a lack of red cells (anemia), white cells (leading to an increased risk of infection) and platelets (which
are needed to prevent bleeding and bruising). Aplastic anemia is nota form of cancer. There is a lack of cells within the blood and the blood forming stem cells within the marrow are replaced by fat cells. Any remaining cells look more or less normal in contrast to leukemia and other blood cancers.
The failure of the stem cells to produce mature blood cells can vary from partial to almost complete thus producing a disease of varying severity in different people. The degree of marrow failure may change with time in a given patient. Symptoms are slow to emerge because the loss of stem cell function is gradual. Often patients only realise that they have been less than fully fit for some time after their symptoms have been investigated with
a blood test.
The diagnosis is suggested by the blood count and by examination of the blood film but it can only be confirmed by a bone marrow examination. There are two parts to a bone marrow examination, the ‘aspirate’ and the ‘trephine’.
The aspirate is obtained by sucking a small amount of cells from the marrow through a hollow needle, spreading it on a glass slide and then stained and examined in the laboratory. This reveals the appearance of individual cells and
helps to exclude other diagnoses such as leukemia. The trephine gives an overall picture of the marrow and is important in determining the severity
of the marrow failure. In normal bone marrow about half of the space is taken up by fat cells with the remainder being blood producing (hemopoietic)
cells. In aplastic anemia almost the entire space is taken up by fat cells.
Occasionally there may be patchy loss of hemopoietic cells within the bone marrow. It may be necessary to repeat the examination at a different site
to be quite sure of the diagnosis.
Though aplastic anemia can occur at any age, it appears to be more common in two age groups, those aged between 10 and 20 years and in people aged 40 years or over. The condition appears to be slightly more
common in men. People of all ethnic groups may be affected. There is a higher frequency in tropical countries and the Far East. This is probably related
to some factor in the environment rather than any particular race. People who move from these regions to Europe or the USA seem to acquire the same
chance of developing aplastic anemia as the local population.
The lack of blood cells produces a potentially very serious or fatal disease unless properly managed. Until about 1980 the majority of patients with
severe disease did not survive more than a year but fortunately new methods of support and treatment have completely changed this gloomy outlook.
Successful treatment requires a long time. Patience and care are required by all involved including the family, friends and the medical team.
Accurate information regarding the epidemiology regarding the incidence of aplastic anemia is generally not available. Studies suggest the incidence is 0.6 to 6.1 cases per million population; this rate is largely based on data from retrospective reviews of death registries.
The male-to-female ratio is approximately 1:1. Although aplastic anemia occurs in all age groups, a small peak in the incidence is observed in childhood. A second peak is found in the 20 to 25-year-old age group.
Two interrelated explanations exist for aplastic anemia: extrinsic immune-mediated suppression of hematopoietic stem cells and intrinsic abnormality of marrow progenitors.
Damaged hematopoietic stem cells mature into self-reactive T-helper cells (T1) that release cytokines interferon-? (IFN?) and tumor necrosis factor (TNF) to propagate a cytotoxic cascade to kill and suppress other hematopoietic stem cells. The exact antigens T1 cells target are unclear, but one appears to be the glucose phosphate inositol (GPI)-linked protein on cell membranes (the mechanism behind pancytopenia in PNH). Also, the genes for apoptosis and death pathways are upregulated. Moreover, immunosuppressive therapy targeting T-cells leads to a response in two-thirds of patients with idiopathic aplastic anemia, and patients with graft-versus-host disease develop aplasia in the setting of healthy bone marrow progenitors.
In the second theory, stem cells with inherent defects lose the capacity to differentiate and proliferative. Their inability to dedifferentiate can lead to clonal evolution into hematologic neoplasms, for example, myelodysplastic syndrome. This is common in patients with Fanconi anemia. Partial defects in telomeres, the component of DNA intertwined with cell division, lead to premature hematopoietic stem cell exhaustion and marrow aplasia as well. Shortened telomeres are present in cells of half the patients with aplastic anemia.
Bone marrow biopsy from patients with aplastic anemia will be markedly hypocellular. Fat cells and fibrotic stroma replace normal bone marrow tissue. Stray lymphocytes and plasma cells remain, the remainder is devoid of marrow progenitors.
History and Physical
Aplastic anemia presents at any age with equal distribution among gender and race. Symptoms related to the absent cell lineage (anemia, progressive weakness, pallor, and dyspnea; neutropenia, frequent and persistent minor infections, or sudden onset febrile illness; thrombocytopenia, ecchymoses, mucosal bleeding, and petechiae). Splenomegaly is not seen, and its presence suggests an alternative diagnosis. Labs will demonstrate macrocytic normochromic anemia with reticulopodia, neutropenia, and thrombocytopenia. There must be no cytologic abnormalities as this would suggest an underlying hematologic process.
The diagnostic criteria for aplastic anemia are the following: the presence of bone marrow hypocellularity and 2 or more cytopenias (reticulopodia less than 1% or less than 40,000/microliter, neutropenia less than 500/microliter, or thrombocytopenia less than 20,000/microliter). The moderate disease has less than 30% bone marrow cellularity; the severe disease has less than 25% cellularity or less than 50% cellularity containing fewer than 30% hematopoietic cells, and very severe meets severe criteria plus neutropenia less than 200/µL. Aspirate of bone marrow has little yield (“dry tap”). Bone marrow biopsy is essential: it will be markedly hypocellular and devoid of marrow progenitors. Genetic testing with flow cytometry and fluorescence in situ hybridization (FISH) is useful to exclude hematologic malignancies responsible for pancytopenia. Additional testing depends on the underlying condition responsible for bone marrow failure, for example, telomerase mutation testing for dyskeratosis congenital.
Treatment / Management
Management of aplastic anemia is directed at the underlying cause. Remove the offending agent(s), if possible. Some drugs have been discontinued in the United States due to their associations with aplastic anemia (e.g., Ticlopidine, a platelet aggregation inhibitor used as primary/secondary stroke prevention or dual antiplatelet therapy following percutaneous coronary intervention; phenylbutazone, a NSAID used as an analgesic and antipyretic). Aplastic anemia associated with pregnancy is self-limited and ends with delivery. Patients with thymoma usually have full bone marrow recovery following thymectomy.
For patients in whom no reversible cause is found, treatment depends on age, disease severity, donor availability, and performance status. Young patients (younger than 50 years) in good health with severe disease should undergo allogeneic hematopoietic cell transplant (HCT) before initial immunosuppressive therapy. Older patients (50 years or older) in good health and young patients without an HCT donor receive full-dose immunosuppressive therapy using eltrombopag, horse/rabbit anti-thymocyte globulin (ATG), cyclosporine A, and prednisone. This combination can be tailored to single-agent eltrombopag, ATG, or cyclosporine A for less healthy individuals. Eltrombopag is a thrombopoietin non-peptide agonist that increases platelet counts and activates intracellular signal transduction pathways to increase proliferation and differentiation of marrow progenitor cells. ATG eliminates antigen-reactive T-lymphocytes and induces hematologic responses in aplastic anemia. Cyclosporine A inhibits the production and release of interleukin-II (IL-2) and inhibits IL-2 induced activation of resting T-lymphocytes. Prednisone induces cell death of immature lymphocytes. Clinical studies are underway for alternative therapies used as second-line agents.
Supportive care includes infection prophylaxis/treatment and transfusions (leukoreduced red blood cells for Hb less than 7 mg/dL or platelets less than 10,000/microliters or less than 50,000/microliters for active blood loss). Monitor for secondary hemochromatosis and administer iron chelators as indicated. Use of growth factors such as erythropoietin or granulocyte colony-stimulating factors is not recommended because there are inadequate precursor cells to generate sufficient responses.
Survival in aplastic anemia depends largely on age, disease severity, and response to initial therapy. Those who recover following drug cessation or treatment of underlying condition have a stable clinical course, as well as those with self-limited processes. Five-year survival is greater than 75% for patients who undergo bone marrow transplant from a suitable donor. The majority of untreated patients die within one year from disease-related complications (e.g., bleeding, infections, or transformation to lymphoproliferative disorders).
Pancytopenia can occur due to myelophthistic syndrome, a pathologic process that replaces normal bone marrow. Etiologies are solid tumor metastases (ex. lung, breast, and prostate malignancies), lymphoid or myeloid neoplasms (ex. acute myelogenous leukemia), myelofibrosis, hemophagocytic lymph histiocytosis, osteopetrosis, or Gaucher disease. The bone marrow biopsy will not be hypocellular and reflect the underlying disease.
Isolated failure of single hematopoietic lineage is common (ex. agranulocytosis, pure red cell aplasia). These share the same causes for aplastic anemia (ex. propylthiouracil and agranulocytosis, thymoma and pure red cell aplasia). Patients will have symptoms related to the cell line involved, not all three.
Survival in aplastic anemia depends largely on age, disease severity, and response to initial therapy. Those who recover following drug cessation or treatment of underlying condition have stable clinical courses, as well as those with self-limited processes. Five-year survival is >75% for patients who undergo bone marrow transplant from a suitable donor. The majority of untreated patients die within one year from disease-related complications (ex. bleeding, infections, or transformation to lymphoproliferative disorders).
The most common complications of aplastic anemia include bleeding, infections, or transformation to lymphoproliferative disorders. These are managed by surveillance and symptomatic treatment including antibiotics, chemotherapy, and/or transfusions.
Deterrence and Patient Education
Aplastic anemia is a condition in which the body is unable to make blood cells that perform vital functions including infection control, oxygen transport, and tissue repair following injury. While there are many causes for this disease, many patients never find the underlying issue. Recovery is excellent for patients with identifiable causes or disease that resolves spontaneously. Patients can opt for bone marrow transplant and additional medications to provide blood products to the body. Monitor for disease complications such as bleeding, cancers or infections, and notify physicians of any changes.
Pearls and Other Issues
Pancytopenia can occur due to the myelophthisic syndrome, a pathologic process that replaces normal bone marrow. Etiologies are solid tumor metastases (e.g., lung, breast, and prostate malignancies), lymphoid or myeloid neoplasms (e.g., acute myelogenous leukemia), myelofibrosis, hemophagocytic lymph histiocytosis, osteopetrosis, or Gaucher disease. The bone marrow biopsy will not be hypocellular and reflect the underlying disease.
Isolated failure of a single hematopoietic lineage is common (agranulocytosis, pure red cell aplasia). These share the same causes for aplastic anemia (e.g., propylthiouracil and agranulocytosis, thymoma and pure red cell aplasia). Patients will have symptoms related to the cell line involved, not all three.
Enhancing Healthcare Team Outcomes
The management of patients with aplastic anemia is an interprofessional team endeavor. The disorder can affect many organ systems and besides the disease itself, many complications can result occur following immunosuppressive therapy and hematopoietic cell transplantation. These patients need close monitoring for infections and bleeding. Because of the neutropenia, the diet has to be tailored made and should exclude dairy products, raw meat and most vegetables and fruits because of colonization by a number of microorganisms. All patients should avoid intense physical activity because they are at a risk for bleeding. Premenopausal women can develop heavy periods and should be advised to be on hormonal therapy. Finally, all patients should be educated on the need to maintain good hand and personal hygiene because they are at a very high risk for infections.