Aplastic Anaemia

Question 1

What is aplastic anaemia?

Answer 1

• pancytopenia = anaemia + leukocytopenia + thrombocytopenia
  
  • May present with sequelae of neutropenia (infections), anaemia (fatigue, pallor, dyspnoea, tachycardia), or thrombocytopenia (bleeding, bruising)
• with hypocellular marrow and no abnormal cells.
• At least 2 of the following peripheral cytopenias must be present: haemoglobin <100 g/L (<10 g/dL), platelets <50 × 10⁹/L, absolute neutrophil count <1.5 × 10⁹/L.
• Bone marrow should show hypocellularity without evidence of significant dysplasia, blasts, fibrosis, or other abnormal infiltrate.

Question 2

Run through the differentiation of haematopoetic stem cells (end products)

Answer 2

Question 3

How is aplastic anaemia classified?

Answer 3

Acquired AA

• Idiopathic (most common)
• Secondary
  
  • Drug or toxin exposure (strong association with chloramphenicol and non-steroidal anti-inflammatory drugs; weak association with penicillamine, gold therapy, benzene, and dipyrone)[2][3]
  • Viral; in particular post-hepatitis (although not by the common A-E hepatitis viruses)
  • Pregnancy
  • Paroxysmal nocturnal haemoglobinuria
  • Eosinophilic fasciitis, systemic lupus erythematosus, coeliac disease, Sjogren syndrome, thymoma.

Inherited marrow failure syndromes

• Fanconi anaemia
• Dyskeratosis congenita
• Shwachman-Diamond syndrome
• GATA2 deficiency.

Question 4

What is the aetiology of inherited aplastic anaemia?

Answer 4

Inherited marrow failure syndromes

• Fanconi anaemia
  
  • _​_usually autosomal recessive, but can also be X-linked. Mutations in 13 genes have been identified, and these code for proteins that form a nuclear complex involved in the DNA damage response. However, the precise mechanisms by which the mutations produce bone marrow failure are not known
• Dyskeratosis congenita
  
  • classical X-linked DC is characterised by the triad of abnormal nails, reticulated skin rash, and leukoplakia. Autosomal- dominant and autosomal-recessive inheritance patterns have been observed. The genetic defects all decrease telomerase function. Telomeres maintain chromosomal stability, and the bone marrow is heavily dependent on telomere preservation to support its high rate of cell proliferation. Loss of telomerase produces bone marrow failure
• Shwachman-Diamond syndrome
  
  • rare autosomal-recessive disease that produces exocrine pancreatic dysfunction, neutropenia (which can be intermittent), aplastic anaemia, myelodysplastic syndrome/acute myelogenous leukaemia (often with abnormalities of chromosome 7), and skeletal abnormalities. About 90% of patients harbour mutations in a gene known as the SBDS gene, but the relationship of the mutations to bone marrow failure is not fully understood
• GATA2 deficiency.
  
  • ​

GATA2 is an important zinc finger transcription factor involved in haematopoiesis. Germline mutations of GATA2 (leading to GATA2 deficiency) have been described and linked to a wide spectrum of clinical phenotypes including cytopenias, myelodysplastic syndromes, acute leukaemias, infections (bacterial, mycobacterial, viral), immunodeficiency, lymphoedema, and pulmonary alveolar proteinosis.

* Heterozygous GATA2 mutations have been identified in approximately 10% of patients with congenital neutropenia and AA.

Question 5

What is the aetiology of acquired aplastic anaemia?

Answer 5

Acquired AA

• Idiopathic (most common)
• Secondary
  
  • Drug or toxin exposure (strong association with chloramphenicol and non-steroidal anti-inflammatory drugs; weak association with penicillamine, gold therapy, benzene, and dipyrone)
  • Viral; in particular post-hepatitis (although not by the common A-E hepatitis viruses)
  • Pregnancy
  • Paroxysmal nocturnal haemoglobinuria
  • Eosinophilic fasciitis, systemic lupus erythematosus, coeliac disease, Sjogren syndrome, thymoma
• Acquired AA is usually an idiopathic occurrence.*
• While in some cases the disease reflects direct toxic injury to the haematopoietic stem cells, in most cases the pathogenesis is thought to be a CD4 T cell-mediated autoimmune attack directed against the haematopoietic system.*
• Deficiency and dysfunction of T regulatory cells and increase in CD4 T-helper cells (namely Th17, Th1, and Th2 cells) in AA are believed to contribute to impaired suppression of oligoclonal cytotoxic CD8 T-cells, which creates a pro-inflammatory environment that results in apoptosis of haematopoietic stem cells.*

Question 6

What are the risk factors for aplastic anaemia?

Answer 6

• paroxysmal nocturnal haemoglobinuria (PNH)
• recent hepatitis (viral)
• drug exposure (such as non-steroidal anti-inflammatory drug [NSAID] therapy).
  
  • Drugs (e.g., chloramphenicol and non-steroidal anti-inflammatory drugs)
  • toxins (e.g., chemicals or pesticides)
  • lag time = weeks to months

weak

• pregnancy
• autoimmune disease
  
  • Anecdotal reports exist for an association between AA and SLE, thymoma, eosinophilic fasciitis, and coeliac disease
  • mechanism unclear
• family history of AA or cancer
  
  • may suggest congenital AA.
  • Increased incidence of cancer among family members may also suggest congenital AA

Question 7

Summarise the epidemiology of aplastic anaemia

Answer 7

• incidence of acquired AA is about 2 per million population per year in North America and Europe
  
  • There is no gender imbalance.
  • Patients can be affected at any age, although there is a biphasic age distribution with peaks from 10 to 25 years and >60 years
  • The incidence of AA is reported to be 2 to 3 times greater in East Asia than in North America and Europe.
    
    • Possible reasons include increased exposure to drugs, toxins, and viruses; higher incidence of inherited AA or genetic predisposition, such as polymorphisms of tumour necrosis factor-alpha, interferon-gamma, and drug detoxifying enzymes (GSTM1 and GSTT1); and regional variations in the diagnostic criteria and classification of AA and other bone marrow disorders (e.g., hypoplastic myelodysplastic syndrome).
• Congenital AA was previously considered rare, but an increasing number of patients with presumed acquired AA are now being diagnosed with germline mutations (e.g., inherited telomeropathies) with the use of next-generation sequencing
  
  • One of the most common congenital causes is Fanconi anaemia.
  • Patients with congenital AA most commonly present in early childhood, but can sometimes present as young adults and occasionally in their 30s or 40s, and very rarely, in their 50s.

Question 8

What are the presenting symptoms of aplastic anaemia?

Answer 8

• fatigue
  
  • May indicate underlying cytopenia.
• pallor
  
  • ​May indicate underlying cytopenia.
• history of recurrent infection
  
  • ​May indicate underlying cytopenia.
• history of bleeding or easy bruising
  
  • ​May indicate underlying cytopenia.
• dyspnoea
  
  • May indicate underlying cytopenia.
  • Dyspnoea due to pulmonary fibrosis may suggest dyskeratosis congenita
• persistent warts
  
  • May suggest inherited GATA2-related disorder.

Question 9

What are some uncommon presenting symptoms of aplastic anaemia?

Answer 9

• hearing loss or deafness
  
  • May suggest Fanconi anaemia or inherited GATA2-related disorder.
• short stature, pigmentation abnormalities, or urogenital abnormalities
  
  • ​May suggest Fanconi anaemia
• nail malformations, reticular rash, oral leukoplakia, or epiphora
  
  • ​May suggest dyskeratosis congenita
• osteoporosis
  
  • ​May suggest dyskeratosis congenita
• premature hair loss/premature greying
  
  • ​May suggest dyskeratosis congenita
• hyperhidrosis
• dysphagia
• extensive dental caries or tooth loss
• steatorrhoea
• skeletal dysplasia
• monocytopenia
• non-tuberculous mycobacterial infections
• pulmonary alveolar proteinosis
• congenital lymphoedema, Emberger syndrome
• immunodeficiency (DCML [dendritic cell, monocyte, B cell, and NK cell deficiency])

Question 10

What are the signs of aplastic anaemia O/E?

Answer 10

​Anaemia Signs:

• tachycardia
• Pallor

Thrombocytopaenia Signs:

• Petechiae
• Bruises

Leukopaenia Signs:

• Multiple bacterial and fungal infections
• No hepatomegaly, splenomegaly or lymphadenopathy

Question 11

What are the primary investigations for ?aplastic anaemia?

Answer 11

bloods:

• FBC
• reticulocyte count

other

• bone marrow biopsy and cytogenetic analyses
  
  • ​= A hypocellular marrow is a definitive diagnostic finding for AA. Moreover, there should be an absence of abnormal cell population (such as blasts) and no fibrosis.

Question 12

What are some possible secondary investigations for aplastic anaemia?