Aplastic Anemia (AA)

Aplastic anemia (AA) is a bone marrow failure disorder.

Normally, blood-forming stem cells in the bone marrow continuously produce red blood cells, white blood cells, and platelets. In aplastic anemia, these stem cells are greatly reduced in number or function, so the bone marrow cannot produce enough blood cells.

This can lead to:

• Low red blood cells, causing anemia

• Low neutrophils and other white blood cells, increasing the risk of infection

• Low platelets, increasing the risk of bleeding

Despite the word “anemia” in its name, aplastic anemia can affect several types of blood cells, not just red blood cells.

Based on blood counts and bone marrow findings, aplastic anemia may be classified as non-severe, severe, or very severe. This classification plays an important role in treatment decisions.

Aplastic anemia can occur as an acquired disorder or as part of an inherited bone marrow failure syndrome. Acquired aplastic anemia is more common.

In most people with acquired AA, no specific trigger can be identified. The disease is thought to be largely immune-mediated, with abnormal immune cells—particularly activated T cells—suppressing or damaging blood-forming stem cells.

Some cases may be associated with:

• Certain medications or chemical exposures

• Benzene and other toxic substances

• Certain viral infections or immune responses following infection

• Previous cancer treatment

• Some autoimmune conditions

• Rare pregnancy-associated cases

Inherited bone marrow failure syndromes can sometimes resemble aplastic anemia, and some may not become apparent until adulthood. Genetic evaluation may therefore be needed in younger patients, those with a suggestive family history, or patients with other clinical features.

Symptoms of aplastic anemia depend mainly on which blood cell types are low and how severe the decrease is.

Some people develop the condition gradually, while others experience a more rapid decline in blood counts.

Low Red Blood Cell Counts

Anemia may cause:

• Ongoing fatigue or weakness

• Shortness of breath

• Dizziness

• Heart palpitations

• Pale skin

Low White Blood Cell Counts

Low neutrophil counts in particular may cause:

• Recurrent infections

• Fever

• Mouth or throat infections

• In severe cases, serious or life-threatening infections

Low Platelet Counts

Low platelet counts may cause:

• Easy bruising

• Nosebleeds

• Bleeding gums

• Tiny red or purple spots under the skin

• Heavy menstrual bleeding

• In severe cases, bleeding in internal organs or other sites

Low blood cell counts alone are not enough to diagnose aplastic anemia because many other conditions can cause pancytopenia.

Diagnosis usually involves a complete blood count, reticulocyte count, bone marrow aspiration, and bone marrow biopsy, along with testing to rule out conditions such as hypoplastic myelodysplastic syndromes, acute leukemia, inherited bone marrow failure syndromes, paroxysmal nocturnal hemoglobinuria (PNH), and other causes of bone marrow failure.

Blood Tests

A complete blood count measures red blood cells, white blood cells, and platelets.

A reticulocyte count shows how effectively the bone marrow is producing new red blood cells. Reticulocyte levels are usually low in aplastic anemia.

Additional testing may include liver and kidney function, viral testing, vitamin levels, and other tests to look for alternative causes of low blood cell counts.

Bone Marrow Tests

Bone marrow aspiration and biopsy are central to the diagnosis of aplastic anemia.

In typical cases, the bone marrow is markedly hypocellular, with much of the normal blood-forming tissue replaced by fat. The biopsy also helps rule out abnormal tumor cell infiltration, significant fibrosis, and other causes of bone marrow failure.

Testing for PNH

Some patients with acquired aplastic anemia have a detectable paroxysmal nocturnal hemoglobinuria (PNH) clone.

Flow cytometry of peripheral blood may be used to test for PNH. This can help with diagnosis and may also provide useful information for ongoing monitoring.

Cytogenetic and Genetic Testing

Cytogenetic and molecular testing may be performed to help distinguish aplastic anemia from conditions such as MDS.

Younger patients, those with a family history, congenital abnormalities, or other features suggesting an inherited bone marrow failure syndrome may also need germline genetic testing.

Severity Classification

The severity of aplastic anemia is assessed using factors such as bone marrow cellularity, absolute neutrophil count, platelet count, and reticulocyte count.

The disease is generally classified as:

• Non-severe aplastic anemia (NSAA)

• Severe aplastic anemia (SAA)

• Very severe aplastic anemia (VSAA)

Severe AA is characterized by marked bone marrow hypocellularity together with very low neutrophil, platelet, and/or reticulocyte counts. Very severe AA includes even more profound neutropenia.

Severity classification directly influences treatment decisions and timing.

Treatment for aplastic anemia depends on disease severity, age, overall health, whether the disease is acquired, donor availability, and previous treatment.

Patients with severe or very severe AA generally need prompt evaluation for allogeneic hematopoietic stem cell transplantation or immunosuppressive therapy, rather than long-term observation alone.

Monitoring

Some patients with non-severe disease, stable blood counts, and few or no symptoms may be monitored by a hematologist.

Follow-up generally includes blood counts, reticulocyte counts, and clinical assessment.

Treatment should be reassessed if blood counts worsen, transfusion needs increase, infection or bleeding risks rise, or the disease progresses to severe aplastic anemia.

Supportive Care

Supportive care is important throughout the course of aplastic anemia. It may include:

• Red blood cell transfusions for symptomatic anemia

• Platelet transfusions for severe thrombocytopenia or bleeding

• Prevention and treatment of infections in patients with severe neutropenia

• Management of iron overload in patients who require repeated red blood cell transfusions

For patients who may undergo transplantation, transfusion strategies are also planned with future transplant needs in mind.

Immunosuppressive Therapy

Because acquired aplastic anemia is usually driven by an abnormal immune attack on blood-forming stem cells, immunosuppressive therapy (IST) is an important treatment for severe AA.

A standard approach is based on antithymocyte globulin (ATG) plus cyclosporine.

For many patients with severe or very severe acquired AA who are candidates for immunosuppressive therapy, eltrombopag may also be added to improve blood cell recovery.

The choice of IST depends on factors such as age, donor availability, disease severity, other health conditions, and treatment options.

Hematopoietic-Stimulating Therapy

Traditional blood cell growth factors are not a substitute for immunosuppressive therapy or transplantation in severe aplastic anemia.

Hematopoietic-stimulating treatments may be used in selected situations, and eltrombopag now has a more established role in acquired severe AA, often as part of immunosuppressive therapy or in selected patients based on previous treatment response.

Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important potentially curative treatment for aplastic anemia.

For patients with severe or very severe acquired AA, whether transplantation is used as first-line therapy depends on factors including:

• Age

• Overall health

• Availability of an HLA-compatible donor

• Infections or other complications

• Previous treatment and disease status

Traditionally, younger patients with an HLA-matched sibling donor are strong candidates for first-line allo-HSCT. As transplant techniques have improved, matched unrelated donor and haploidentical donor transplantation are also becoming options for selected patients.

Transplantation is therefore not simply a “last resort” after medications fail. For some patients with severe AA, donor search and transplant evaluation should begin soon after diagnosis.

Treatment of Infections

Patients with severe neutropenia have a high risk of infection.

Fever or other signs of infection require prompt evaluation. Antibiotics, antifungal medications, or antiviral medications may be used depending on the type of infection and individual risk.

Preventing and treating infection is a key part of care for severe and very severe aplastic anemia.

Clinical Trials

Treatment for aplastic anemia continues to evolve, including new immunosuppressive approaches, treatments that promote blood cell production, and transplant strategies using different donor sources and conditioning regimens.

Patients can discuss available clinical trials with their healthcare team based on disease severity, previous treatments, and donor options.