Aplastic Anemia – Classification, Treatment and Prognosis

Aplastic anemia is a rare hematological (blood) disorder in which the bone marrow is damaged resulting in failure to produce all the three major types of blood cells.

Bone marrow is a sponge-like tissue inside the bones that makes stem cells which develop into red blood cells (RBCs), white blood cells (WBCs), and platelets.

It is also called hypoplastic anemia.

The fundamental feature is the reduction in the amount of hematopoietic tissue causing pancytopenia (reduced number of RBCs, WBCs and platelets resulting in the simultaneous presence of anemia, leucopenia and thrombocytopenia).

The term aplastic anemia was introduced in 1888 by Ehrlich to describe a disorder of unknown etiology characterized by anemia, leucopenia and thrombocytopenia resulting from aplasia of the bone marrow.

Types of Aplastic Anemia

It is classified as follows:

Acquired

1. Idiopathic when no obvious or known cause can be identified. It constitutes about half of all the cases.
2. Secondary when the disease is the result of exposure to certain drugs or chemicals, a sequel to certain viral infections or other specific conditions.

Inherited or Constitutional

When associated with inherited defects in DNA repair such as Fanconi’s syndrome.

Classification Based on Severity

Severe Aplastic Anemia:

Bone marrow cellularity < 30%

In addition, two of the following three cytopenias should be present

• Absolute neutrophil count (ANC) < 0.2 ×10⁹/L
• Platelet count< 20  ×10⁹/L
• Corrected reticulocyte count < 1%

Very Severe Aplastic anemia

Patients with a neutrophil count below 0.2 ×10⁹/L  are classified as having very severe aplastic anemia.

Epidemiology

The exact incidence is not known. Available data is based on retrospective reviews of death registries. Incidence in US and Europe is estimated to be 0.6-6.1 cases per million population. It is thought to be more common in Asia than in the West and is probably related to an increased exposure to toxic chemicals.

The disease is more frequent in people in their teens and early twenties but is also common among the elderly. The incidence is the same among males and females.

Causes and Etiology

Factors that can temporarily or permanently injure bone marrow and affect blood cell production include:

Drugs

Certain drugs including chloramphenicol, carbamazepine, phenylbutazone, trimethadione, gold salts, etc can cause aplastic anemia. Two distinct patterns can be seen:

• Dose-dependent reversible hematopoietic depression which usually occurs in all individuals.
• Idiosyncratic aplastic anemia which occurs in a small proportion of people and has no relationship with the dosage of the drug.

Toxic chemicals

Exposure to toxic chemicals, such as benzene, certain pesticides and insecticides such as lindane, chlordane, DDT, etc have been linked to aplastic anemia.

Viral infections

Several viral infections including hepatitis, Epstein-Barr, cytomegalovirus, parvovirus B19 and HIV have been linked to the development of aplastic anemia.

Radiation and chemotherapy treatments

Exposure to ionizing radiation and chemotherapeutic agents can damage healthy cells of bone marrow besides cancerous cells.  Aplastic anemia can be a temporary side effect of these treatments.

Autoimmune disorders

An autoimmune disorder, in which the immune system starts attacking healthy cells of the body, may involve and damage the stem cells in the bone marrow.

Aplastic anemia that occurs in pregnancy is usually related to autoimmunity.

Signs and Symptoms

Clinical features are related to the decrease in bone marrow production of hematopoietic cells. The onset is usually insidious.

Anemia

Presenting features include pallor, generalized weakness, dyspnea, headache, palpitations, etc.

Neutropenia

May manifest as infections or fever with chills and sweating. Infections can result in sore throat, mouth and pharyngeal ulcerations, skin infections, recurrent chest infections, septicemia, etc.

Thrombocytopenia

May result in hemorrhage into the skin (as ecchymoses or petechiae), epistaxis, menorrhagia, bleeding from gums and alimentary tract. Cerebral hemorrhage can also occur and can be fatal.

Differential Diagnoses

All causes of pancytopenia and hypocellular bone marrow should be considered in the differential diagnosis.

• Paroxysmal Nocturnal Hemoglobinuria
• Myelodysplastic Syndrome
• Acute Leukemia
• Non-Hodgkin Lymphoma
• Human Herpesvirus 6 Infection
• Megaloblastic Anemia
• Multiple Myeloma
• Inherited marrow failure syndromes
  • Fanconi anemia
  • Dyskeratosis congenita
  • Shwachman Diamond syndrome
• Myelophthisic Anemia
• Metastatic cancer
• Osteopetrosis
• Primary Myelofibrosis
• Sepsis

Investigations

The mainstay of diagnosis is blood and bone marrow examination. Aplastic anemia presents with pancytopenia and a hypoplastic bone marrow which is replaced by fatty tissue.

Complete Blood Counts

Reduced values for hemoglobin, hematocrit, WBC count, neutrophils and platelets are seen. The degree of cytopenia is useful in assessing the severity of aplastic anemia.

Reticulocyte Count

The absolute reticulocyte count (a measure of bone marrow activity) is depressed.

ESR

Is usually elevated, sometimes to high values.

Peripheral Blood Film

Anemia is usually of normocytic normochromic type although some degree of macrocytosis may be observed. There is a relative lymphocytosis. Red and white cell precursors (nucleated RBCs, myelocytes, metamyelocytes, etc) are almost never seen in the blood and if present, an alternate cause of pancytopenia should be thought of.

Bone Marrow Aspiration and Biopsy

It is required for confirmation and to rule out other causes of pancytopenia (leukemia, metastatic cancer or myelofibrosis).

In aplastic anemia, bone marrow is hypocellular and is replaced by fatty tissue. However, the involvement is patchy and some fragments may even be hypercellular.

Bone marrow biopsy is superior to the aspiration for assessing the cellularity. Also, in case of a dry or bloody tap in which no bone marrow particles can be aspirated, bone marrow trephine biopsy needs to be performed to assess the cellularity of bone marrow.

Erythropoiesis and leucopoiesis are equally reduced or one is relatively less affected. Plasma cells, reticulum cells, and lymphocytes may be prominent and constitute the majority of cells.

Aplastic anemia should be distinguished from Myelodysplastic syndrome (MDS) which shows features of marked dyserythropoiesis along with granulocytic and megakaryocytic abnormalities.

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Blood Tests for Paroxysmal Nocturnal Hemoglobinuria (PNH)

Aplastic anemia can occur together with PNH. Ham test or sucrose hemolysis test was used to diagnose PNH in the past. More recent and accurate tests for diagnosing PNH include fluorescence-activated cell sorter (FACS) profiling and fluorescent-labeled inactive toxin aerolysin (FLAER) testing (flow cytometry).

Liver Function Tests

Kidney Function Tests

Serologic Testing

Serological testing for hepatitis and other viral infections, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human immunodeficiency virus (HIV).

Tests for Autoimmune Diseases

Vitamin B₁₂ and Folate Levels

Bone Marrow Culture

It can help to diagnose bacterial including mycobacterial infections

Magnetic Resonance Imaging

Since bone marrow may show patchy areas of hypercellularity, aspiration and biopsy of bone marrow may yield misleading results if the sample is taken from one of those hypercellular areas. Magnetic resonance imaging (MRI) scans of the marrow areas of the axial skeleton can give a better assessment of bone marrow cellularity in such cases.

1. Chest X-ray: to detect infections
2. Computed tomography (CT) and Ultrasonography scans: to detect enlarged lymph nodes in case of lymphoma), kidneys and bones in arms and hands (abnormal in Fanconi anemia)

Treatment

• Identification and elimination of exposure to causative agent
• Symptomatic treatment: It consists of blood transfusions along with prevention and treatment of infections and hemorrhage
• Mild cases may require only observation. Any worsening of the blood counts or aggravation of signs and symptoms would require prompt action and further treatment. Moderately severe cases require medications and blood transfusions. Severe cases usually require bone marrow transplant.

Immune-suppression

Intravenous administration of antithymocyte globulin (ATG) and treatment with cyclosporine to modulate the immune system is an effective line of treatment.

ATG, targets T-cells, which are believed to attack and destroy the bone marrow. Treatment with cyclophosphamide is also effective but has more toxicity than ATG.

Corticosteroids are generally ineffective, though they are used to relieve serum sickness caused by ATG.

Anabolic agents

Oxymetholone and other androgens by increasing the hemoglobin levels have proved to be beneficial in milder cases of aplastic anemia.

Treatment of Infections

Infections are a major cause of mortality in patients with aplastic anemia due to prolonged neutropenia. Proper hygiene should be maintained to reduce the chances of infections. Broad based antibiotic and anti-fungal treatment is given for both treatment as well as for prophylaxis in patients with extremely low neutrophil counts (below 0.2 ×10⁹/L). 

Cytokine support with granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) may be considered in refractory infections.

Blood transfusion

It is not a cure for aplastic anemia. It is a type of symptomatic treatment which provides blood cells to the body thus relieving signs and symptoms.

Transfusions of red blood cells increase the RBC count. Thus anemia and symptoms associated with it are relieved. Transfusions of platelets help prevent excessive bleeding.

When performed over prolonged time, blood transfusions can result in iron- overload and damage to vital organs. To prevent this iron-chelating treatment should be carried out.

Bone marrow transplant

It offers a definitive cure for aplastic anemia and is the treatment of choice for younger people with severe aplastic anemia who have a matching donor — most often a sibling.

The patient’s bone marrow is replaced with the donor’s multipotent stem cells which will give rise to all three blood cell types, thereby giving the patient a new immune system, red blood cells, and platelets.

Risks include:

• Infection.
• Rejection of the transplanted marrow by the body (graft failure). Drugs are given after transplant which help to prevent rejection.
• The newly created white blood cells may attack the rest of the body (graft-versus-host disease).

Course, Monitoring and Prognosis

Mild cases resolve on their own. Elimination of exposure of the causative agent can hasten recovery in few cases. In others, it remains as a chronic condition in spite of withdrawal of causative factors.

Severe aplastic anemia is a serious disorder and can be life-threatening if untreated. Death usually occurs due to bleeding and/or infection. The risk of death remains greater than normal even in long-term survivors.

The five-year survival of aplastic anemia patients varies from 50% to 80% in different series. Younger patients have a high survival rate and a much better prognosis. Patients not having severe disease have an excellent prognosis with survival rates >90%.

Survival rates for stem cell transplantation are more in younger patients and those who receive transplants from a well-matched donor in comparison with unrelated donors.

Follow-up for patients with aplastic anemia is necessary to monitor the need for transfusions, to identify relapse and to detect the development of other hematological disorders. The frequency of follow-up depends on the severity of the disease.

Paroxysmal nocturnal hemoglobinuria sometimes develops during the course of the disorder with the major manifestation being intravascular hemolysis. Few patients having severe aplastic anemia evolve into myelodysplastic syndrome and leukemia.

Patients who undergo stem cell transplantation should be monitored for transplantation-related complications such as infection, graft versus host disease, and development of secondary malignancy.