Aplastic anaemia Flashcards
Define aplastic anaemia.
Pancytopenia with hypocellular marrow and no abnormal cells. At least 2 of the following peripheral cytopenias must be present:
- haemoglobin <100g/L (<10g/dL)
- platelets <50 × 10⁹/L
- absolute neutrophil count <1.5× 10⁹/L
Bone marrow should show hypocellularity without evidence of significant dysplasias, blasts, fibrosis or other abnormal infiltrate.
How common is aplastic anaemia?
- 2 per million
- Biphasic age distribution 10-25yrs and >60yrs
- Congenital AA is increasing e.g. Fanconi anaemia which is the most common
What is the aetiology of aplastic anaemia?
ACQUIRED AA
Primary: Idiopathic (most common)
Secondary:
- Drug or toxin exposure (e.g. chloramphenicol and NSAIDs)
- Viral; in particular post-hepatitis (not by the common A-E viruses)
- Pregnancy
- Paroxysmal nocturnal haemoglobinuria
- Eosinophilic fasciitis, SLE, coeliac, Sjogren’s, thymoma.
INHERITED marrow failure syndromes
- Fanconi anaemia
- Dyskeratosis congenita
- Shwachman-Diamond syndrome
- GATA2 deficiency.
What is the pathophysiology of aplastic anaemia?
Acquired - usually idiopathic. Haematopoietic stem cells are attacked by CD4+ autoimmune T cells.
Congenital - DNA damage repair mechanism defect (Fanconi’s); abnormalities of telomerase maintenance and ribosomal function (others). GATA2 mutations also implicated in AA.
What are the risk factors for aplastic anaemia?
Drug/toxin exposure - weeks to months post chloramphenicol, NSAIDs, chemicals, pesticides
Paroxysmal nocturnal haemoglobinuria (PNH) - closely related to AA. Proposed that PNH cells escape AI attack in AA.
Recent hepatitis - in 5-10%, usually viral
Pregnancy
AI disease
FH
What are the clinical features of AA?
Slow (months) or rapid (days) onset:
Anaemia - tiredness, lethargy, dyspnoea, pallor
Thrombocytopaenia - easy bruising, bleeding gums, epistaxis, petechiae, bruises
Leukopenia - high frequency and severity of infections, fungal and multiple bacterial, splenomegaly, hepatomegaly, lymphadenopathy
_Congenital feature_s:
Fanconi - short stature, pigmentation defects, urogenital abnormalities
Dyskeratosis congenita - nail malformations, reticular rash, oral leukoplakia, epiphora, osteoporosis, alopecia/premature greying, hyperhydrosis
Shwachman-Diamond syndrome - dental caries or tooth loss, steatorrhoea, skeletal dysplasia
GATA2-related disorders - non-TB mycobacterial infections, persistent warts, hearing loss, Emberger syndrome
What investigations would you do for aplastic anaemia?
BLOODS + BIOPSY required for diagnosis.
Blood -
-
FBC -
- low Hb, normal MCV
- low plt,
- low WCC
- Reticulocyte count - <1%
- +/- Flow cytometry for GPI-anchored proteins - PNH clones may be detected
- +/- Serum B12 and folate - normal
- +/- Autoantibody screen
Blood film - exclude leukaemia (absence of abnormal circulating WBC)
Bone marrow trephine biopsy -
- for diagnosis (hypocellular marrow with a decrease in all elements; the marrow space is composed mostly of fat cells and marrow stroma)
- and exclusion of other causes (lymphoma, leukaemia, malignancies, myeloma, myelofibrosis)
What is the criteria for severe aplastic anaemia?
Criteria for severe AA:
BM cellularity <25% normal cellularity plus 2 of the following:
- neutrophils<0.5x10^9/L
- platelets<20x10^9/L
- reticulocytes<40x10^9/L
What is the management of AA?
Acquired:
- Immunosuppressive therapy e.g. ATG and ciclosporin (calcineurin i)
- Allogeneic SCT (_<_50yrs)
- +/- Remove cause e.g. NSAIDs or chloramphenicol
- +/- Promote BM recovery - TPO recepor agonist (eltrombopag) , oxymethone
-
+/- Supportive care -
- blood transfusions/platelets
- antibiotics/antifungals
- iron chelation therapy
Congenital:
- Allogeneic SCT
- Androgen therapy (e.g. danazol, oxymetholone) - used if SCT is not an option
- NB: immunosuppression does not work
- +/- Supportive care
What is the MOA of eltrombopag?
Oral thrombopoietic receptor agonist
What are the complications of AA?
SCT:
- Graft failure after SCT
- GvHD
- Morbidity
Immunosuppressants:
- Avascular necrosis
- Relapse 35% over 15yrs
- Clonal haematological disorders e.g. PNH, MDS, AML
- Solid tumours
What is the prognosis with AA?
5yr overall survival is 61%
Non-severe AA has a very good prognosis
Improved survival with ATG therapy
From pathology:
Which drugs can cause bone marrow failure?
- PREDICTABLE (dose-dependent, common) e.g. Cytotoxic drugs
- IDIOSYNCRATIC (NOT dose-dependent, rare) e.g. Phenylbutazone, Gold salts
- ANTIBIOTICS e.g. Chloramphenicol, sulphonamide
- DIURETICS e.g. Thiazides
- ANTITHYROID DRUGS e.g. Carbimazole
From pathology:
What is the inheritance of Fanconi’s?
Autosomal recessive
or X linked
From pathology:
What other congenital features are present in Fanconi’s?
- Short Stature
- Hypopigmented spots and café-au-lait spots
- Abnormality of thumbs
- Microcephaly or hydrocephaly
- Hyogonadism
- Developmental delay
- No abnormalities 30%
BUT AA is the most common complication of Fanconi’s.
From pathology:
What is the classical triad of dyskeratosis congenita?
- Skin pigmentation
- Nail dystrophy
- Leukoplakia
Genetic basis is telomere shortening. Can be X linked, recessive or dominant.
