Aplastic Anaemia and Pancytopenia

Introduction

Pancytopenia - a simultaneous fall in haemoglobin, white cell count and platelets - is a common finding that always demands explanation, since the differential ranges from a benign, reversible process to acute leukaemia. Aplastic anaemia is the prototype cause: true bone marrow failure, in which the marrow becomes hypocellular and simply stops producing enough of all three cell lines.¹

Aplastic anaemia is rare (annual incidence of around 2-4 per million in the UK) but important, because it is potentially curable with prompt recognition and the right treatment, and rapidly fatal if missed.

Causes of pancytopenia

Before assuming aplastic anaemia, the broader differential of pancytopenia must be considered, since management differs completely between categories:

• Reduced marrow production: aplastic anaemia, marrow infiltration (leukaemia, lymphoma, myeloma, metastatic malignancy), myelodysplastic syndrome, severe B12/folate deficiency (megaloblastic pancytopenia), myelofibrosis
• Increased peripheral destruction/sequestration: hypersplenism (pooling and destruction of all three cell lines), disseminated intravascular coagulation
• Combined/other: sepsis, HIV, systemic lupus erythematosus, drug toxicity (many chemotherapy agents cause transient pancytopenia by design)

Aplastic anaemia specifically refers to pancytopenia from an intrinsically hypocellular bone marrow with no infiltration by malignant or dysplastic cells - a diagnosis that can only be confirmed histologically.

Aetiology of aplastic anaemia

Acquired (the large majority)

• Idiopathic - the commonest category, now understood in most cases to be autoimmune, with cytotoxic T cells attacking haematopoietic stem cells
• Drugs - chloramphenicol (classic exam association, now rarely used), NSAIDs, carbimazole, sulfonamides, gold, and as an expected effect of cytotoxic chemotherapy and ionising radiation
• Viral infections - parvovirus B19, hepatitis (typically seronegative hepatitis), EBV, HIV
• Toxins - benzene and other industrial solvents, insecticides
• Pregnancy - rare

Inherited

• Fanconi anaemia - the commonest inherited bone marrow failure syndrome, autosomal recessive, associated with short stature, skeletal abnormalities (absent thumbs/radii), skin pigmentation, and a markedly increased risk of leukaemia and solid tumours
• Dyskeratosis congenita and other rarer telomere biology disorders

Clinical features

Features reflect failure of all three cell lines, and typically develop gradually:

• Anaemia - fatigue, pallor, dyspnoea
• Neutropenia - recurrent or severe infections, which may be the presenting feature
• Thrombocytopenia - easy bruising, petechiae, mucosal bleeding, epistaxis, menorrhagia

Investigations

• FBC - pancytopenia. Anaemia is usually normocytic (though can be macrocytic), and the reticulocyte count is low, reflecting failure of production rather than peripheral destruction
• Blood film - excludes blast cells (against leukaemia) and abnormal red cell morphology or fragments (against other causes), and is otherwise unremarkable other than the cytopenias
• Bone marrow aspirate and trephine biopsy - the definitive investigation. Shows a hypocellular marrow with increased fat spaces, and critically, no infiltration by leukaemic blasts, lymphoma or dysplastic cells¹
• Virology - parvovirus B19 PCR, hepatitis and HIV serology
• Vitamin B12 and folate - to exclude severe megaloblastic pancytopenia, an important and reversible mimic
• PNH clone testing by flow cytometry at diagnosis - aplastic anaemia and paroxysmal nocturnal haemoglobinuria share a common immune-mediated pathophysiology and frequently co-exist
• Cytogenetics - to help exclude an evolving myelodysplastic syndrome
• Chromosome breakage studies if Fanconi anaemia is suspected (e.g. young patient, characteristic dysmorphic features), since this changes transplant conditioning and screening for associated malignancy

Differential diagnosis

The bone marrow biopsy is what separates aplastic anaemia from its key mimics:

Management

Definitive treatment

• Allogeneic haematopoietic stem cell transplant is the treatment of choice, offering the best chance of cure, particularly for younger patients with a matched sibling or unrelated donor and severe disease²
• Immunosuppressive therapy - a combination of antithymocyte globulin (ATG) and ciclosporin - for patients who are not suitable transplant candidates (e.g. older age, no matched donor). Reflects the autoimmune basis of most acquired disease, and produces a response in a majority of patients, though relapse and clonal evolution (to MDS/AML or PNH) remain risks

Supportive care

• Blood and platelet transfusion as needed - irradiated and leucodepleted products are used in transplant candidates to reduce alloimmunisation and prevent transfusion-associated graft-versus-host disease
• Prompt treatment of infection, with a low threshold for empirical broad-spectrum antibiotics in a febrile neutropenic patient (see neutropenic sepsis)
• Avoid the causative drug or toxin if identified
• Growth factors (G-CSF) may be used adjunctively in specific situations but do not replace definitive treatment
• Iron chelation if the patient becomes transfusion-dependent long term

Complications

• Life-threatening infection - the major cause of early death, given profound neutropenia
• Severe or fatal haemorrhage, including intracranial bleeding, from profound thrombocytopenia
• Clonal evolution to myelodysplastic syndrome or acute myeloid leukaemia
• Paroxysmal nocturnal haemoglobinuria, which can emerge or expand over time
• Transfusion-related iron overload and alloimmunisation with prolonged supportive care
• Graft-versus-host disease and other transplant-related complications in those undergoing stem cell transplant

Red flags

Prognosis

Untreated severe aplastic anaemia carries a high mortality within months, predominantly from infection and haemorrhage - it is a genuine hae­matological emergency.¹ With modern treatment, however, outcomes have improved substantially.

Allogeneic stem cell transplant in younger patients with a matched donor offers long-term survival in the majority, and is considered curative. Immunosuppressive therapy produces a response in around 60-80% of patients but carries ongoing risks of relapse and of clonal evolution to MDS, AML or PNH, so long-term surveillance continues even after apparent remission.