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Haematology > the Hb molecule and thalassaemia > Flashcards

the Hb molecule and thalassaemia Flashcards

1
Q

what is the number of red cells in an average sized human

A

3.5-5 x10(power 12)

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2
Q

how many moleules of Hb does each red cell contain *

A

640 million molecules

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3
Q

what is the normal conc of Hb in blood

A

110 - 165g/L

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4
Q

what is the rate of production of Hb *

A

90mg/kg produced and destroyed in the body every day

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5
Q

where is Hb found and why *

A

exclusively in RBC

toxic if free - potent oxidative properties

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6
Q

how much iron is in a g of Hb

A

3.4mg

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7
Q

when does synthesis of Hb occur *

A

development of erythroblast

65% in erythroblast stage

35% in reticulocyte stage

all before RBC enter blood - lost nucleus and ribosomes so couldnt make any more

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8
Q

what is the structure of normal adult HB *

A

2 a and 2 B chains

heme molecule associated with Fe atom at centre

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9
Q

describe the synthesis of Haem *

A

in mt

Fe introduced to cell bound to transferrin - endocytosed - transported to mt

under regulatory control of δ-Aminolevulinic acid (δ-ALA) - excess haem = -ve feedback to ALA

proto-porphyrin is formed by pathway involving ALA and added to haem

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10
Q

describe the structure of haem *

A

also in other proteins eg myoglobin, cytochromes, peroxidases, catalases, tryptophan

same in all types of Hb

combination of protoporpyrin ring with central Fe atom (ferroprotoporphyrin)

iron in ferrous form (Fe2+) - able to bind reversibly to O2

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11
Q

summarise the synstesis of globin *

A

various types of globin

8 functional globin genes arranged in 2 clusters:

a cluster on chromosome 16: a and zeta cain synth

B cluster on chromosome 11: B Y d and E globin genes

zeta gene involved in making Hb in embryo

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12
Q

describe the production of globin chains from a cluster through development *

A

zeta first to be made - stop in early embryo eg 7wks

a takes over - predominant chain from a cluster - if defect in production of a chain = loss of embryo early

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13
Q

describe the production of globin chains from B cluster in development *

A

gamma - most important from b cluster - foetal Hb have 2 a and 2 gamma

still make foetal Hb for firts 3-6 months of life - then B chain takes over

if defect oin B chain production - not seen until 3 months

still gave a small amount of HbF in adults

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14
Q

what are the normal adult Hb *

A

table

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15
Q

how can you identify the normal adult Hb *

A

high performance liquid chromatography

separates hb on electophoretic charge and molecular mass

get different peaks - from L to R - foetal, HbA, HbA2

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16
Q

describe the structure of globin *

A

priamry structure - a has 141 AA, non-a has 146 AA
secondary - 75% a and B chains in a helical arrangement

tertiary - approx sphere, hydrophilic surface (charged polar side chains), hydrophobic core, haem pocket (when 4 chains assemble - area where haem compartment sits

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17
Q

describe the structures of oxy and deoxyhaemoglobin *

A

oxy - allow ox to bind

deox - globin chain has diff config = oxygen dissociation

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18
Q

what does the oxygen dissociation curve show and why is it a sigmoid shape *

A

Ox carrying capacity of Hb at different ppO2

sigmoid - because of coopertaive binding

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19
Q

what is p50 *

A

pp of O2 at whic Hb is half saturated with O2

for HbA this is at 26.6mmHg

it is an estimate of different Hb affinity for O2

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20
Q

what causes the ox dissociation curve to shift L *

A

decrease in 2,3-DPG and H+ conc

foetal Hb

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21
Q

what is the effect of the ox dissociation curve shifting L *

A

ox bind more readily, and released less

eg so HbF can get O2 from placenta - higher affinty than maternal Hb

22
Q

what shifts O2 dissociation curve to R *

A

elevated 2, 3 DPG (in metbolising cell), and H+ conc, CO2 conc

sickle Hb

23
Q

what is the effect of ox dissociation curve shifted to R *

A

favour deoxyfied state - and dissociation

give up O2 more readily

lower affinity

24
Q

what are the 2 generic causes of haemoglobinopathies *

A

structural varients of Hb - abnormal varients are being produced because of mutation eg HbS

genetic defects in globin chain synth - reduced production of a/B chains

25
Q

thalassaemia epi

A

overlap with endemic malaria - protective

widespread distribution where there is a dense population - mainly mediterranian, arabian peninsula, iran, indian subcontinent, africa, southern china, SE Asia

26
Q

how do you classify thalassamia *

A

by the globin chain affected - a and B

clinical severity: minor ‘trait’ - carrier, intermedia (non-transfusion dependant), major (transfusion dependant)

27
Q

describe the pathophysiology of thalassamia *

A

deletion/mutation in B globin genes = reduced or absent B chains

autosomal recessive - see pedigree

can have differnet mutations BB(superscript o), more severe than BB+

B+ can make some chains - just reduced

28
Q

how do you diagnose b thalassaemia *

A

full blood count - microcytic hypochromic, increased RBC relative to Hb

blood film - target cells, poikilocytosis, no anisocytosis

Hb EPS/HPLC - a = normal bA2 and HbF ( +/- HbH when have damage to 3 out of 4 a genes)

B = raised HbA2 and HbF

globin chain synth/DNA studies - genetic analysis for B thalassaemia mutations and Xmnl polymorphism, look for common mutations or whole genes, (in B thal when not sure about mutation/diagnosis/clinical effect) and a thalassamia genotype in all cases

29
Q

blood film for B thalassamia trait *

A
30
Q

describe B-thalassaemia major *

A

carry 2 abnormal copies of B globin gene = loss of production of B globin

severe anaemia, transfusion dependant

clinical presentation in 3-6 months

31
Q

blood film for B thal major *

A

more anaemic - red cells sparse

more variation in shape

hypocromic

32
Q

describe the red cell occlusions in B thalassaemia *

A

nucleated red cells

a chain precipitates - difficult to pick up

pappenhiemer bodies from iron deposits

33
Q

what is the clinical presentation of thalassaemia major *

A

severe anaemia after 4 months

hepatosplenomegaly - extramedullary haematopoeisis to produce red cells

film - hypochromia, poikiloctosis, and nucleated RBCs

bone marrow - erythroid hyperplasia

34
Q

what are the clincial features of B thalassaemia *

A

chronic fatigue

failure to thrive

jaundice - due to chronic haemolysis a chains are unstable, more likely to go through haemolysis

delay in growth and puberty

skeletal deformity

splenomegaly

iron overload

extra-medullary haematopoiesis leading to expansion of frontal and maxillary bones

35
Q

what are complications of B thalassaemia *

A

cholelithiasis (gall stone disease) and bilary sepsis because of chronic haemolysis = increased serum BR

cardiac failure, endocrinopathies, liver failure due to Fe overload - iron deposits here

cardiac disease = main cause of death

36
Q

treatment of thalassaemia major *

A

regular blood transfusions

iron celation therapy - because of iron overload caused by transfusions/increased gut absorption (in thal minor) and downregulation of hepsidin

splenectomy when have hhig transfusion requirements - risk of tromboembolic dusease or risk of clotting

hormone therpay to treat the endocrinopathies

hydroxyurea to boost HbF

bone marrow transplant - curative

37
Q

describe transfusions for thalassamia *

A

phenotyped red cells

aim for pre-transfusion Hb 95-100g/L - reduce risl of extramedullary haematopoiesis

regular transfusion 2-4 weekly

match donor cells to blood gp - reduce risk of alloantibodies/ alloimmunisation

38
Q

describe management of infection in thalassaemia *

A

infectiuon from encapsulated bacteria - yersinia, other gram -ve sepsis (thrive in Fe rich env)

propylaxis in splenectomised pts - immunisation and Ab

39
Q

describe iron chelation therapy

A

start after 10-12? transfusions or wen serum ferritin >1000mcg/L

audiology/opthalmology screening prior to starting

improved survival - reduce cardiac failure

however poor compliance because SC for 12 hours - burden with social life/stigma

40
Q

describe deferasirox for iron chelation *

A

newer than desferrioxamine

oral once daily

dose 20-40mg/kg

SE - rash, GI symptoms, hepatitis, renal impairment

half life 12-16hrs

excretion - feacal

adv - oral = better compliance, control of body iron, specific

disadv - short clinical experience (new drug), cardiac protection uncertain, toxicity limited but long term

41
Q

describe desferrioxamine for iron chelation *

A

long established

SC for 8-12 hrs, 5-7 days a week

dose - 20-50mg/kg a day

SE - vertebral dysplasia, pseudo-rickets, genu valgum, retinopathy, high tone, sensorineural loss, increased risk of klebsiella and yersinna infection

compliance is a prolem

half life is 20-30 mins

adv - long clinical experience, survival benefit, HF prevented and reversed

disadv - SC, dose dependant toxicity of ocular, auditory and skeletal

exretion - urinary or feacal

advantage -

42
Q

describe deferiprone for iron chelation *

A

oral

5-100mg/kg/day

effective in reducing myocardial iron

SE - GI disturbance, hepatic impairment, neutropenia, agranulocytosis (sudden drop in white cell count - risk of infection), athropathy (Zn deficiency)

adv - oral, cardiac protection

disadv - 3x a day, short plasma t1/2, unpredictable control of body iron, toxicity - agranulocytosis, arthropathy, zinc deficiency

43
Q

describe the process of administering chelation therapy *

A

combination therapy - limit toxicity of any one drug because you can use a lower dose of it

44
Q

how do you monitor iron overload

A
45
Q

describe HbE thalassaemia *

A

common in SE asia

clinical variable - can be as severe as B thal major

46
Q

describe a thalassaemia *

A

deletion/mutation in a globin chains = reduced/absent production

affects foetus/adult

express B and Y chains - form tetramers of HbH and Hb Barts resepctively

severity depends on number of a genes affected

47
Q

describe thalassaemia B minor/trait *

A

carry single abnormal copy of B globin gene

usually asymptomatic

mild anaemia

48
Q

describe HbH disease *

A

it is a form of thalassaemia intermedia with the loss of function of 3a chains - therefore is alpha thalassaemia

there is more poikocytosis than in thalassaemia trait

red cells well haemoglobinised

on the HPLC - a chains are still being produced, there are 2 abnormal peaks at the start of the spectrum: made of complexes of B globin chains HbH and Hb Barts (Hb that consists of 4 gamma Hb) - fast moving hb

49
Q

describe problems of treating thalassaemia in developing countries *

A

lack of awareness

lack of experience

lack of blood for transfusions

cost and compliance to iron chelation

lack of availability of marrow transplant

cost of marrow transplant

50
Q

describe screening and prevention for thalassaemia *

A

counselling

xtended family screening

pre-marital screening

discourage marriage between relatives

antenatal testing

pre-natal diagnosis - CVS

51
Q

if both parents are carriers of thalassamia major - what is the chance of child having thalassaemia major *

A

25%

52
Q

what are the axis for an O dissocialtion curve *

A

y - hb saturation

x- pp of o2

Haematology (11 decks)

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