Myelodysplastic Syndrome, Aplastic Anaemia and

Paroxysmal Nocturnal Haemglobinuria

Kate Leung

1
Content
 Aplastic Anaemia
 Essential Haematology (8th Ed) p273-280
 Myelodysplastic Syndromes
 Essential Haematology (8th Ed) p197-205
 Paroxysmal Nocturnal Haemoglobinuria
 Essential Haematology (8th Ed) p277-278

2
Diagnostic overlap

Paroxysmal
nocturnal
haemoglobinuria

The term “Myelodysplastic Neoplasms” replace

“Myelodysplastic Syndrome” in WHO 2022

3
Case 1
 M/52
 Worked in China (garment factory)
 Non-smoker, social drinker
 Good past health
 Presented to China hospital with URI symptoms
 P/E: unremarkable
 Blood checking done (LRFT normal)
 Hb 11.6 g/dL 13.4-17.1 g/dL
 RBC 3.2 x 1012/L 4.3-5.9 x1012/L
 MCV 108.7 fL 82-97 fL
 WBC 7.0 x 109/L 3.7-9.2 x109/L
 Plt 67 x 109/L 145-370 x109/L

 USG abdomen: no hepatosplenomegaly

4
 PBS review:
 Macrocytic anaemia
 WBC differential unremarkable
 Thrombocytopenia confirmed

5
Brainstorm
 More information:
 CBC indices persist after resolution of URI symptoms
 Deny any drugs or herbs taken

 Summary:
 52 yo male, good past health, incidental finding of anaemia &
thrombocytopenia
 Asymptomatic

 What is your differential diagnosis?

 Further investigations?
 No?
 Yes, what then?

6
Importance of PBS review
 CBC = complete blood count
 Hb/RBC/MCV
 WBC
 Platelet
 PBS = peripheral blood smear
 Morphology
 Medical haematological emergency (anaemia &
thrombocytopenia for this case):
 Microangiopathic haemolytic anaemia (MAHA) – red cell fragments or
schistocytes, polychromasia
 Acute leukaemia or high grade myelodysplastic syndrome – blasts,
dysplastic neutrophils

7
Macrocytosis or macrocytic anaemia

• B12/folate deficiency
• Chronic liver disease
Common •
•
Excess alcohol
Drugs

• Hypothyroidism
Less • Haemolysis
• Myelodysplasia and other bone
common marrow disorders

8
Thrombocytopenia

• Immune: autoimmune thrombocytopenic

Increased purpura
• Non-immune: DIC (disseminated
intravascular coagulation), TTP
destruction (thrombotic thrombocytopenic purpura)

• Bone marrow failure (inherited and

Decreased acquired)
• Myelodysplasia. leukaemia and other bone

production
marrow disorders (such as myeloma)
• Marrow infiltration by tumors or infection
• Megaloblastic anaemia

9
Other blood tests
 Repeat CBC and LRFT
 Lactate Dehydrogenase (LDH)
 Haptoglobin
 Vitamin B12 and folate levels
 Iron profile: iron, total iron binding capacity (TIBC),
ferritin
 Thyroid function test (TFT)
 Autoimmune marker
 Direct antiglobulin test (DAT)

10
Case 1 (other blood tests):
 Hb 10 g/dL 13.4-17.1 g/dL
 MCV 112 fL 82-97 fL
 WBC 4.9 x 109/L 3.7-9.2 x 109/L
 Plt 28 x 109/L 145-370 x 109/L

 Bilirubin 24 umol/L 5-21 umol/L

 LDH 591U/L <248 U/L
 Haptoglobin <0.08 g/L 0.14 - 2.58 g/L

 Iron 47.2 umol/L 12.5 - 32.2 umol/L

 TIBC 57.2 umol/L 44.8 - 76.0 umol/L
 Ferritin 1734 pmol/L 53 - 739 pmol/L
11
Case 1 ( Bone Marrow Aspirate, 5/2015)

 Normocellular marrow
 Active erythropoiesis with mild megaloblastoid changes
 Active granulopoiesis and megakaryocytopoiesis
 No dysplastic changes

12
 Case 1 (Trephine Biopsy, 5/2015)

 Normocellular marrow with

adequate trilineage
haemopoiesis

13
Cytopenia
 One or two or three lineages
 If all three lineages (Hb/WBC/Plt)  pancytopenia

Increased • Immune: autoimmune disease

• Non-immune: splenomegaly
destruction
• Bone marrow failure (inherited and acquired)
Decreased • Myelodysplasia, leukaemia and other bone
marrow disorders (such as myeloma)

production • Marrow infiltration by tumors or infection

• Megaloblastic anaemia (vitamin B12 or folate
deficiency)

14
Cytopenia
 One or two or three lineages
 If all three lineages (Hb/WBC/Plt)  pancytopenia

Increased • Immune: autoimmune disease

• Non-immune: splenomegaly
destruction
• Bone marrow failure (inherited and acquired)
Decreased • Myelodysplasia, leukaemia and other bone
marrow disorders (such as myeloma)

production • Marrow infiltration by tumors or infection

• Megaloblastic anaemia (vitamin B12 or folate
deficiency)

15
Bone marrow failure
BMF
syndromes

Inherited
Acquired
(~10%)

Idiopathic Secondary Fanconi anaemia

(~70%) (~10-15%) Dyskeratosis congenita
…

Inevitable: cytotoxic drugs

Industrial: benzene
Idiosyncratic: drugs
Infections: viruses (EBV, hepatitis, HIV)
Immune disease: SLE, …
16
Aplastic anaemia
 Characterized pancytopenia with hypoplastic bone
marrow
 Causes: primary (inherited vs acquired) or secondary

17 Essential Haematology 8th Ed (p274)

Bone marrow failure
BMF
syndromes

Inherited
Acquired
(~10%)

Idiopathic Secondary Fanconi anaemia

(~70%) (~10-15%) Dyskeratosis congenita
…

Inevitable: cytotoxic drugs

Industrial: benzene
Idiosyncratic: drugs
Infections: viruses (EBV, hepatitis, HIV)
Immune disease: SLE, …
18
Inherited BMF syndrome
 Rare
 Multi-lineage:
 Fanconi’s anaemia
 Dyskeratosis congenita
 Single lineage:
 Diamond Blackfan anaemia
 Shwachman-Diamond syndrome
 Congenital amegakaryocytic thrombocytopenia with absent
radii
 Some cases may progress to complete bone marrow failure
 All have increased risk of developing haematological
malignancy at variable levels

19
Clues to inherited BMF syndromes
Fanconi’s anaemia Diamond Blackfan
anaemia

Congenital thrombocytopenia
Dyskeratosis congenita with absent radii

20 Hoffman (2005)
Fanconi anaemia
 Autosomal recessive (most) or X linked recessive
 Heterogeneous with multiple genes involved
 Disruption of FA pathway  defective DNA repair
 FA cells are genomic unstable (chromosomal fragility)  increase chromosomal
breakage and hypersensitivity to DNA cross-linking agents such as
diepoxybutane (DEB)
 Abnormal cell death and cell growth

 Progressive BM failure and increased predisposition to malignancy

 90% developed BM failure at 40 years old
 10% progress to myelodysplastic syndrome (MDS) or acute myeloid leukaemia
(AML)

 Associated with growth retardation and other somatic abnormalities:

 Skin (café au lait spots or hypo-/hyper-pigmentation)
 Skeletal (absent thumbs, radial hypoplasia, scoliosis)
 Genitourinary (underdeveloped gonads, horseshoe kidneys)
 1/3 have no physical abnormalities
21
Dyskeratosis congenita
 Most are X-linked recessive
 Mutation in genes involved in maintenance of telomere
length  shortened telomere lengths

 Present in childhood
 Mucocutaneous triad of abnormal skin pigmentation, nail
dystrophy and mucosal leukoplakia
 Pulmonary fibrosis
 Like FA, associated with bone marrow failure and increased
risks of malignancy
 80 % BM failure before age of 20

22
Diamond Blackfan Anaemia
 Present in infancy or less than one year of age as pure red cell
aplasia (pallor or failure to thrive)
 Macrocytic anaemia
 Reticulocytopenia
 BM: absent erythropoiesis

 May have other physical abnormalities such as short stature,

craniofacial, cardiac and urogenital malformations
 Think of acquired causes (transient or chronic pure red cell
aplasia)
 Management: supportive treatment
23
Bone marrow failure
BMF
syndromes

Inherited
Acquired
(~10%)

Idiopathic Secondary Fanconi anaemia

(~70%) (~10-15%) Dyskeratosis congenita
…

Inevitable: cytotoxic drugs

Industrial: benzene
Idiosyncratic: drugs
Infections: viruses (EBV, hepatitis, HIV)
Immune disease: SLE, …
24
Idiopathic acquired aplastic anaemia
 Most common type of aplastic anaemia

 Age of presentation: biphasic (10-25 and 60 years old)

 Pancytopenia (>2 lineages involved) + Hypocellular BM
 Anaemia (normocytic or macrocytic, Hb <10 g/dL)
 Leucopenia (WBC <1.5 x 109/L)
 Thrombocytopenia (<50 x 109/L)

 Most cases are immune-related (cytotoxic CD8+ T cells) and linked to

clonal haematopoiesis

 Clonal haematopoiesis with somatic mutations of genes such as PIGA, BCOR,

BCORL1, ASXL1, RUNX1 and DNMT3A (*non-neoplastic)

 BUT …10% progress to MDS and 7% progress to AML within 10 years of

immunosuppressive treatment

25
Pathogenesis of aplastic anaemia

26 BJH (2017)
Diagnosis
 Straightforward
 Cytopenia (at least 2 lineage):
 Hb < 10 g/dL
 Neutrophil <1.5 x 109/L
 Plt <50 x 109/L
 Bone marrow: age-adjusted cellularity <25% (trephine biopsy)
 No other abnormal infiltrates
 No genetic abnormalities suggestive of inherited BMF or MDS

 Consider
 Inherited bone marrow failure in younger patients
 Hypoplastic myelodysplastic syndrome in older patients

27
 Treatment
 Depends on severity
 Severity:
 SAA: Severe (retic <20 x 109/L , absolute neutrophil <0.5 x 109/L, plt <20 x 109/L)
 VSAA: Very severe (absolute neutrophil <0.2 x 109/L)
 NSAA: Non-severe (not so severe as above)

 Supportive
 Transfusion (+/- iron chelation therapy)
 Prophylactic antibiotics

 ‘Specific’
 Immunosuppressive therapy: antithymocyte globulin, ciclosporin,
alemtuzumab (anti-CD52)
 Stem cell transplantation
 Others: eltrombopag, androgens, haemopoietic growth factors (G-CSF)

28
Cytopenia
 One or two or three lineages
 If all three lineages (Hb/WBC/Plt)  pancytopenia

Increased • Immune: autoimmune disease

• Non-immune: splenomegaly
destruction
• Bone marrow failure (inherited and acquired)
Decreased • Myelodysplasia, leukaemia and other bone
marrow disorders (such as myeloma)

production • Marrow infiltration by tumors or infection

• Megaloblastic anaemia (vitamin B12 or folate
deficiency)

29
Myelodysplastic syndromes/neoplasms
(MDS)
 A group of clonal haemopoietic stem cell disorder
characterized by bone marrow failure in association with
dysplasia in one or more myeloid cell line

 Ineffective haemopoiesis: Cytopenia + Hypercellular BM

 Some MDS (~20%): pancytopenia with hypocellular bone marrow 
hypoplastic MDS

 Neoplastic nature  myelodysplastic neoplasms (previously

termed myelodysplastic syndromes)

 < 20% blasts in blood and bone marrow

 Note: if >20% blasts  acute leukaemia

30
Myelodysplastic syndromes/neoplasms
(MDS)
 Most cases are primary (de novo)
 Some are secondary
 Arise from germline mutations or inherited BMF such as
Fanconi anaemia
 Some are secondary to chemotherapy or radiation
therapy given due to other malignancies (therapy-related
MDS)

 Disease of elderly (median age of onset 70 years old)

31
  Diagnosis of MDS
 Cytopenia
Dysplasia
Definition


 Clonality (CG abnormality)

 Classification of MDS
 Dysplasia
 Single VS Multi-lineage
 % of ring sideroblasts (erythroid
dysplasia)
 % of blasts
Genetic abnormalities (CG or
molecular)

Myelodysplastic syndromes

Myelodysplastic neoplasms (5e WHO, 2022)

32
  Diagnosis of MDS
 Cytopenia
Dysplasia
Definition


 Clonality (CG abnormality)

 Classification of MDS
 Dysplasia
 Single VS Multi-lineage
 % of ring sideroblasts (erythroid
dysplasia)
 % of blasts
 Genetic abnormalities (CG or
molecular)

Myelodysplastic syndromes

Myelodysplastic neoplasms (5e WHO, 2022)

33
Dyserythropoiesis
 Nuclear budding
 Inter-nuclear bridging
 Karyorrhexis
 Multinuclearity
 Megaloblastoid maturation
 Vacuolation

 Ring sideroblast
 PAS +ve erythroblasts

34
Dyserythropoiesis
 Nuclear budding
 Inter-nuclear bridging
 Karyorrhexis
 Multinuclearity

 Megaloblastoid maturation
 Vacuolation

 Ring sideroblast
 PAS +ve

35
Dyserythropoiesis
 Nuclear budding
 Inter-nuclear bridging
 Karyorrhexis
 Multinuclearity

 Megaloblastoid maturation
 Vacuolation

 Ring sideroblast
 PAS +ve

36
Dyserythropoiesis
 Nuclear budding
 Inter-nuclear bridging Ring sideroblasts: presence of 5 or more
iron granules encircling one third or more of
 Karyorrhexis the nucleus

 Multinuclearity
 Megaloblastoid maturation
 Vacuolation

 Ring sideroblast
 PAS +ve erythroblasts
PAS = Periodic acid-Schiff

37
Dysgranulopoiesis
 Small size

 Nuclear hypolobulation,
pseudo-Pelger Heut
 Hypersegmentation

 Hypogranularity
 Pseudo-Chediak Higashi
granules

38
Dysgranulopoiesis
 Small size

 Nuclear hypolobulation,
pseudo-Pelger Heut
 Hypersegmentation

 Hypogranularity
 Pseudo-Chediak Higashi
granules

39
Dysgranulopoiesis
 Small size

 Nuclear hypolobulation,
pseudo-Pelger Heut
 Hypersegmentation

 Hypogranularity
 Pseudo-Chediak Higashi
granules

40
Blasts

41
Dysmegakaryocytopoiesis
 Hypolobulated micro-
megakaryocyte
 Non-lobulated nuclei in
megakaryocyte of all sizes
 Multiple, widely separated
nuclei

42
Dysmegakaryocytopoiesis
 Hypolobulated micro-
megakaryocyte
 Non-lobulated nuclei in
megakaryocyte of all sizes
 Multiple, widely separated
nuclei

43
 Classification of MDS
 Dysplasia
 Single VS Multi-
lineage
 % of ring sideroblasts
(erythroid dysplasia)
 % of blasts
 Genetic abnormalities

 Refractory cytopenia
(unexplained & persisted for
>3 months)
 Cytopenia generally
corresponding to the
dysplasia lineages
 But may be discordance

44 Essential Haematology 8th Ed (p197)

WHO classification (2016)

Peripheral blood Bone marrow Cytogenetic abnormality

MDS with single lineage Cytopenia 1-2 <5% blasts Any*

dysplasia (MDS-SLD) <1 % blasts <15% ring sideroblasts (or <5% Classification of MDS
No Auer rods RS with SFSB1 mutation present)
1 dysplastic lineage  Dysplasia
MDS with multilineage Cytopenia 1-3 <5% blasts Any*
dysplasia (MDS-MLD) <1% blasts <15% ring sideroblasts (or <5%  Single VS Multi-
No Auer rods RS with SFSB1 mutation present)
2-3 dysplastic lineages lineage
MDS with ring sideroblasts (MDS-RS)
 % of ring sideroblasts
MD-RS with single Cytopenia 1-2 <5% blasts Any*
lineage dysplasia (MDS- <1% blasts >15% ring sideroblasts (or >5% (erythroid dysplasia)
RS-SLD) No Auer rods RS with SFSB1 mutation present)
1 dysplastic lineage
 % of blasts
MDS-RS with Cytopenia 1-3 <5% blasts Any*
multilineage dysplasia <1% blasts >15% ring sideroblasts (or >5%  Genetic abnormalities
(MDS-RS-MLD) No Auer rods RS with SFSB1 mutation present)
2-3 dysplastic lineages
MDS with excess blasts (MDS-EB)
MDS-EB-1 Cytopenia 1-3 5-9% blasts Any
2-4% blasts 0-3 dysplastic lineages
No Auer rods
MDS-EB-2 Cytopenia 1-3 10-19% blasts Any
5-19% blasts 0-3 dysplastic lineages
+/- Auer rods
MDS with isolated Cytopenia 1-3 <5% blasts Del (5q)
del(5q) <1% blasts 1-3 dysplastic lineage
No Auer rods
MDS, unclassifiable Variable Variable Any or MDS-defining abnormality
(MDS-U)
Refractory cytopenia of Cytopenia 1-3 <5% blasts Any (no known germline * Not fulfilling MDS with
childhood45
(provisional) <2% blasts 1-3 dysplastic lineages mutation)
isolated del(5q) criteria
Genetic profile
 Chromosomal abnormalities (frequent)
 MDS-defining abnormality
 Cytogenetic Scoring System: prognostic stratification

46
Risk scoring in MDS

 IPSS-R (International prognostic scoring  Lower risk Vs Higher risk MDS

system - revised)  Different treatment plan
 Cytogenetic (very good to very  Supportive for lower risk MDS
poor karyotype) or elderly
 % bone marrow blasts  More aggressive for higher risk
 Cytopenias: unilineage Vs (consider other co-morbids)
multilineage
47
Essential Haematology 8th Ed (p199 )
What’s new in 2022?
WHO classification (2022)

Peripheral blood Bone marrow Genetic abnormality

Classification of MDS
MDS with defining genetic abnormality
MDS with low blasts <2% blasts <5% blasts Del (5q)  Dysplasia
and isolated 5q
deletion (MDS-5q)  Single VS Multi-
MDS with low blasts
and SFSB1 mutation
<2% blasts <5% blasts SFSB1 mutation
Absence of 5q deletion,
lineage
(MDS-SFSB1) monosomy 7, or complex
karyotype  % of ring sideroblasts
MDS with biallelic <20% blasts <20% blasts TP53 mutations (erythroid dysplasia)
TP53 inactivation Usually complex
(MDS-biTP53) cytogenetics
 % of blasts
MDS, morphologically defined
MDS with low blasts <2% blasts <5% blasts Any*  Defining genetic
(MDS-LB)
abnormalities
MDS, hypoplastic <2% blasts <5% blasts Any*
*overlap with PNH & <25% BM cellularity
AA
MDS with increased 2-19% blasts 5-19% blasts Any*
blasts (MDS-IB)
• MDS-IB1 2-4% blasts 5-9% blasts
• MDS-IB2 5-19% blasts/Auer rods 10-19% blasts/Auer rods
• MDS with fibrosis 2-19% blasts 5-19% blasts
Childhood MDS (<18 years old)
Childhood MDS with <2% blasts <5% blasts Any*
low blasts
Childhood MDS with 2-19% blasts 5-19% blasts Any*
48
increased blasts
* Not fulfilling MDS with
defining genetic abnormality
 MDS (Diagnosis & Classification)
 Diagnosis Cytopenia Dysplasia Clonality BM blasts

 Cytopenia MDS + + + <20%

CCUS + - + <5%
 Consider:
 Other DDx ICUS + - - <5%
 Idiopathic cytopenias of undetermined
CHIP/ - - + <5%
significance (ICUS)
ARCH
 Dysplasia
 r/o non-neoplastic (reactive) causes
 Clonality (genetic
abnormalities)
 Presence of genetic mutation is
insufficient to establish a diagnosis of
MDS, especially for elderly (age >65)  Classification (2022)
 Consider:
 Clonal haematopoieis of indeterminate  % of blasts
potential (CHIP) or ageing-related clonal
haematopoiesis (ARCH)  Defining genetic
Clonal cytopenia of undetermined

significance (CCUS) abnormalities

49
Progression to AML (blasts > 20%)

50 JHO (2013)
Diagnostic overlap

Paroxysmal
nocturnal
haemoglobinuria

The term “Myelodysplastic Neoplasms” replace

“Myelodysplastic Syndrome” in WHO 2022

51
Aplastic anaemia (AA)
 Immune destruction of
haemopoietic stem cells
 Increase apoptosis
 Decrease proliferative
capacity
 Bone marrow failure
 Peripheral cytopenia
 Hypocellular bone marrow
(aplasia)

52 Lancet (2005)
Paroxysmal nocturnal haemoglobinuria
(PNH) or Myelodysplastic syndrome (MDS)
 Direct insult of
haemopoietic stem cells
 Increase apoptosis
 Clonal mutation and
expansion of abnormal
clone (ineffective
haemopoiesis)
 Myelodysplastic
syndrome
 Peripheral cytopenia
 Hypercellular bone
marrow

53 Lancet (2005)
AA/PNH/MDS
 Immune attack of
haemopoietic stem cells
 Increase apoptosis
 Clonal mutation and
expansion of abnormal
clone (ineffective
haemopoiesis)
 Myelodysplastic
syndrome
 Peripheral cytopenia
 Hypocellular bone marrow
(Hypoplastic MDS)

54 Lancet (2005)
Diagnostic overlap

Paroxysmal
nocturnal
haemoglobinuria

The term “Myelodysplastic Neoplasms” replace

“Myelodysplastic Syndrome” in WHO 2022

55
Paroxysmal Nocturnal Haemoglobinuria
 Rare
 Acquired clonal stem cell disorder
 Deficient synthesis of glycosylphosphatidylinositol (GPI)
anchor
 GPI attaches many surface proteins to the cell membrane
 Mutations in the phosphatidylinositol glycan protein class A
(PIG - A) on chromosome X
 Direct damage VS immune attack (~ AA and MDS)

56
GPI-linked proteins
 CD55 = DAF (decay
activating factor)
 CD59 = MIRL (membrane
inhibitor of reactive lysis)

Absence of CD55 and CD59 render red

cells sensitive to lysis by complement

57 Essential Haematology 8th Ed (p247 )

Pathogenesis of PNH

58 Am J of Blood Res (2015)

Clinical presentation
 Classic:
 Haemolytic anaemia (complement-mediated, chronic
intravascular haemolysis)
 Thrombosis
 Bone marrow failure
 PNH associated with other bone marrow disorders
(aplastic anaemia, myelodysplastic syndromes or others)
 May have haemolysis
 Subclinical
 May be a small clone in patients with AA or MDS
 No haemolysis

59
Case 1 (5/2015)
 Hb 10 g/dL 13.4-17.1 g/dL
 MCV 112 fL 82-97 fL
 WBC 4.9 x 109/L 3.7-9.2 x 109/L
 Plt 28 x 109/L 145-370 x 109/L

 Bone marrow: normocellular marrow

60
Case 1 (PNH screen, 6/2015)

PNH granulocyte & monocyte PNH Type 1/II/III red cells – 80%/6%/14%
clone – 64% and 60%
Notes: Type I = normal CD59 expression (i.e. normal red
61 cells)
Case 1 (12/2015)
 Hb 6.6 g/dL 13.4-17.1 g/dL
 MCV 87 fL 82-97 fL
 WBC 4.3 x 109/L 3.7-9.2 x 109/L
 Plt 12 x 109/L 145-370 x 109/L

 Evolving into Aplastic Anaemia with PNH clone

Repeat Trephine Biopsy:

- Adequate core of trephine biopsy
62
Case 1 (Repeat Bone Marrow,12/2015)

 Markedly hypocellular marrow

 Reduced trilineage haemopoiesis
 No dysplastic changes
 No increase in blasts

63
Case 1 (12/2015)
 Treatment
 Immunosuppressants
 Anti-thymocyte globulin (ATG)
 Cycloporin A
 Prednisolone
 Supportive transfusion
 Red cell
 Platelets

64
Case 2
F/26, presented with anaemic symptoms
On presentation Reference Interval

Hb 6.6 g/dL 11.7-14.9 g/dL

WBC 4.8 x 109/L 3.7-9.2 x 109/L
Plt 160 x 109/L 145-370 x 109/L

Bilirubin 44 umol/L 5-21 umol/L

LDH 4192 U/L <248 U/L
Haptoglobin <0.08 g/L 0.35-2.50 g/L

Iron 32 umol.L 7-26 umol/L

TIBC 65% 15-50%
Ferritin 48 ng/mL 7-283 ng/mL

65
Case 2
 Summary:
 F/26
 Evidence of haemolysis: anaemia, raised LDH and bilirubin, low
haptoglobin
 Direct antiglobulin test (DAT) negative
 Iron deficiency anaemia with no underlying causes found
 Urine for haemosiderin: positive

 Subsequently developed abdominal pain (3 episodes in

one year)

66
PNH Screen

PNH Type 1/II/III red cells – 70%/2%/28%

PNH granulocyte & monocyte
clone – 89% and 86% Notes: Type I = normal CD59 expression (i.e. normal
red cells)
67
Case 2
 Diagnosis:
 Classic paroxysmal nocturnal haemoglobinuria (PNH)
 Presented with haemolytic anaemia (PNH granulocyte clone
>50%)

 Treated with Eculizumab (humanized monoclonal

antibody against C5 that inhibits terminal complement
activation)

 Developed inferior vena cava and portal vein thrombosis

during pregnancy despite anticoagulation given,
emergency caesarean section at 28 weeks of gestation

68
Case 2 (Follow-up)
On presentation After use of Reference Interval
eculizumab

Hb 6.6 g/dL 9.9 g/L 11.7-14.9 g/dL

WBC 4.8 x 109/L 3.2 x 109/L 3.7-9.2 x 109/L
Plt 160 x 109/L 111 x 109/L 145-370 x 109/L

Bilirubin 44 umol/L 24 umol/L 5-21 umol/L

LDH 4192 U/L 281 U/L <248 U/L

Haptoglobin <0.08 g/L <0.04 g/L 0.35-2.50 g/L

Iron 32 umol.L 18 umol/L 7-26 umol/L

TIBC 65% 32% 15-50%
Ferritin 48 ng/mL 189 ng/mL 7-283 ng/mL
69
Diagnostic overlap
 Incidence in West
 PNH: 1 in million
 AA: 2 in million
 MDS: 10 to 50 in million

 AA and PNH are rare

Myelodysplastic
Paroxysmal Neoplasms (MDS) disease
nocturnal
haemoglobinuria  50% of AA has PNH clone
 20% Hypocellular MDS has
PNH clone
 AA can evolve into MDS

70
Summary
 Aplastic Anaemia
 Cytopenia + Hypoplastic bone marrow (production defect)
 Inherited VS Acquired causes
 Myelodysplastic Neoplasms
 Cytopenia + Hypercellular bone marrow with dysplastic changes
(ineffective haemopoiesis)
 Some: Cytopenia + Hypocellular bone marrow with dysplastic
changes [MDS, hypoplastic]
 Rare cases with overlapping myeloproliferative features [Essential
Haematology (8th Ed) p204]
 Paroxysmal Nocturnal Haemoglobinuria
 Classic (Haemolytic anaemia + Thrombosis + Bone marrow failure)
 PNH clones in association with AA, MDS or other myeloid disorders
(survival advantage or immune-related)
 Subclinical

71