Aplastic Anemia

Mr. Topesh Patle

Introduction

  • Aplastic anaemia is a rare and potentially life-threatening hematologic condition characterised by bone marrow failure.
  • The bone marrow, which is responsible for producing red blood cells, white blood cells, and platelets, becomes damaged or fails to produce adequate numbers of these cells.
  • This leads to pancytopenia, which is the reduction in all three major types of blood cells (erythrocytes, leukocytes, and thrombocytes).
  • Symptoms often include fatigue, weakness, paleness, frequent infections, and bleeding tendencies.
  • It can be classified into acquired (the most common form) and inherited types.
  • The severity of aplastic anaemia can range from mild to life-threatening, depending on the degree of marrow failure and the presence of complications.

Etiology 

The aetiology of aplastic anaemia can be divided into acquired and inherited causes.

Acquired Aplastic Anemia

  1. Idiopathic (Unknown Cause):

    • In many cases, the cause of aplastic anemia remains unclear, which is termed idiopathic aplastic anemia.

    • This form represents about 50% of cases. It is thought to be due to an immune-mediated mechanism, where the body’s own immune system mistakenly attacks the hematopoietic stem cells in the bone marrow.

  2. Autoimmune Mechanism:

    • Aplastic anemia is considered to be an autoimmune disorder in most idiopathic cases, where T-cells (a type of white blood cell) attack and destroy the bone marrow stem cells.

    • This immune response can be triggered by infections, drugs, or environmental toxins.

  3. Environmental and Drug Exposures:

    • Chemicals: Benzene exposure is strongly linked to aplastic anemia, especially in those working with industrial chemicals. Long-term exposure can cause chromosomal abnormalities in hematopoietic stem cells.

    • Medications: Certain medications like chemotherapy agents (e.g., cyclophosphamide), antibiotics (e.g., chloramphenicol), NSAIDs, and anticonvulsants can damage bone marrow cells and lead to marrow failure.

    • Radiation: Exposure to radiation or toxic levels of X-rays can cause bone marrow suppression.

  4. Viral Infections:

    • Viruses can cause immune-mediated damage to the bone marrow or directly infect the marrow cells. Viruses like Hepatitis, Epstein-Barr Virus (EBV), and Cytomegalovirus (CMV) are known triggers. In these cases, aplastic anemia often follows the acute viral infection, and in some cases, the virus may persist in the marrow and contribute to its failure.

  5. Pregnancy:

    • Although rare, aplastic anemia can develop during pregnancy. The underlying cause remains unclear, but it may involve a combination of hormonal changes, immune responses, and increased stress on the bone marrow during pregnancy.

 

Inherited Aplastic Anaemia

  1. Fanconi Anemia:

    • This is the most common inherited cause of aplastic anemia.

    • Fanconi anemia is caused by mutations in genes responsible for DNA repair, particularly the Fanconi anemia (FA) gene.

    • It is an autosomal recessive disorder, meaning that both parents must pass on the gene for the child to develop the disease.

    • Patients with Fanconi anemia have a high risk of developing leukemia and solid tumors later in life.

    • They may also present with congenital abnormalities, such as short stature, skin pigmentation changes, and skeletal anomalies.

  2. Shwachman-Diamond Syndrome:

    • This genetic condition is caused by mutations in the SBDS gene.

    • Patients present with bone marrow failure and may also have pancreatic insufficiency, resulting in malabsorption and growth retardation.

  3. Dyskeratosis Congenita:

    • This inherited disorder is caused by mutations in genes that regulate telomere maintenance, leading to premature telomere shortening.

    • The short telomeres lead to bone marrow failure and other systemic manifestations like skin pigmentation changes, nail abnormalities, and a predisposition to cancers.

 

Epidemiology 

Aplastic anemia is a rare disorder, but its incidence varies based on age, geographic location, and environmental factors.

  • Incidence: Aplastic anemia affects 2 to 5 per million people per year. The condition is most commonly diagnosed in young adults (ages 15-25) and older adults (above 60), although it can occur at any age.

  • Geographic Variation: The prevalence of aplastic anemia may be higher in certain parts of the world due to regional differences in environmental exposures and healthcare quality. For example, countries with industrial exposure to chemicals or limited access to medical care may see higher rates.

  • Gender: Some studies show a slight male predominance, but the difference is not significant. However, inherited forms like Fanconi anemia tend to be diagnosed early in life and affect both genders equally.

  • Age: Acquired aplastic anemia occurs most frequently in young adults and older individuals (typically in their 60s), while inherited conditions tend to present much earlier in life, often in childhood or adolescence.

 

Pathophysiology 

Aplastic anemia results from bone marrow failure, where the marrow is unable to produce sufficient numbers of blood cells. The pathophysiology varies depending on the underlying cause but typically involves the following mechanisms:

  1. Bone Marrow Hypocellularity:

    • Bone marrow biopsies in aplastic anemia show hypocellularity, meaning there are fewer hematopoietic cells than normal.

    • This is accompanied by an increase in fat cells and fibrosis within the marrow.

  2. Immune-mediated Destruction of Hematopoietic Stem Cells:

    • In most acquired cases, T lymphocytes (a type of white blood cell) play a central role.

    • These cells target and destroy the hematopoietic stem cells that produce blood cells.

    • The autoimmune attack is often triggered by viral infections or drug exposure.

    • This destruction leads to pancytopenia, which causes the hallmark clinical features of anemia, neutropenia, and thrombocytopenia.

  3. Genetic Mutations in Inherited Forms:

    • In inherited aplastic anemia (e.g., Fanconi anemia), mutations in genes responsible for DNA repair mechanisms impair the ability of the bone marrow cells to repair DNA damage.

    • This leads to cellular senescence and loss of hematopoietic stem cells.

  4. Cytokine Imbalance:

    • Cytokines such as interferon-gamma (IFN-γ) are elevated in the bone marrow of patients with aplastic anemia.

    • These immune molecules contribute to the destruction of hematopoietic cells and the dysregulation of marrow function.

 

Laboratory Investigation 

1. Complete Blood Count (CBC) with Reticulocyte Count

The Complete Blood Count (CBC) is the first and most essential test for diagnosing aplastic anemia. It provides valuable information about the number of blood cells in the body and can reveal characteristic findings.

Findings in Aplastic Anemia:

  • Pancytopenia: A reduction in all three blood cell types—red blood cells, white blood cells, and platelets—is typically observed in aplastic anemia.

    • Anemia: A decrease in red blood cells, leading to low hemoglobin levels and hematocrit. This results in fatigue, paleness, and shortness of breath.

    • Leukopenia (Neutropenia): A reduction in white blood cells, particularly neutrophils, increases the risk of infections.

    • Thrombocytopenia: A reduction in platelets leads to bleeding tendencies, such as easy bruising, prolonged bleeding from cuts, or petechiae.

  • Reticulocyte Count: Reticulocytes are immature red blood cells. A low reticulocyte count in the context of anemia suggests ineffective erythropoiesis (reduced or absent red blood cell production), which is a hallmark of aplastic anemia.

Additional Blood Tests:

  • Peripheral Blood Smear: This test can provide additional clues. In aplastic anemia, the smear may show normocytic or macrocytic red blood cells, but few or no immature cells (i.e., reticulocytes) and a decrease in white blood cells and platelets.

2. Bone Marrow Biopsy and Aspiration

A bone marrow biopsy is the gold standard for confirming the diagnosis of aplastic anemia. It helps assess the cellularity and function of the bone marrow, which is typically the primary site of hematopoiesis (blood cell formation).

Findings in Aplastic Anemia:

  • Hypocellular Marrow: The hallmark feature of aplastic anemia is the hypocellular marrow, where there is a significant reduction in hematopoietic cells (precursors to blood cells). In severe cases, fatty infiltration can replace normal marrow cells, leading to very few bone marrow cells seen on histologic examination.

  • Fatty Infiltration: As the hematopoietic cells are replaced by fat, the bone marrow appears “empty,” with the only remaining cells being fatty cells and small amounts of stroma (connective tissue).

Bone Marrow Aspiration:

  • During the biopsy, an aspiration (removal of marrow cells with a needle) may also be performed to assess the morphology and confirm the lack of hematopoietic cells. In mild forms, the marrow may still show a reduced but not absent number of hematopoietic cells.

  • Bone marrow aspirate may show a normal or increased number of megakaryocytes (platelet precursors) in early or less severe stages.

3. Flow Cytometry

Flow cytometry is used to analyze the immune-mediated aspect of aplastic anemia. It is particularly useful in acquired aplastic anemia to assess whether autoimmune destruction of bone marrow stem cells is occurring.

In Aplastic Anaemia:

  • T-cell Activation: Flow cytometry can help identify the presence of activated T-cells that are involved in the autoimmune attack on the hematopoietic stem cells. These activated T-cells can target and damage bone marrow cells, leading to pancytopenia.

  • Immune Profiling: In patients with suspected autoimmune aplastic anemia, flow cytometry can also assess the presence of autoantibodies that may target hematopoietic stem cells.

4. Reticulocyte Count

The reticulocyte count is often used to assess the bone marrow’s erythropoietic response. A low or absent reticulocyte count in the setting of anemia is a critical clue that the bone marrow is not producing new red blood cells effectively.

Reticulocyte Count in Aplastic Anemia:

  • In severe cases of aplastic anemia, the reticulocyte count is usually very low or absent, indicating the bone marrow’s inability to produce new blood cells.

  • Compensatory increase in reticulocytes may be observed in cases of anemia that have a lesser degree of marrow failure.

5. Cytogenetic Testing and Chromosomal Analysis

Cytogenetic testing, often through karyotyping or fluorescence in situ hybridization (FISH), may be performed if a genetic syndrome or clonal disease is suspected. This is especially important in cases of inherited aplastic anemia, such as Fanconi anemia.

In Aplastic Anemia:

  • Fanconi Anemia: This inherited condition is associated with chromosomal instability. Testing can reveal abnormalities in specific DNA repair genes. Patients with Fanconi anemia often have a higher risk of leukemia and solid tumors later in life.

  • Telomere Analysis: In some inherited forms of aplastic anemia (such as Dyskeratosis Congenita), telomere shortening can be detected through genetic tests and telomere length assays. This is a key diagnostic tool for some inherited forms.

6. Viral Studies

Since infections, particularly viral infections, are common triggers for aplastic anemia, viral studies are often conducted to rule out underlying infections that could contribute to marrow suppression.

Viral Infections Associated with Aplastic Anemia:

  • Hepatitis: Hepatitis-associated aplastic anemia is a known entity, where the immune system’s response to the viral infection causes bone marrow suppression.

  • Epstein-Barr Virus (EBV): EBV infection has been associated with autoimmune aplastic anemia.

  • Cytomegalovirus (CMV): This virus can also cause bone marrow suppression, particularly in immunocompromised patients.

  • Parvovirus B19: This virus infects red blood cell precursors and can cause red blood cell aplasia, leading to a temporary form of aplastic anemia in certain populations.

7. Serology and Autoimmune Markers

In patients with suspected autoimmune aplastic anemia, tests to assess autoimmune markers are important. These tests look for autoantibodies that might indicate an underlying autoimmune process.

Tests to Consider:

  • Antinuclear Antibodies (ANA): High levels of ANA may indicate an autoimmune disorder that could be contributing to bone marrow failure.

  • Anti-Granulocyte Antibodies: In some cases of aplastic anemia, autoantibodies may target specific hematopoietic cells, and testing for these antibodies can help confirm the diagnosis.

8. Iron Studies

  • Iron studies are sometimes conducted to assess whether the patient has iron deficiency, which can mimic anemia.
  • However, in the case of aplastic anemia, the iron levels are typically normal or elevated because the body’s iron stores are not being utilized effectively due to the lack of red blood cell production.

Treatment and Management 

  1. Supportive Care:

    • Blood Transfusions: Patients with severe aplastic anemia often require regular red blood cell transfusions to treat anemia and platelet transfusions to prevent bleeding due to thrombocytopenia.

    • Infection Control: Due to the high risk of infections from neutropenia (low white blood cell count), antibiotic therapy, antifungal agents, and antiviral drugs may be prescribed to prevent or treat infections. Granulocyte colony-stimulating factor (G-CSF) may be used to boost white blood cell production.

  2. Immunosuppressive Therapy:

    • Antithymocyte Globulin (ATG): ATG is used to deplete the T lymphocytes responsible for attacking hematopoietic stem cells. It is typically used in patients with severe, acquired aplastic anemia who do not have a suitable donor for a stem cell transplant.

    • Cyclosporine: This immunosuppressive drug is used in conjunction with ATG to block T-cell activation and further reduce the immune attack on the bone marrow.

  3. Hematopoietic Stem Cell Transplantation (HSCT):

    • HSCT is considered the curative treatment for severe aplastic anemia, particularly in young patients with a matched sibling donor. The patient’s diseased bone marrow is replaced with healthy stem cells from a donor. This therapy has a high success rate but requires a suitable donor, which may be challenging for patients without sibling matches.

  4. Eltrombopag:

    • Eltrombopag, a thrombopoietin receptor agonist, can stimulate the production of blood cells in some patients with severe aplastic anemia who are unresponsive to immunosuppressive therapy.

  5. Bone Marrow Growth Factors:

    • Medications like G-CSF (granulocyte colony-stimulating factor) and Erythropoiesis-stimulating agents may help stimulate the production of white blood cells and red blood cells, respectively.

 

Management

The management of aplastic anemia is focused on preventing complications and improving quality of life.

  1. Monitoring:

    • Regular follow-ups to assess blood counts, monitor for infections, and track the response to treatment are essential. Bone marrow biopsies may be repeated to assess recovery.

  2. Psychosocial Support:

    • Living with a chronic illness like aplastic anemia can be stressful. Patients may require counseling and psychosocial support to cope with the emotional impact of the disease and its treatment.

  3. Long-term Follow-up:

    • After treatment, long-term monitoring for the risk of leukemia, graft-versus-host disease (GVHD) (after stem cell transplant), and secondary cancers is essential for managing the long-term health of patients.