haemoglobin

Question 1

2 categories of haemoglobinopathies

Answer 1

structural variants of Hb e.g. HbS; genetic disorders characterised by defects in globin chain synthesis (most common inherited single gene disorder; haem always constant but globin varies, so thalassaemia)

Question 2

distribution of thalassaemia and malaria

Answer 2

striking overlap between malaria and thalassaemia (in carrier states, offer protection vs malaria)

Question 3

how is thalassaemia classified

Answer 3

globin type affected, clinical severity

Question 4

3 classifications of clinical severity for thalassaemia

Answer 4

minor “trait”, intermedia (non-transfusion dependent), major (transfusion-dependent)

Question 5

chromosome defects for a- and B-thalassaemia

Answer 5

a-thalassaemia: chromosome 16 defect; B-thalassaemia: chromosome 11

Question 6

B thalassaemia: what is it

Answer 6

deletion or mutation in B globin gene(s), causing reduced or absent production of B globin chains

Question 7

B thalassaemia: inheritance and explanation for varying severity where b is normal production, b+ is reduced production (less severe mutation) and b0 is no production (more severe mutation)

Answer 7

autosomal recessive Mendelian as only 2 genes; degree of suppression of globin chain synthesis: b0b0 is severe, b+b0 is intermedia, bb0 and bb+ are trait, bb is normal

Question 8

thalassaemia: features of being a carrier

Answer 8

minor/trait, carry single abnormal copy of B globin gene, asymptomatic except for microcytic hypochromic indices and mild anaemia

Question 9

thalassaemia: 4 laboratory diagnosis techniques in order

Answer 9

FBC, film, Hb EPS/HPLC, globin chain synthesis/DNA studies

Question 10

thalassaemia laboratory diagnosis: FBC

Answer 10

microcytic hypochromic indices without iron deficiency, increased red blood cells relative to Hb

Question 11

thalassaemia laboratory diagnosis: film

Answer 11

target cells, poikilocytosis with no anisocytosis (varied shape but uniform size)

Question 12

thalassaemia laboratory diagnosis: Hb EPS/HPLC in a-thalassamia

Answer 12

normal HbA2 and HbF; if severe (loss of function of 3 or 4 genes) +/- HbH

Question 13

thalassaemia laboratory diagnosis: Hb EPS/HPLC in B-thalassamia

Answer 13

raised HbA2 and raised HbF

Question 14

thalassaemia laboratory diagnosis: globin chain synthesis/DNA studies

Answer 14

genetic analysis for B-thalassamia mutations and Xmnl polymorphism (B-thalassaemias), a-thalassaemia genotype (all cases)

Question 15

B thalassaemia trait blood film and HPLC

Answer 15

hypochromic, microcytic red cells, poikilocytic; HbA predominant, but raised HbF and HbA2

Question 16

B thalassaemia major: genetics

Answer 16

carry 2 abnormal copies of B globin gene

Question 17

B thalassaemia major: clinical presentation and time

Answer 17

severe anaemia, hepatosplenomegaly (due to extra-medullary haematopoiesis), erythroid hyperplasia in bone marrow (attempt to increase Hb production), incompatible with life without regular blood transfusions, presents usually after 4-6 months of life (HbF not present then)

Question 18

B thalassaemia major: blood film

Answer 18

gross hypochromia, poikilocytosis, many nucleated red blood cells

Question 19

red blood cell inclusions in B thalassaemia

Answer 19

precipitated Hb in some red cells; a chain precipitates, Pappenheimer bodies (iron deposits)

Question 20

7 clinical features of B thalassaemia

Answer 20

chronic fatigue, failure to thrive, jaundice, delay in growth and puberty, skeletal deformity, splenomegaly, iron overload

Question 21

4 other complications of B thalassaemia due to iron overload

Answer 21

cholelithiasis and biliary sepsis, cardiac failure, endocrinopathies, liver failure; all can result in death

Question 22

7 treatments of thalassaemia major

Answer 22

regular blood transfusions, iron chelation therapy, splenectomy, supportive medical care, hormone therapy, hydroxyurea to boost HbF, bone marrow transplant

Question 23

B thalassaemia major treatment: what is given in transfusions, how often, and what to do if high requirement

Answer 23

phenotyped red cells, regular (2-4 weekly); if high requirement, consider splenectomy

Question 24

B thalassaemia major: agents of infection, including if spleen removed

Answer 24

if spleen removed, risk from encapsulated bacteria and those that thrive on iron; Yersinia and other gram negative sepsis

Question 25

B thalassaemia major: splenectomised patient management of infection

Answer 25

prophylaxis with immunisation and antibiotics

Question 26

B thalassaemia major treatment: when does iron chelation therapy start, what must be done before starting, and purpose

Answer 26

start after 10-12 transfusions, or when high serum ferritin; audiology and opthalmology screening prior to start; prevents iron overload, either due to massive production of Hb, or increased iron reuptake in GIT

Question 27

B thalassaemia major treatment: main iron chelator issue and reason

Answer 27

non-compliance, as previously was subcutanenous injection so carried stigma

Question 28

B thalassaemia major treatment: 3 types of iron chelators

Answer 28

desferrioxamine (desferal; DFO), deferiprone (ferriprox), deferasirox (exjade)

Question 29

B thalassaemia major treatment: deferasirox as iron chelator - administration, dose and side effects

Answer 29

oral, 20-40mg/kg dose, side effects: rash, GI symptoms, hepatitis, renal impairment

Question 30

B thalassaemia major treatment: DFO as iron chelator - administration, dose and side effects

Answer 30

subcutaneous infusion 8-12 hours 5-7 days per week, 20-50mg/kg/day dose, side effects: vertebral dysplasia, pseudo-rickets, genu valgum, retinopathy, high tone sensorineural loss, increased risk of Klebsiella and Yersinia infection

Question 31

B thalassaemia major treatment: deferiprone as iron chelator - administration, dose, effect and side effects

Answer 31

oral, 5-100mg/kg/day dose, effective in reducing myocardial iron, side effects: GI disturbance, hepatic impairment, neutropenia (so susceptible to sudden infection), agranulocytosis, arthropathy

Question 32

B thalassaemia major treatment: iron chelator combination therapy advantage

Answer 32

any 2 iron chelator drugs can be used in combination, limiting toxicity and side effects as reduced dose of individual drug

Question 33

4 techniques for monitoring iron overload

Answer 33

serum ferritin, liver biopsy (rare - invasive and may not be representative), T2 cardiac and hepatic MRI, ferriscan (R2 MRI)

Question 34

monitoring iron overload: serum ferritin - level of significant complication increase, when to check

Answer 34

> 2500 associated with significantly increased complications, acute phase protein, check 3 months if transfused, otherwise annually

Question 35

monitoring iron overload: T2 cardiac and hepatic MRI - level of increased liver function impairment risk, when to check

Answer 35

<20ms is increased risk of impaired liver function, check annually or 3-6 months if cardiac dysfunction

Question 36

monitoring iron overload: ferriscan (R2 MRI) - advantages

Answer 36

non-invasive quantitation of liver iron concentration, not affected by inflammation or cirrhosis

Question 37

monitoring iron overload: ferriscan (R2 MRI) - level of normal and cardiac disease, and when to check

Answer 37

normal is <3mg/g, >15mg/g associated with cardiac disease, check annually or 6 monthly if result >20

Question 38

sickle B thalassaemia

Answer 38

slide 53

Question 39

HbE B thalassaemia

Answer 39

clinically variable expression, and can be as severe as B thalassaemia major

Question 40

a thalassaemia: what is it

Answer 40

deletion or mutation in a globin gene(s), causing reduced or absent production of a globin chains

Question 41

a thalassaemia: who does it affect

Answer 41

foetus and adult

Question 42

a thalassaemia: what do excess B chains form

Answer 42

tetramers of HbH

Question 43

a thalassaemia: what do excess y chains form

Answer 43

tetramers of Hb Barts

Question 44

a thalassaemia: what does severity depend on

Answer 44

number of a globin genes affected

Question 45

HbH disease - blood film

Answer 45

loss of function of 3 a-globin genes, so more poikilocytosis but still relatively well haemoglobinised

Question 46

HbH disease - HPLC

Answer 46

still producing HbA, but abnormal peaks made up of B-globin chains (e.g. Hb Barts)

Question 47

5 problems associated with treating thalassaemia in developing countries

Answer 47

lack of awareness of problems, lack of experience of health care providers, availability of blood, cost and compliance with iron chelation therapy, availability and very high cost of bone marrow transplant

Question 48

6 techniques for screening and prevention of thalassaemia

Answer 48

counselling and health education for thalassaemics, family members and general public; extended family screening; pre-marital screening; discourage marriage between relatives; antenatal testing; pre-natal diagnosis (CVS)