Aplastic Anemia

Aplastic anaemia is a rare but serious haematological disorder in which the bone marrow fails to produce adequate numbers of blood cells. In healthy individuals, haematopoietic stem cells within the bone marrow continually generate red blood cells, white blood cells and platelets. In aplastic anaemia, these stem cells are depleted or dysfunctional, leading to pancytopenia—a reduction in all three major blood cell lineages. The condition affects people of all ages but is most common in adolescence, early adulthood and in older populations. It may arise from immune-mediated destruction of marrow cells, inherited conditions, environmental exposures or infections, though in many cases no definitive cause is identified.

Clinical Features

The symptoms of aplastic anaemia reflect deficiencies across all blood cell types. Anaemia typically leads to fatigue, pallor, shortness of breath and tachycardia. Thrombocytopenia results in bruising, petechiae and a heightened risk of bleeding due to impaired clot formation. Leukopenia predisposes to recurrent and severe infections, as the body is unable to mount effective immune responses. Patients may present with a combination of these features, and symptoms often develop gradually.

Causes and Associated Factors

Aplastic anaemia may be acquired or inherited, though most cases are acquired. In around half of patients, no specific cause is found. Known contributing factors include:

• Immune-mediated destruction of bone marrow cells, driven by dysregulated T lymphocytes that attack haematopoietic stem cells.
• Drug and chemical exposure, such as benzene or rare idiosyncratic reactions to drugs including chloramphenicol, carbamazepine, felbamate, phenytoin and phenylbutazone. Although widely reported, the probability of these drugs causing aplasia in any individual patient is very low.
• Ionising radiation, historically highlighted by the case of Marie Curie, which can severely damage marrow tissue.
• Viral infections, including hepatitis viruses, Epstein–Barr virus, cytomegalovirus, HIV and parvovirus B19. Parvovirus B19 binds to the P antigen on red cell precursors and can trigger profound reticulocytopenia, particularly in individuals with underlying haemolytic disorders.
• Inherited conditions, such as Fanconi anaemia, although these represent a minority of cases.

In animals, additional mechanisms can occur. For example, in ferrets, prolonged exposure to high oestrogen levels during extended oestrus can lead to marrow suppression and aplasia.

Diagnosis

Diagnosis requires careful differentiation from other causes of pancytopenia, particularly pure red cell aplasia, which affects only erythroid cells. A clinical evaluation is accompanied by blood tests including full blood count, renal and liver function, thyroid function and assays for vitamin B₁₂ and folate to exclude other contributory conditions. Viral studies, imaging investigations and immunological assessments may help identify secondary causes.
The definitive diagnosis is made through bone marrow aspiration and biopsy, which typically reveals a markedly hypocellular marrow, often yielding a “dry tap” due to absent haematopoietic tissue. Normal marrow contains 30–70% haematopoietic cells, whereas in aplastic anaemia it is largely replaced by fat.

Pathogenesis

Modern understanding of acquired aplastic anaemia emphasises a dominant autoimmune mechanism. Dysregulated T cells, often characterised by abnormal expression of transcription factors such as TBX21 (T-bet), stimulate excess production of cytokines including interferon-γ and tumour necrosis factor, which inhibit haematopoietic stem cell proliferation and induce apoptosis.
Further findings include:

• Expansion of dysfunctional cytotoxic T cell populations capable of directly damaging marrow progenitors.
• Decreased regulatory T cell activity, contributing to a loss of immune tolerance.
• Increased Th17 cells, which secrete interleukin-17 and amplify inflammatory signalling.
• Overexpression of the Fas receptor on CD34⁺ progenitor cells, promoting apoptosis via Fas-mediated pathways.
• Associations with specific HLA alleles, particularly HLA-DR2 and HLA-DR15, which may enhance antigen presentation and contribute to disease susceptibility.

Research using serological screening of fetal liver cDNA libraries has identified numerous candidate autoantigens targeted by marrow-reactive antibodies, further supporting an autoimmune basis.

Treatment

Management strategies depend on the patient’s age, severity of disease and availability of compatible donors. Standard first-line therapy includes immunosuppressive treatment, most commonly antithymocyte globulin or antilymphocyte globulin combined with corticosteroids and ciclosporin. These treatments aim to reduce immune-mediated destruction of marrow stem cells and allow residual stem cells to recover. Up to 80% of patients with severe disease show some response to such therapy.
For younger patients, particularly those under 30 years of age who have an HLA-matched sibling donor, haematopoietic stem cell transplantation offers the possibility of cure. Transplantation is also considered for patients who fail to respond to immunosuppressive therapy or who experience relapse. Supportive care—including transfusions, infection prophylaxis and treatment of complications—remains a central component of clinical management.

Epidemiology and Notable Cases

Aplastic anaemia has a worldwide distribution and affects individuals of all ethnic backgrounds. Several well-known figures, such as Marie Curie, Eleanor Roosevelt, Luana Reyes and Molly Holzschlag, are believed to have died as a result of the condition or its complications, illustrating its potential severity.

Immunological and Molecular Insights

Expanding research has continued to refine the understanding of the immune dysregulation inherent in aplastic anaemia. Studies have identified distinct populations of regulatory T cells with characteristic gene expression signatures and phenotypes. Responses to immunosuppressive therapy have been associated with specific immunological profiles, including increased expression of FOXP3, Fas receptor, CCR4 and components of the IL-2 receptor–STAT5 pathway. Higher frequencies of certain HLA types may increase susceptibility by enhancing antigen presentation to CD4⁺ T cells.
Apoptosis of CD34⁺ progenitor cells is a consistent feature and has been demonstrated across multiple studies, underscoring the central role of cytokine-induced and Fas-mediated cell death in marrow failure. These insights continue to shape therapeutic research, including efforts to modulate cytokine pathways, rebalance T cell subsets and protect haematopoietic stem cells from immune destruction.