Approach to Pancytopenia in

elderly
Ewe Lean Theng
August 2024
Introduction
• Reduction in all peripheral blood lineages and is present when all
three cell lines are below the normal reference range.
Cell line Value
RBC (Hb) Nonpregnant women - <12 g/dL
• According to WHO: Men - <13 g/dL
WBC (ANC) <1800/µL
𝑃𝑃𝑃𝑃𝑃𝑃 % + 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 %
*ANC = TWBC (cells/µL) x [ ]
100
Mild 1.0 – 1.5

Moderate 0.5 – 1.0

Severe 0.2 – 0.5

Very severe <0.2

PLT <150,000/µL.
Causes of pancytopenia

Adapted from UpToDate 2024

A 72 years old man was referred to the haematology clinic for
pancytopenia. His full blood count upon arrival was -
Hb : 89g/L
WBC : 2.9 x 10^9/L
PLT : 90 x 10^9/L
Causes of pancytopenia

Megaloblastic anaemia

Aplastic anaemia

Acute leukemia

MDS

Metastatic cancer

HLH

Adapted from UpToDate 2024

History
 Symptoms and duration associated with pancytopenia – acute vs
chronic
 Underlying medical illness
 Constitutional symptoms, including fevers, night sweats, and/or
weight loss – malignancy
 Diet history – megaloblastic anaemia
 Drugs history – immunosuppressant eg: azathioprine
Physical examination
• Massive splenomegaly – PMF
• Jaundice, painful glossitis (beefy-red tongue), angular cheilosis –
megaloblastic anameia
• Lymphadenopathy
• Bruises
• Gum swelling – AML M4
• Bleeding tendency – APML
• Mass – primary malignancy
• Oral lesions (i.e. thrush) – immunocompromised
Laboratory tests
Complete blood count
• MCV – raised MCV suggestive of megaloblastic anaemia
• Reticulocyte count – reflects BM productivity (eg. Raised count may
indicate peripheral consumption; low count in megaloblastic
anaemia, MDS)
• ANC count – classification of aplastic anaemia
ANC Hb PLT
<1.5 x 10^9/L <10.0 g/dL <50 x 10^9/L Aplastic anaemia
<0.5 <20 x 10^9/dL (retic) <20 Severe
<0.2 Very severe

• Marked lymphopenia - HIV

Full blood picture
• Blasts – acute leukemia
• Oval macrocytes, hypersegmented neutrophils – megaloblastic
anaemia
• Macrocytic red cells, dysplastic neutrophils (pseudo-Pelger
abnormality, hypogranulation) – MDS
• NCNC anaemia, LE picture; circulating malignant cells very rare –
carcinoma
• Dysplastic changes/ toxic granulation in neutrophils – infection
• Leucoerythroblastic picture, tear-drop poikilocytes, +/- blast cells &
mild basophilia – PMF
Bone marrow aspiration
Causes Bone marrow findings
Megaloblastic anaemia  Hypercellular,
 Erythroid precursor shows megaloblastoid maturation (open, fine, lacy
chromatin but normal cytoplasmic haemoglobinization)
 Giant metamyelocytes
MDS  Hypercellular
 Dysplastic features (≥10%):
 Erythroid – multinuclearity, nuclear budding, internuclear bridging, ring
sideroblast
 Myeloid – pseudo-Pelger-Huet anomaly, hypogranulation, pseudo-
Chediak-Higashi granules
 Megakaryocytes - ≥10% dysplastic megakaryocytes based on evaluation
of ≥ 30 megakaryocytes; micromegakaryocytes, multiple widely
separated nuclei, monolobated
 Determine percentage of blasts – for classification
 Perl’s stain – ring sideroblast
Acute leukemia  Hypercellular
 Diffuse sheet of blast and other haematopoietic cells suppressed
 Quantification of blasts:
 >20% - acute leukemia
 If <20% then proceed with cytogenetic – if t(8;21), inv(16), t(15;17) positive
also consider AML
 Describe the morphology of blast for AML & ALL
 Proceed with cytochemistry stain for to differentiate blasts – MPO, PAS
 Hypergranular APML strongly positive for MPO
 Proceed with IPT to differentiate lineage and for confirmation
 Blast – CD34
 AML – MPO, CD13, CD33, CD117
 ALL – Tdt, CD19, CD79a
Aplastic anaemia  Hypocellular
 Loss of haematopoietic tissue with replacement by fat
 Relavent increase of lymphocytes and plasma cells
 To differentiate from hypoplastic MDS:
 Significant dysplasia (most often micromegakaryocytes)
Hypoplastic MDS  Increased blasts (identified by CD34 staining of biopsy)
 Abnormal karyotype (excludeing trisomy 8 because also seen in some AA)
Causes Bone marrow findings
PMF (overt)  Dry tap
 Hypocellular
 Megakaryocytic proliferation & atypia:
 Atypical megakaryocytes – clustering (frequently adjacent to the BM
vascular sinuses), abnormal N:C ratio, abnormal chromatin clumping with
hyperchromatic nuclei, cloud-like nuclei, frequent occurrence of bare
nuclei
Metastatic carcinoma  May lead to reactive myelofibrosis – dry tap
 Neoplastic cells – usually larger, cohesive, pleomorphic
HLH  Increase histiocytes with abnormal haemophagocytic activity
Trephine biopsy
Causes Findings
Megaloblastic anaemia  Rarely useful
 Hypercellular
 Erythroid hyperplasia with predominance of immature precursors – large,
round-to-oval nuclei with elongated nucleoli, moderate amount of intense
basophilic cytoplasm
 Giant metamyelocytes
MDS  Hypercellular (majority)
 Cytological dysplasia
 Abnormal topography –
 ALIP (abnormal localization of immature precursor) – granulocytic
precursors being found in the central part of intertrabecular spaces;
erythroid precursors and megakaryocytes in the paratrabecular regions
 Erythroid – singly dispersed, not in small islands
 Megakaryocytes – normally scattered within paratrabecular area but
now may show clustering
Acute leukemia  Hypercellular with diffuse infiltration of blast cells
 Other hematopoietic cells are suppressed
 Confirm the lineage with IHC stain
Aplastic anaemia  Patchy cellular areas in a hypocellular background
 Main cells present are lymphoyctes and plasma cells
TB  Epithelioid granuloma which composed of loose or discrete aggregates of
eosinophilic histiocytes / macrophages with variable giant cell formation and
central caseation / necrosis
 Do ZN staining to identify GNR
Causes Findings
PMF  Severe marrow fibrosis (silver staining show dense reticulin network)
 Proliferation of vessels - marked tortuosity, luminal distension, conspicuous
intrasinusoidal haematopoiesis
 Megakaryocytic proliferation
Metastatic carcinoma  More sensitive than BMA – due to desmoplastic stromal reaction that renders
neoplastic cells more difficult to aspirate
 Fibroblast proliferation with depositin of reticulin, neoangiogenesis, inflammatory
response, necrosis, osteolysis, osteosclerosis
 Some well-differentiated neoplastic cells show distinctive morphology – suggest
the likely site of origin
 IHC –
 Distinguish neoplastic cells from haemopoietic cells
 Determine the site of origin of metastatic tumour when the primary is
unknown
IHC is useful in –
 PMF – reticulin stain to asses grade of fibrosis
 AML
 ALL
 MDS – to look for excess blast and ALIP
Flowcytometry
• Fail to react with antibodies to CD45 - raise the suspicion of a non-
haemopoietic tumour
Cytogenetic and molecular genetic analysis
Causes Cytogenetics Molecular
MDS  Important in evaluation of prognosis  SF3B1 – associated with ring
 Classification sideroblasts; favourable prognosis
 del(5q) – diagnostic of MDS even in the  TET2, ASXL1
absence of morphological abnormalities;
favourable clinical course
 Complex karyotype (≥ 3 abnormalities) –
unfavourable
 Monosomy 5, monosomy 7, trisomy 8,
del(7q)
PMF  Loss of long arm of chromosome 5 or 7,  JAK2 V617F (50-60%), CALR (30%), MPL
trisomy 8, 11q23 rearrangement – higher (8%) – confirms clonality
risk of AML transformation  ~12% triple negative
 BCR-ABL1
 Cytogenetic Molecular
AML  Favourable prognosis – t(8;21), inv(16),  Favourable – NPM1, CEBPA (biallelic)
t(15;17)  Unfavourable – FLT3-ITD (internal tandem
 Unfavourable prognosis – KMT2A repeat), TP53, RUNX1, ASXL1, splicing
rearrangement, deletions of chromosome 5 mutation
or 7 or 17p, inv(3), t(6;9)
ALL  Favourable – normal or hyperploidy (>50  Favourable – absence of high-risk
chromosomes), ETV6 rearrangement mutations
 Unfavourable – t(9;22), most translocation  Unfavourable – TP53, NRAS, NR3C1, BTG
involving 11q23 (MLL), hypoploidy (<44
chromosomes)
Aplastic  Performed to exclude inherited forms or  Favourable – PIGA, BCOR, BCORL1
anameia MDS  Higher likelihood of progression to
 Usually karyotype is normal MDS/AML – ASXL1, RUNX1, splicing factor
 May exhibit monosomy 7, trisomy 8 genes, short leucocyte telomere
Other investigations
Causes Tests
Megaloblastic anaemia  Low serum vitamin B12, folate
 Increase serum/ urine methylmelonic acid
 Increase unconjugated bilirubin, LDH
APML  DIVC screening
HLH Refer next slide
PMF  High serum urate, LDH
Metastatic tumour  Tumour markers – PSA, CEA, CA125
 Biopsy for HPE if any mass
 Imaging – CT, PET scan
Infections  Miliary TB – sputum AFB, sputum culture, CXR, HPE
 HIV – serology, NAT
Autoimmune disease  Autoimmune screening
HLH
Causes of pancytopenia in children
Acquired Congenital

IBMFS

Richa Sharma, Grzegorz Nalepa; Evaluation and Management of Chronic

Pancytopenia. Pediatr Rev March 2016; 37 (3): 101–113.
https://doi.org/10.1542/pir.2014-0087
Pancytopenia causes for paeds to discuss in
essay

1. Acute leukemia
2. Aplastic anaemia
3. IBMFS
4. Immunodeficiency
5. HLH
6. BM infiltration eg: neutroblastoma
7. Congenital infection (for newborn)
Thank you