Aplastic anaemia

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

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Aplastic anaemia

The term aplastic anaemia is a misnomer in that the disorder so described is characterised by a pancytopenia arising from failure of production of all the normal cells of peripheral blood. The underlying cause is a reduction in the number of pluripotential stem cells. This deficit may be exacerbated by an abnormality in the marrow microenvironment or an autoimmune reaction against the abnormal haematopoietic tissue.

Aplastic anaemia is rare (approximately 2–5 cases/million/year worldwide) and affects all ages. It must be emphasised that it is not a subtype of leukaemia. However, the disease’s presenting clinical characteristics, the management problems of marrow failure (including fulminating septicaemia and haemorrhage) and the possible evolution to a clonal marrow disorder dictate its inclusion in this section.

Classification and aetiology

Aplastic anaemia (AA) may be part of a congenital syndrome, be secondary to well-defined insults to the bone marrow, or arise apparently spontaneously with no identifiable cause. A simple classification is shown in Table 26.1. The most common congenital disorder is Fanconi’s anaemia. Affected children suffer from defective DNA repair and the aplasia often coexists with skeletal deformities, skin pigmentation (Fig 26.1) and renal abnormalities. To date, fifteen genes (termed FANC) have been identified. Dyskeratosis congenita, another form of constitutional aplasia, is distinguished by a later onset, nail dystrophy, leukoplakia of mucosal surfaces and a high incidence of epithelial tumours. There is defective telomere maintenance and patients usually have very short telomeres. This is also observed in 10–15% of patients with acquired AA.

Table 26.1

Classification of aplastic anaemia

1. Idiopathic AA
2. Congenital AA	Fanconi’s anaemia
	Dyskeratosis congenita
3. Secondary AA	Drugs – idiosyncratic or dose-related
	Chemicals
	Ionising radiation
	Infection

Fig 26.1 Fanconi’s anaemia.
(a) Digital abnormalities in brothers with the syndrome. (b) Skin pigmentation.

Infections known to predispose to AA include viral hepatitis and parvovirus infection. Exposure to chemicals, drugs and radiation can damage stem cells. Drugs may depress haematopoiesis idiosyncratically or predictably (Table 26.2). In roughly two-thirds of patients, no cause is apparent and AA is termed ‘idiopathic’. Improved haematopoiesis following immunosuppression (see below) suggests that in at least some cases the abnormal stem cell compartment is further compromised by poorly defined immune phenomena.

Table 26.2

Drugs associated with aplastic anaemia ¹

Predictable	Cytotoxic agents
Idiosyncratic	Chloramphenicol
	Sulfonamides
	Phenylbutazone
	Indometacin
	Gold salts
	Penicillamine
	Carbamazepine
	Phenytoin
	Carbimazole

¹ This is a selective list of more commonly implicated agents.

Clinical features

Patients with marrow failure predictably present with anaemia, unusually frequent or severe infections (caused by neutropenia) and a haemorrhagic tendency (caused by thrombocytopenia). The onset may be gradual or fulminant. Symptoms or signs of an underlying systemic disorder (e.g. Fanconi’s) or possible trigger (e.g. hepatitis) may be present. An exhaustive history, including drug and occupational exposure, and a thorough examination are mandatory.

Diagnosis

There are really two questions. Is the pancytopenia due to aplastic anaemia? Is this idiopathic AA or aplasia secondary to an identifiable cause (Table 26.3)?

Table 26.3

Causes of pancytopenia

Marrow failure or infiltration

Aplastic anaemia

Myelodysplastic syndrome

Leukaemia

Myelofibrosis

Infiltration by other malignancy (e.g. lymphoma, carcinoma)

Infection (e.g. tuberculosis)

Megaloblastic anaemia

Prolonged starvation

Hypersplenism

Portal hypertension

Felty syndrome (rheumatoid arthritis)

Storage disorders

A reasonable sequence of investigations is as follows:

1 Blood count and film

There is a pancytopenia and reticulocytopenia. To define AA there must be at least two of the following: (1) haemoglobin less than 100 g/L; (2) neutrophils less than 1.5 × 10⁹/L; (3) platelets less than 50 × 10⁹/L. There are no abnormal cells in the blood film.

2 Bone marrow aspirate and trephine

This is the key diagnostic test. The marrow aspirate can be highly suggestive of aplasia with grossly hypocellular particles but a trephine biopsy is necessary to confirm the diagnosis and quantify the degree of hypocellularity (Fig 26.2). Aplasia may be patchy and if the trephine is surprisingly cellular in the context of the blood count, then further samples should be obtained. In practice the only likely confusion is with hypocellular myelodysplastic syndrome (see p. 50) or an atypical presentation of acute leukaemia, the latter particularly in childhood.

Fig 26.2 Bone marrow trephine in severe aplastic anaemia.
The cellularity is markedly reduced. (Compare with normal bone marrow appearance, p. 2.)

3 Tests for an underlying cause

These include liver function tests, viral titres, vitamin B₁₂ and folate levels and tests for paroxysmal nocturnal haemoglobinuria (see p. 31) and the inherited bone marrow failure syndromes. Cytogenetic analysis of the hypocellular bone marrow is often problematic but will reveal abnormal cytogenetic clones in some patients.

Measurement of severity

This is crucial as the severity defined from peripheral blood and bone marrow measurements predicts the response to treatment and survival (Table 26.4). The median survival of untreated severe AA is 3–6 months with only 20% of patients surviving longer than 1 year.

Table 26.4

Severity of aplastic anaemia

AA is defined as non-severe (NSAA) unless it is:

1. Severe (SAA). Requires two of three peripheral blood criteria:

Neutrophils less than 0.5 × 10⁹/L

Platelets less than 20 × 10⁹/L

Reticulocytes less than 20 × 10⁹/L

Within the bone marrow:

Less than 25% haematopoietic cells, or 25–50% haematopoietic cells and less than 30% cellularity

2. Very severe (VSAA). Requires a neutrophil count less than 0.2 × 10⁹/L in the presence of at least one other peripheral blood criterion and the bone marrow features given for SAA

Management

Removal of cause

Where an agent such as a drug or a chemical is implicated this should be removed.

Immunosuppression or SCT?

Younger patients (less than 30 years) with SAA and a matched sibling donor should be transplanted. In VSAA (see Table 26.4) in this age group, the lack of a family donor should prompt a search for an HLA-matched unrelated donor. In patients 30–40 years with SAA, sibling SCT and immunosuppression produce similar survivals over 2–5 years. However, a significant proportion of patients receiving immunosuppression alone, approximately 25% at 10 years, evolve to clonal marrow diseases such as paroxysmal nocturnal haemoglobinuria, myelodysplastic syndrome and acute myeloid leukaemia. Thus in this group matched sibling SCT probably gives a better long-term prognosis. In older patients with SAA, and patients with non-severe AA, immunosuppression is generally the treatment of choice.