Dr Nilukshi Perera

Consultant Haematologist
 A reduction in all 3 types of cellular components
in peripheral blood is termed pancytopenia and
this involves anaemia, neutropenia, and
thrombocytopenia.
 Unless the underlying cause is already apparent the
presence of pancytopenia always warrants
investigations.
 The presence of severe pancytopenia (symptomatic

anaemia, WBC <0.5 x 10^9/L and platelets <20 x

10^9/L calls for urgent investigation .
 Approach to Pancytopenia
Pancytopenia

Inc. destruction Sequestration Dec. production

• Immune PNH,SLE • Hypersplenism • B12 déficiency
• Sepsis • AA
•Myeloma
•Myelofibrosis
• MDS
• BM infiltration
• Drugs
• Viruses
• Radiation
•Haemophagocyt
ic syndrome
 Introduction
 Aetiology
 Pathogenesis
 Clinical features & diagnosis
 Treatment
 Paroysmal Nocturnal Haemoglobinuria (PNH)
 17 year old female
 Fatigue
 Sore throat
 Bleeding gums
 Petechial rash
 Fever
 OE: Gum bleeding+
 Febrile
 Oral ulcers+
 Abd- soft
 No lymphadenopathy
 Hb – 8.9 g/dL
 RBC – 3.0 x 1012/L
 MCV – 103 fL
 Plt – 18 x 109/L
 WBC – 2.2 x 109/L
 Neuts – 0.2 x 109/L
 Lymphs –2.3 x 109/L
 ESR 43mm/1st hr
 Reticulocytopenia
 Peripheral blood pancytopenia and a
hypocellular marrow in which normal marrow
is replaced by fat cells.
 Abnormal cells are not found.
 No BM fibrosis
 Paul Ehrlich (1854-1915) described the first
case of aplastic anaemia in a pregnant
woman who died of marrow failure in1888.
 The term “aplastic anaemia” first used by

Anatole Chauffard in 1904.

 Suspect from signs Male Female

and symptoms Hb 13.5- 11.5-16g/dl

 Made by check of 17.5g/dl
PCV 38-50% 36-45%
full blood count,
FBC MCV 76-96 fl 76 – 96 fl
MCH 27-34pg 27-34pg
WBC 4-11x109/l 4-11x109/l
Neut 2.0-7.5 2.0-7.5
Lymph 1.5-4 1.5-4
Platelet 150 -450 150 -450
 Red cell life span 120 days.
 Platelet life span 6 days.
 Granulocyte life span < 24 hours.
 Constant marrow activity needed to replace

dead cells.
 Should have any two of following

 Neutrophils <0.5x 10^9/L

 Platelets <20X 10^9/L
 Reticulocytes <20 X 10^9/L

+
 BM cellularity < 25%
 INHERITED(20%)  ACQUIRED(80%)
o Fanconi Anaemia o Idiopathic
o Dyskeratosis congenita o Drug induced
o Viral (hepatitis, EBV)
o Ionising radiation
o Toxins (pesticides,
benzene, arsenic)
o Pregnancy
o leukaemic
 Important diagnosis to make.
 Detailed history and examination.
 Nail dystrophy, skin pigmentation and
leukoplakia may suggest dyskeratosis.
 Short stature, microcephaly,
microphthalmia, absent thumb and radii,
horse shoe kidney may indicate aplastic
anaemia.

 Check for gene mutations can help.

 Rare condition; 2-5/million per year in
Europe, but is reported to be a
common disease in South East Asia.
 male to female incidence = equal
 Disease of young adults, 2nd peak in

4th -5th decade of life.

 Primary defect or damage to haematopoietic
stem cell.
 possible Immunological attack on stem cells.
 Oligoclonal expression of cytotoxic T cells
 They destroy autologous stem cells by

inducing apoptosis
 Anaemia; tiredness & fatigue, palpitations,
SOB.
 Low white count; recurrent infections, flu-like

illness.
 Low platelets; easy bruising and bleeding.
 No organomegaly
 Ina patient’s own words:
I had gone to the emergency room
after fainting.
I had an extremely heavy period, a terrible
headache, a bleeding sinus infection, painful
mouth sores, bruises from where my cat
jumped on my lap, red spots all over, and no
energy.
 FBC
 Reticulocyte count
 Blood film.
 B12/folate.
 Liver function tests
 Virology
 Bone marrow aspirate & trephine
 PNH screen.
BM Aspiration BM Biopsy
Bone Marrow Examination
 
    
    
    
    
    
    
    
    
 Hypoplasia with loss of haemopoietic tissue
and replacement by fat.
 Trephine biopsy is essential and may show

patchy cellular areas in a hypocellular

background.
 Main cells present are lymphocytes and

plasma cells.
 Removal of any offending agent
 Supportive care
 Androgens-eg Oxymetholone
 Immunosuppressive therapy
 Antithymocyte globulin with Cycolosporin A

 Allogenetic BM transplant from matched sibling donor

 Most effective and can be curative
 Matched unrelated donor BM transplant
 Not as successful
 Immunosuppressive therapy
 Antithymocyte globulin with Cycolosporin A

 Androgens

 Supportive care
 RBC, platelet transfusions, cytokines (EPO and G-CSF)
 Indicated for patients > 40 years
 Patients with no HLA matched sibling donors.
 Anti-Thymocyte Globulin(ATG) or anti-

lymphocyte globulin (ALG), cyclosporin,

methylprednisolone.
 Those with lesser degree have better
prognosis
 In 10-20% PNH clone emerge.
 Some may develop in to MDS or acute

leukaemia
 Sings of anemia: fatigue, weakness, pallor etc
 BM failure: Pancytopenia
 May have congenital malformations: microcephaly,
skin pigmentations, short height, malformed
thumbs, crossed eyes, mental retardation and
various others characteristics.
 Developmental problems: low birth weight, poor
appetite etc
 Often found in childhood, a complete medical
history is important, because it is an inherited
disorder
 Peripheral Blood
Similar to AA, the pancytopenia is seen at 5-
10 years of age.
HbF is elevated, which results in a decrease in
HbA
Chromosomal instability is common
 Chromosome breakage test: diepoxybutane (DEB) or
mitomycin C (MMC) is added to the sample, this
increases the number of breaks, gaps and
rearrangement of the chromosomes in FA

Radiological imaging
 View the skeletal system to identify abnormalities
 An acquired haematopoietic stem cell defect
with predominant haemolytic anaemia.
 A descriptive term for the clinical

manifestation of haemolysis and

haemoglobinuria manifest by dark coloured
urine in the morning.
 Acquired haemolytic anaemia
 Thrombosis in large vessels e.g. hepatic

abdominal, cerebral.
 Pancytopenia or aplastic anaemia.
 This triad makes PNH a unique syndrome
 PNH may present as aplastic anamia.
 Historically test was Ham’s test; showed red
cell lysis by complement activation in
acidified serum.
 Currently test for absent proteins on cell

surface. CD55(DAF) and CD59(MIRL)

 Treat symptoms
 Folic acid for increased erythropoeisis
 May need iron if deficient
 Transfusions
 Anticoagulation
 Eculizumab (antibody against complement

C5)
 Complement inhibition = risk of infection

esp meningococcal. Vaccination required.

 BM – Hypocellular
 Hams test- Negative
 Chromasomal breakage study, negative
 Flow cytometry for CD55 and CD59 negative
 On supportive care
 Awaiting ATG therapy
.
 Myelo – Refers to the marrow
 Dysplasia – Abnormal maturation

Refers to disorders arising in the marrow

from a multipotent stem cell defect
The myelodysplastic syndromes have
characteristic morphological features in the
bone marrow and peripheral blood

They have a tendency to evolve in to acute

leukaemia /chronic leukaemia

Majority affected are elderly

The marrow shows features of ‘ineffective

haemopoiesis’
The bone marrow is hypercellular but
peripherally there are cytopenias

Why does this happen?

What other conditions do you know where

ineffective haemopoiesis is present?

Megaloblastic anaemia
Thalassaemia major
• Clonal haemopoietic stem cell
disorders
• Characterized by :
(1) Cytopenias in one or more of
the myeloid cell lines
(2) Ineffective haemopiesis
(3) Increased risk of development of
acute myeloid leukaemia

• Affects a median age of 70yrs

• Male predominance
 MDS was previously called refractory anaemia
Why?
The anaemias did not respond to any known
haematinic
It was also called ‘pre leukaemia’
Why?
Because the disease has a tendency to progress
to leukaemias eventually
In 1982 FAB group classified the syndromes to
five sub types
(FAB- French, American,British)
Refractory anaemia(RA)
Refractory anaemia with ringed
sideroblasts(RARS)
Refractory anaemia with excess blasts (RAEB)
Refractory anaemia with excess blasts in
transformation (RAEB - t)
Chronic myelomonocytic leukaemia (CMML)
• Refractory cytopenias with unilineage dysplasia
(RA) (RN)(RT)
• Refractory anaemia with ring sideroblasts(RARS)
• Refractory cytopenia with multilineage dysplasia
• Regractory anaemia with excess blasts -1(RAEB1)
• Regractory anaemia with excess blasts -2(RAEB2)
• Myelodysplastic syndrome unclassified
• Myelodysplastic syndrome with deletion 5q-
• Primary
• Secondary :
Radiation
Cytotoxic Drugs :
Cyclophosphamide
Nitosureas
Underlying genetic disorders
Down syndrome
Fanconi anaemia
 Anaemia
 Infections
 Bleeding manifestations

Because…
The defect is in all three types of blood cells
Where the disease arises…
 Changes in the Neutrophils

Hypolobular,hypogranular neutrophils

Macropolycyte
 Myeloid

blast cells
 A 66-year-old woman with
myelodysplastic syndrome.
She had a localized, erythematous,
violaceous, tender rash on the upper scapular
regions. The lesions were pustular; some had
blistered. The remaining physical findings
were unremarkable.
Recurrent blood transfusions are needed
because of the refractory anaemia
Siderotic granules around the nucleus in
Refractory Anaemia with Ringed sideroblasts
(RARS)
 Erythroblasts with
iron granules
arranged like a
ring around the
nucleus

Ring
sideroblasts

Positive 15% of
nucleated red
cells =RARS
Normal
megakaryocyte

Other cells of erythroid and

myeloid lineage
 Marked
dyerythropoiesis

Abnormal
erythroid
precursor & a
Myeloid
precursor with
a ring nucleus
Abnormal
megakaryocytes in the
bone marrow
 Symptomatic
Blood transfusions
Antibiotics for infection
Platelet transfusion
Curative
Bone marrow transplant