Aplastic Anaemia

Aplastic anaemia is a rare, potentially life-threatening failure of haemopoiesis characterised by pancytopenia and hypocellular bone marrow. Aplastic anaemia is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin.¹ Most cases are acquired and immune mediated but there are also inherited forms. Environmental triggers include drugs, viruses and toxins, but most cases are idiopathic.²

• The annual incidence of aplastic anaemia in about 2 cases per million population.²
• Aplastic anaemia is 2-3 times more common in Asia than in the West.
• Acquired aplastic anaemia most commonly presents between the ages of 15 years and 25 years, but there is a second smaller peak in incidence after age 60 years.
• Certain histocompatibility locus specificities, especially HLA DR2, are associated with an underlying predisposition to acquired aplastic anaemia.

Causes

Approximately 80% of cases are acquired.

• Congenital or inherited, e.g. Fanconi anaemia, Diamond-Blackfan syndrome: congenital aplastic anaemia is very rare, the commonest type being Fanconi's anaemia (inherited as an autosomal recessive disorder).
• Acquired
  • Idiopathic
  • Infection: e.g. hepatitis viruses, Ebstein-Barr virus, HIV, parvovirus, and mycobacteria
  • Toxic exposure: radiation, chemicals (e.g. benzene)
  • Drugs: e.g. chloramphenicol, sulphonamides, gold, penicillamine, phenylbutazone, indomethacin, diclofenac, naproxen, piroxicam, phenytoin, carbamazepine, carbimazole, thiouracil, dothiepin, phenothiazines, chlorpropamide, chloroquine¹
  • Transfusional graft versus host disease
  • Pregnancy
  • Sickle cell anaemia: aplastic crisis associated with parvovirus infection

Presentation

• A family history of cytopenias should raise suspicion of an inherited disorder even when no physical abnormalities are present. In children and young adults, short stature, cafe au lait spots and
  skeletal anomalies suggest the possibility of a congenital form of aplastic anaemia.¹
• A preceding history of jaundice, usually 2-3 months before, may indicate a post-hepatitic aplastic
  anaemia.
• The history should include drug exposure and occupation (exposure to chemicals or pesticides).
• Aplastic anaemia can present abruptly over or insidiously over weeks to months. Clinical manifestations are proportional to the peripheral-blood cytopenias and include:
  • Patients with aplastic anaemia most commonly present with symptoms of anaemia (pallor, headache, palpitations, dyspneoa, fatigue, or ankle oedema) and thromocytopenia (skin or mucosal haemorrhage, visual disturbance due to retinal haemorrhage, petechial rashes).
  • Infection is a less common presentation.
  • There is no lymphadenopathy or hepatosplenomegaly (in the absence of infection).

• Hypersplenism
• Hypocellular myelodysplasia, acute myeloid leukaemia
• Hypocellular acute lymphoblastic leukaemia
• Hairy cell leukaemia
• Lymphoma
• Mycobacterial infections
• Anorexia nervosa or prolonged starvation
• Myeloma
• Systemic lupus erythematosus

• Full blood count, reticulocyte count, blood film
• HbF% in children
• Bone marrow aspirate and trephine biopsy, including cytogenetics
• Peripheral blood cytogenetics to exclude Fanconi's anaemia if under 35 years old
• Ham test and/or flow cytometry to exclude paroxysmal nocturnal haemoglobinuria
• Urine haemosiderin if Ham test positive or phosphatidylinositol glycan-anchored protein deficiency
• Vitamin B₁₂ and folate
• Liver function tests
• Viral studies: hepatitis A, B and C, EBV, CMV
• Anti-nuclear antibody and anti-dsDNA
• Chest X-ray: to exclude infection
• Abdominal ultrasound scan: an enlarged spleen and/or enlarged lymph nodes raise the possibility of a malignant haematological disorder as the cause of the pancytopenia. In younger patients, abnormal or anatomically displaced kidneys are features of Fanconi's anaemia.¹

High incidence of concomitant myelodysplastic syndrome and paroxysmal nocturnal haemoglobinuria.²

• Wide range of disease activity from very mild to severe.
• The risk of morbidity and mortality from aplastic anaemia correlates better with the severity of the cytopenias than with bone-marrow cellularity.
• Acquired aplastic anaemia is classified as non-severe, severe, or very severe on the basis of the degree of peripheral-blood pancytopenia:²
• Non-severe: hypocellular bone marrow but the cytopenias do not meet the criteria for severe disease.
• Severe:
  • Bone marrow cellularity <25%, or 25-50% with <30% residual haemopoietic cells
  • Two out of three of the following:
    • Neutrophils <0.5 x 10⁹/l
    • Platelets <20 x 10⁹/l
    • Reticulocytes <20 x 10⁹/l
• Very severe: as for severe but neutrophils <0.2 x 10⁹/l

There is little evidence on the outlook for patients with non-severe aplastic anaemia. Although the disorder can progress, many patients remain stable for years, and some spontaneously improve even without specific treatment.²

• Treatment should be based on the degree of cytopenia, not the marrow cellularity. Patients with asymptomatic cytopenias probably need no treatment.
• Whether treatment of non-severe aplastic anaemia affects survival is not clear.
• There are three effective treatments for acquired severe aplastic anaemia:²
  • Allogeneic bone-marrow transplantation:
  • Immunosuppressive therapy with antithymocyte globulin and ciclosporin:
  • High-dose cyclophosphamide without transplantation of bone marrow.

Supportive Care

• Transfusions:
  • For patients in whom marrow transplantation may be attempted, transfusions may lead to a worse therapeutic outcomes.
  • Risks and benefits also need careful evaluation in view of potential complications, e.g. CMV infection.
  • Iron overload can cause significant problems in heavily transfused patients. Subcutaneous desferrioxamine is often required.
• There have been anecdotal reports of vaccination producing bone marrow failure or triggering relapse of aplastic anaemia, so vaccinations should only be given when absolutely necessary.¹
• Growth factors:
  • Deficiency of haemopoietic growth factors (such as erythropoietin, granulocyte-colony-stimulating factor, thrombopoietin, and granulocyte-monocyte-colonystimulating factor) is not the cause of the bone-marrow failure in aplastic anaemia. Therefore these factors should not be used instead of definitive therapy.²
  • Haemopoietic growth factors are commonly used after immunosuppressive therapy or high-dose cyclophosphamide to accelerate haemopoietic recovery, but their use has not been shown to improve survival.²
• Antibiotics:
  • Overwhelming sepsis caused by bacteria or fungi (especially aspergillus) is the most frequent cause of death from aplastic anaemia.
  • In most circumstances, prophylactic antibiotics are unnecessary.
  • Patients with a high risk of infection should be managed in isolation when in hospital and should receive prophylactic antibiotics and antifungals, regular mouth care including an antiseptic mouthwash such as chlorhexidene, and food of low bacterial content.¹
  • For patients with absolute neutrophil counts consistently lower than 0.2 x 109/L, oral prophylaxis with a quinolone and a triazole antifungal is often given.
  • Patients with febrile neutropenia should be treated promptly with broad-range antibiotics; in those with persistent fever after the initiation of antibacterial drugs, agents against aspergillus should be added.²
  • Prophylaxis for Pneumocystis carinii pneumonia should be given to all patients for at least 6 months after immunosuppressive therapy, bone-marrow transplantation, or high-dose cyclophosphamide therapy.²

• The major causes of morbidity and mortality from aplastic anaemia include infection and bleeding.
• Complications of bone marrow transplantation, e.g. graft versus host disease, graft failure.
• Paroxysmal nocturnal haemoglobinuria and myelodysplastic syndrome commonly arise in patients with aplastic anaemia.

• Aplastic anaemia has a varied clinical course; some patients have mild symptoms that necessitate little or no therapy, whereas others present with life-threatening pancytopenia representing a medical emergency.
• The 2-year mortality rate with supportive care alone for patients with severe or very severe aplastic anaemia is about 80%; invasive fungal infections and overwhelming bacterial sepsis are the most common causes of death.
• However improvements in bone marrow transplantation and immunosuppression have increased the number of long-term survivors of patients with aplastic anaemia.³
• Non-severe aplastic anaemia is seldom life-threatening, and in most cases no therapy is necessary.