Haematology

Front 1

types of haemoglobin

Back 1

zeta/epsilon - early embryonic period
alpha/gamma - fetal period, gamma is dominant (HbF = a2g2)
alpha/beta - perinatal period

Front 2

major Hbs in adults and children > 6mo

Back 2

HbA (a2b2)
HbA2 (a2d2)

Front 3

populations at risk for thalassaemia

Back 3

Mediterranean
Middle Eastern
African
Indian

Front 4

classification of thalassamia

Back 4

1. Beta or alpha
2. 3beta types: minor (heterozygous), major (homozygous), intermedia (homozygous)
3. Four alpha types: silent carrier (a-/aa), alpha-thal trait (a-/a-), HbH (--/a-), Hb Barts (--/--, hydrops fetalis with g4, b4, Hb Portland (zeta2gamma2))

Front 5

what is HbH

Back 5

--/a-
excess beta chain results in formation of HbH (beta4)
15-30% Hb Barts (gamma4) in neonatal period

Front 6

what is HbBarts

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--/--
> 75% Hb Barts = gamma4

Front 7

what is HbPortland

Back 7

zeta2gamma2, found in Hb Barts disease

Front 8

what pattern of inheritance is found in thalassaemia?

Back 8

Mendelian - recessive

Front 9

how many genes are there for beta and alpha globins respectively?

Back 9

beta - 2 genes, on chromosome 11
alpha - 4 genes, on chromosome 16

Front 10

what is the pathophysiology of beta thalassaemia?

Back 10

point mutations or deletions in one or two genes for beta globin production --> reduced or absent beta globin production

Front 11

beta thalassaemia minor (heterozygous for b0 or b+) - symptoms

Back 11

usually asymptomatic, usually incidental finding of mild anaemia
lethargy, fatigue, dyspnoea

Front 12

beta thalassaemia minor - signs

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often normal examination
pallor
splenomegaly

Front 13

beta thalassaemia minor - investigations

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FBC: reduced Hb
Film: mild microcytic hypochromic anaemia
occasional target cells
Elevated HbA2

Front 14

what are target cells?

Back 14

relative membrane excess
in thalassaemia, it's due to deficiency of haemoglobin

Front 15

IDA vs beta thalassaemia

Back 15

may co-exist
IDA may mask beta-thalassaemia, preventing Dx until it is corrected

Front 16

what is Cooley anaemia?

Back 16

beta thalassaemia major (homozygous)

Front 17

what are the two types of beta thalssaemia major?

Back 17

B0 = no beta globin chains
B+ = insufficient beta chains

Front 18

what is the pathophysiology of Cooley anaemia?

Back 18

excess alpha chains precipitate --> shortened red cell survival & destruction within BM and spleen

Front 19

when do children with beta thalassaemia major (Cooley anaemia) present?

Back 19

between 3 months and 1 year

Front 20

beta thalassaemia major - presentation

Back 20

pallor
hepatosplenomegaly
mild jaundice
later (4-5y): skin pigmentation, frontal bossing, malar prominence

Front 21

why does frontal bossing and malar prominence develop in beta thalassaemia major?

Back 21

expansion of bone marrow after ineffective erythropoeisis

Front 22

beta thalssaemia major - investigation findings

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Hb - very low
Film - microcytic, hypochromic RBCs, stippled RBCs, macrocytes, target cells, nucleated red cells
HbF (a2g2) - elevated
HbA2 - elevated

Front 23

how to differentiate between B+ and B0 thalassaemia

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globin chain synthesis studies

Front 24

long term sequelae of untreated beta thalassaemia major

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severe chronic anaemia --> growth retardation, increased iron resorption (skin pigmentation)
extramedullary haematopoesis --> hepatosplenomegaly, abdo distension
bone marrow expansion --> frontal bossing, maxillary hypertrophy, cortical thinning of lone bones + fractures

Front 25

why does increased skin pigmentation develop in severe beta thal major?

Back 25

increased iron resorption

Front 26

from which conditions does death usually occur in beta thal major?

Back 26

cardiac failure
arrythmias
infections
(iron has toxic effects on myocardium)

Front 27

management of beta thal major

Back 27

transfusions q3-4 weekly
can do a BM or umbilical cord blood transplant if there is an HLA-identical sibling donor. If performed prior to development of hepatomegaly or portal fibrosis, there is a >90% cure rate

Front 28

to which organs is iron toxic (and what are the consequences)

Back 28

myocardium - arrythmias, cardiac failure
pancreas - diabetes
liver - fibrosis
gonads - infertility

Front 29

how are iron chelators administered

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subcut infusion over 10 hours, usually overnight

Front 30

what is an iron chelator

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binds free iron, so it is excreted in urine

Front 31

what alternatives to chelation are available to reduce iron loading?

Back 31

erythrocytapheresis

Front 32

what supplements do patients with beta thal major require?

Back 32

folic acid

Front 33

what vaccinations are required for pts with beta thal major

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HBV
give vaccines prior to splenectomy against encapsulated organisms (Hib, S. pneumoniae, N. meningitides)

Front 34

HbE - spectrum of disease

Back 34

homozygous/heterozygous - asymptomatic
doubly heterozygous with beta-thal --> similar to thalassaemia major

Front 35

HbE - diagnosis

Back 35

FBC + film
Haemoglobin electrophoresis

Front 36

what are the two groups of haemoglobinopathies?

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1. thalassaemias - quantitative deficiency in globin chains
2. structural abnormalities of globins: HbS, HbC, HbE

Front 37

what is the underlying cause of HbS, HbC, HbE?

Back 37

point mutations & single AA substitutions in beta globin

Front 38

when does HbA become predominant over HbF?

Back 38

2-4 months age

Front 39

why are alpha thalassaemias manifest in the newborn, unlike beta thalassaemias?

Back 39

because alpha chains are required for both fetal (HbF) and adult (HbA, HbA2) haemoglobins

Front 40

when do beta thalassaemia and sickle cell disease begin to manifest?

Back 40

after 3-4 months age, when HbF has declined substantially

Front 41

where are the alpha-globin genes located?

Back 41

chromosome 16

Front 42

what is the difference in patterns of alpha-thalassaemia between Africans and Asians?

Back 42

Africans more likely to be silent carriers or have alpha-thal trait
Asians more likely to have the full spectrum of disease - implications for genetic counselling

Front 43

what are the types of alpha-thalassaemia

Back 43

one gene deletion --> silent carrier (0-3% Hb Barts, gamma4)
-/aa or -a/-a --> alpha-thal trait (2-10% HbBarts)
-/-a --> HbH disease (HbH = beta4) (15-20% HbBarts)
--.-- --> hydrops fetalis, >75% HbBarts

Front 44

aa/a- clinical manifestations + Ix

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asymptomatic, normal Hb, normal MCV
neonatal Hb electrophoresis: HbBarts 0-3%

Front 45

-a/aa or -a/-a clinical + lab manifestations

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Slight reduction in MCV and Hb level, mild hypochromia
2-10% Hb Barts on eletrophoresis in neonatal period

Front 46

--/-a clinical + lab manifestations

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this is Haemoglobin H disease. HbH = beta4 chains, with 15-20% Hb Barts present during neonatal period.
Mod-severe microcytic haemolytic anaemia
Hepatosplenomegaly
Bony abnormalities
Jaundice
High retics
Hypochromic, microcytic RBCs
Poikilocytosis
Basophilic stippling

Front 47

How is HbH identified on microscopy?

Back 47

brilliant cresyl blue stain --> shows inclusion bodies formed by denatured HbH

Front 48

--/-- clinical + lab manifestations

Back 48

hydrops fetalis
>75% Hb Barts on electrophoresis
absence of normal fetal or adult Hb
intrauterine anaemia, fetal demise or death after delivery
massive hepatosplenomegaly

Front 49

DDx of alpha-thal trait (two deletions)

Back 49

beta thal minor (will have abnormal Hb eletrophoresis, with insufficient HbA, whereas alpha-thal trait will have normal Hb eletrophoresis)
IDA (thalassaemias have normal or increased serum iron and ferritin)

Front 50

DDx of HbH disease (--/a-)

Back 50

most other haemolytic anaemias have normal MCV and normal colour
HbH will have microcytic, hypochromic red cells, plus all the other features of haemolysis (hepatosplenomegaly, jaundice, high retics, nucleated red cells etc.)

Front 51

DDx of hydrops fetalis

Back 51

other causes of hydrops due to anaemia, e.g. alloimmunisation

Front 52

Treatment of alpha thalassaemia

Back 52

alpha-thal trait (aa/a-): no Rx
HbH: folic acid, avoid oxidant drugs (as in G6PD). beware infections. consider splenectomy later.
Genetic counselling

Front 53

which thalassaemias can be detected on neonatal screening?

Back 53

only the alpha thalassaemias, because they affect HbF, and screening detects Hb Barts.

Front 54

where are the beta globin genes located?

Back 54

chromosome 11

Front 55

what are the types of beta globin genes?

Back 55

normal
B+ (produces insufficient beta globin)
B0 (produces no beta globin)

Front 56

beta thalassaemia intermedia - clinical manifestations

Back 56

more severe than thalassaemia minor
generally not trasnfusion dependent

Front 57

how is beta thalassaemia diagnosed?

Back 57

haemoglobin eletrophoresis after 6-12 mo age
Shows increased HbA2 and/or HbF
Homozygous B0-thalassaemia --> only HbA and HbA2 are present