Aplastic anaemia (bone marrow failure)

Overview

Aplastic anaemia (AA) is a life-threatening bone marrow failure syndrome characterized by pancytopenia resulting from aplasia of the bone marrow.

It occurs due to destruction or suppression of haematopoietic stem cells, leading to reduced production of red blood cells, white blood cells, and platelets.

Aplastic anaemia may be:

• Inherited, for example Fanconi anaemia.

• Acquired, including idiopathic, immune-mediated, chemical-induced, drug-induced, radiation-related, viral infection-associated, or autoimmune causes.

It is a haematological emergency.

Pathophysiology

Most acquired aplastic anaemia is immune-mediated, involving cytotoxic T-cell destruction of haematopoietic stem cells.

Mechanisms include:

• Reduced stem cell number.

• Increased apoptosis.

• Elevated interferon-gamma and TNF-alpha.

• Bone marrow replacement by fat.

• Reduced production of red blood cells, white blood cells, and platelets.

Causes and risk factors

Common acquired causes include:

• Drugs, for example chloramphenicol, chemotherapy, and antiepileptics.

• Viral infections, especially hepatitis, EBV, HIV, and parvovirus B19.

• Autoimmune disorders.

• Pregnancy.

• Radiation exposure.

• Chemical exposure, including benzene.

• Idiopathic causes (majority of cases).

Risk factors include:

• Family history of inherited syndromes.

• Exposure to myelotoxic drugs.

• Viral hepatitis.

• Connective tissue diseases.

• Radiation exposure.

Clinical presentation

Symptoms depend on the severity and degree of cytopenia.

Anaemia features

• Fatigue.

• Pallor.

• Dyspnoea on exertion.

• Tachycardia.

Thrombocytopenia features

• Easy bruising.

• Petechiae.

• Epistaxis.

• Gum bleeding.

• Bleeding tendency.

Neutropenia features

• Recurrent infections.

• Fever.

• Sepsis.

Note:

• Splenomegaly is not a feature of aplastic anaemia and suggests an alternative diagnosis such as leukaemia.

Diagnostic criteria

Diagnosis requires:

• Peripheral pancytopenia.

• Bone marrow hypocellularity.

• Exclusion of other causes.

Bone marrow findings:

• Hypocellular marrow with <30% haematopoietic cells.

• Fatty replacement.

• No malignant infiltration.

Confirmation is done by bone marrow aspiration and trephine biopsy.

Classification by severity

Severe aplastic anaemia

At least two of the following:

• Reticulocyte count <60 × 10⁹/L (automated) or <20 × 10⁹/L (manual).

• Platelet count <20 × 10⁹/L.

• Absolute neutrophil count (ANC) <0.5 × 10⁹/L.

Very severe aplastic anaemia

Criteria are the same as severe aplastic anaemia with:

• ANC <0.2 × 10⁹/L.

Moderate aplastic anaemia

Does not meet criteria for severe aplastic anaemia.

Investigations

Laboratory investigations

• Full blood picture (FBP).

• Peripheral blood smear.

• Reticulocyte count.

• Liver function tests.

• Viral screening:

  • HIV.

  • Hepatitis B.

  • Hepatitis C.

  • EBV.

• Bone marrow aspiration and trephine biopsy.

• Flow cytometry for paroxysmal nocturnal haemoglobinuria (PNH) clone.

• Cytogenetic analysis.

• Autoimmune screening.

Management of Aplastic anaemia (bone marrow failure)

All patients should be referred to a tertiary haematology centre with adequate expertise and facilities.

Management includes supportive treatment and definitive treatment.

Supportive treatment

• Blood transfusion:

  • Preferred irradiated, leucodepleted packed red blood cells when Hb <7 g/dl.

AND

• Platelet transfusion if bleeding or if platelet count is <10 × 10⁹/L.

• See dosage under blood transfusion section.

AND

• Prophylactic antibiotics.

• Maintain good hygiene.

• Isolation of the patient when required.

• Use of masks to prevent neutropenic sepsis in patients with ANC <0.5 × 10⁹/L.

Note:

• Perform culture and sensitivity in patients with neutropenic sepsis.

• Refer to management of neutropenic sepsis under the malignant diseases chapter.

• Avoid NSAIDs and intramuscular injections where possible.

Definitive treatment

Haematopoietic stem cell transplantation

Allogeneic haematopoietic stem cell transplantation is indicated in younger patients, especially:

• Patients younger than 45 years according to guideline criteria.

• Patients with suitable matched donors.

It is a potentially curative treatment.

Immunosuppressive therapy

Used when haematopoietic stem cell transplantation is not available or not suitable.

Treatment includes:

• Anti-thymocyte globulin (ATG) IV 40 mg/kg/day for 4–10 days.

AND

• Cyclosporine PO 2–10 mg/kg/day 12 hourly for 6–24 months.

AND

• Eltrombopag:

  • Children <5 years: 2.5 mg/kg 24 hourly.

  • Children 6–11 years: 75 mg 24 hourly.

  • Patients >12 years: 150 mg 24 hourly for 6 months.

Management of cyclosporine toxicity

For patients who develop cyclosporine toxicity such as nephrotoxicity, hypertension, gingival hypertrophy, and hirsutism, the following drugs may be considered although response rates are low:

• Methylprednisolone PO 5–10 mg/kg for 3–14 days.

OR

• Cyclophosphamide IV 45 mg/kg/day for 4 days.

OR

• Danazol PO 5 mg/kg/day for 6 months.

Monitoring

• Monitor blood counts bi-monthly for outpatients.

• Monitor blood counts as needed for admitted patients.

Complications

• Severe infection.

• Haemorrhage.

• Acute renal failure.

• Clonal evolution to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML).

• Paroxysmal nocturnal haemoglobinuria (PNH).

Prognosis

• Untreated severe aplastic anaemia has high mortality.

• Outcomes are best in younger patients receiving stem cell transplantation.

• Response to immunosuppressive therapy occurs in many patients.

Prevention

• Avoid known myelotoxic drugs.

• Limit radiation exposure.

• Early treatment of viral hepatitis.

• Genetic counselling in inherited cases.

Referral

Immediate referral to a tertiary haematology centre is essential for:

• Bone marrow biopsy.

• Transplant evaluation.

• Advanced supportive care.