MDS, Aplastic Anaemia and PNH Flashcards
Approach to asymptomatic macrocytic anaemia and thrombocytopenia
Hx: any infection (may cause mild marrow suppression), any herbs/drugs taken
Blood smear very important!!:
- check for spurious thrombocytopenia due to clumping
- need to r/o medical emergencies e.g. MHA due to DIC/TTP/HUS (schistocytes, polychromasia); acute leukaemia or high grade MDS (blasts, dysplastic neutrophils)
DDx of macrocytic anaemia and thrombocytopenia
Macrocytic anaemia
- common: B12, folate deficiency, alcoholism, CLD, drugs
- uncommon: hypothyroid, haemolysis, MDS
Thrombocytopenia
- increased destruction: immune (ITP), non-immune (DIC, TTP)
- decreased production: BM failure (AA, MDS, leukaemia, marrow infiltration by tumours or infection), megaloblastic anaemia
Other tests for macrocytic anaemia and thrombocytopenia
Repeat CBC and LRFT LDH, Haptoglobin Vit B12 and folate levels TFT Autoimmune marker Direct Coombe's test or DCT/DAT Iron profile
Recall causes of cytopenia/pancytopenia
Increased destruction: autoimmune, splenomegaly
Decreased production: BM failure, MDS, leukaemia, marrow infiltration, megaloblastic anaemia
(details in RBC flashcards)
Aplastic Anaemia - diagnostic definition, causes
Diagnosis: **PANCYTOPENIA with HYPOPLASTIC bone marrow (<25% cellularity)
- consider inherited BM failure in young patients + hypoplastic MDS in older patients
Causes: Primary acquired (70%) - idiopathic Primary inherited (10%) - Fanconi's anaemia, dyskeratosis congenita, diamond blackfan anaemia (single lineage)
Secondary (10-15%) - ionising radiation, cytotoxic drugs, insecticides, benzene, HSR (gold, chloramphenicol), post-viral infection
Fanconi’s anaemia: inheritance, pathogenesis, prognosis, clinical manifestations, diagnosis, treatment
AR (mostly) or XR
- heterogenous
- increased chromosomal breakage and HSR to DNA cross-linking agents
Progressive BM failure and increased predisposition to malignancy and MDS
- 90% BM failure at 40 yrs old
- 10% progress to AML
Clinical manifestations - skin (hypo/hyperpigmentation) - skeletal deformities (radial hypoplasia, absent thumbs) - GU (horseshoe kidney) - mental retardation 1/3 normal
Diagnosis: increased random chromosomal breaks
Treatment: androgens +/- HSCT, prophylactic antibiotics
Dyskeratosis congenita - inheritance, manifestations, prognosis
XR
- defective telomere maintenance with shortened telomere lengths
Present in childhood
- mucocutaneous triad of abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia
- pulmonary fibrosis
Also a/w BM failure and increased risk of malignancy
80% BM failure by 20 yrs old
Diamond Blackfan anaemia - presentation, CBC, BM, management
Present in infancy or <1 yrs old as PURE RED CELL aplasia
Macrocytic anaemia, reticulocytopenia
BM: absent erythropoiesis
May have other physical abnormalities such as short stature, craniofacial, cardiac and urogenital malformations
Think of acquired causes e.g. infections that suppress red cell - parvovirus B19
Management: supportive treatment (life-long red cell transfusion)
Idiopathic aplastic anaemia - age of presentation, assessment of severity, treatment
Vast majority of cases
- believed to be immune-related
Age of presentation: biphasic (10-25 and 60)
Severity:
- severe = retic <20%, ANC <0.5, Plt <20
- very severe = ANC <0.2
- non-severe
Treatment:
- ATG (anti-thymocyte globulin), cyclosporin A, prednisolone
- supportive transfusion if severe
Pathogenesis of AA, genetic factors
Proliferation defect of stem cells/precursors due to immune reaction against haemopoietic tissue (increase apoptosis and decrease differentiation of HSPCs)
Genetic factors: HLA-DR2 and HLA-DR15 (roles in Ag recognition)
Myelodysplastic syndromes - characteristic features, causes
Group of clonal haemopoietic stem cell disorder characterised by DYSPLASIA and INEFFECTIVE haemopoiesis (increased apoptosis)
Disease of elderly
<20% blasts in blood and BM (>20 = leukaemia!)
PANCYTOPENIA with HYPERCELLULAR BM (lots of cells not effectively matured and released)
- note there may be hypoplastic MDS in some cases!
Causes
- primary (mostly) – hx of benzene exposure, smoking, fanconi anaemia
- some secondary – chemoRT for other conditions
Myelodysplastic features vs Myelodysplastic syndrome
MD features may be present transiently e.g. chemotherapy, megaloblastic anaemia but will recover
MDS presents consistently, need chemo and drugs to kill off abnormal clone
Examples of myelodysplastic features
> 50% cells with dysplasia = dysplastic
Dyserythropoiesis
- nuclear budding, karyorrhexis (fragmentation), multinuclearity, vacuolation of cytoplasm, inter-nuclear bridging
- ring sideroblast, PAS+ve
Dysgranulopoiesis
- small
- nuclear hypolobulation (pseudo-Pelger Heut), hypersegmentation
- hypogranularity, pseudo-chediak higashi granules (very big granules)
Dysmegakaryocytopoiesis
- hypolobulated micromegakaryocyte
- non-lobulated nuclei in any megakaryocyte
- multiple, widely separated nuclei
Classification of MDS and risk stratification/relevant management approach
Dysplasia (single or multilineage)
% ring sideroblasts
% blasts
Cytogenetic abnormalities
IPSS-R system
- cytogenetic: very good to very poor
- % blasts: <2 to >10
- cytopenias: unilineage vs multilineage
Management
- more aggressive for high risk MDS (risk of progression to AML due to accumulation of aberrant growth signals and reduced apoptosis)
- supportive for low risk MDS or elderly
PNH - pathogenesis, classical presentation, associations, subclinical type, screening tests, treatment
Very rare acquired clonal stem cell disorder
Deficient GPI anchor due to mutation in PIG-A on chromosome X –> reduced function of GPI linked proteins e.g. CD55 (decay activating factor) and CD59 (membrane inhibitor of cell lysis)
==> complement mediated lysis of RBC
Classical Presentation: Haemolytic Anaemia (chronic intravascular – haemosiderinuria), Thrombosis, BM failure (already dysfunctional originally)
Associated with other BM disorders e.g. AA, MDS
SUBCLINICAL (small clone in MDS/AA patients due to survival advantage, no haemolysis)
PNH screening tests (flow cytometry; FLAER, CD24 GPI linked proteins + PNH Type I [normal]/II/III red cells)
Treatment: Eclulizumab (monoclonal antibody against C5; very effective but expensive), anticoagulation, immunosuppression
