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Year 2 - MCD - Haematology > Haemoglobin molecules and thalassemia > Flashcards

Haemoglobin molecules and thalassemia Flashcards

1
Q

Where are haem and globin synthesised?

A

Haem: synthesised in mitochondria
Globin: synthesised in ribosomes

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2
Q

Facts about RBCs

A
  • Carry oxygen from lungs to tissues
  • Transfer CO2 from tissues to lungs
  • 3.5-5 x 1012 /L
  • Contain haemoglobin (Hb)
  • Each RBC contains approx. 640 million molecules of Hb
  • Mature RBCs do not have nucleus or mitochondria
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3
Q

Facts about Hb

A
  • Found exclusively in RBCs
  • MW 64-64.5 kDa
  • Normal concentration in adults:120-165g/L
  • Approximately 90 mg/kg produced and destroyed in the body every day
  • Each gram of Hb contains 3.4mg Fe
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4
Q

Why is Hb packaged and not free in the blood?

A
  • It is toxic by itself
  • oxidative properties
  • in certain diseases with heamolysis the Hb can cause damage.
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5
Q

When in the cell stage is Hb synthesised?

A

Synthesis occurs during development of RBC and begins in pro-erythroblast:
65% erythroblast stage
35% reticulocyte stage

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6
Q

What is HbA made up of?

A

2 alpha and 2 beta chains with a Haem group containing iron in the centre.

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7
Q

Where can the haem component be found?

A
  • Also contained in other proteins e.g. myoglobin, cytochromes, peroxidases, catalases, tryptophan
  • Same in all types of Hb
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8
Q

Structure of Haem

A
  • Combination of protoporphyrin ring with central iron atom (ferroprotoporphyrin)
  • Iron usually in ferrous form (Fe2+)
  • able to combine reversibly with oxygen
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9
Q

In what form is iron found in haem?

A
  • usually in ferrous form (Fe2+)
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10
Q

Regulation of haem synthesis

A
  • haem exerts negative feedback on delta-ALA

- this is a regulatory step in the production of haem

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11
Q

Synthesis of globin

A
  • Various types which combine with haem to form different haemoglobin molecules
  • Eight functional globin chains, arranged in two clusters:
    • b- cluster (b, g, d and e globin genes) on the short arm of chromosome 11
    • a- cluster (a and z globin genes) on the short arm of chromosome 16
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12
Q

Complete inability to produce alpha globes - consequences?

A

usually results in embryonic death.

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13
Q

Globin gene clusters

A
  • alpha gene cluster in chromosome 16 is composed of zeta gene as well as a1 and a2
  • zeta genes are involved in the embryonic stage of development
  • beta globin cluster on chromosome 11 - beta, delta and gamma.
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14
Q

When do pathologies in the beta globin chains present?

A
  • usually after brith
  • later than alpha
  • there is a switch from HbF to Hba
  • thalassemia (beta) usually presents at about 3 months
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15
Q

Normal adult Hb fractions

A

HbA: 96-98%
HbA2: 1.5 - 3.2 %
HbF:- 0.5 - 0.8%

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16
Q

Globin structure

A
  • primary: alpha 141 AA; non alpha 146 AA;
  • secondary:75% α and b chains-helical arrangement
  • tertiary: Approximate sphere,
    Hydrophilic surface (charged polar side chains); hydrophobic core; Haem pocket;
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17
Q

2,3 DPG

A
  • causes oxygen unbinding, favours O2 disscociation

- 2,3 diphosphoglycerate

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18
Q

Oxygen-Hb dissociation curve

A
  • O2 carrying capacity of Hb at different pO2
  • Sigmoid shape:
  • Binding of one molecule facilitate the second molecule binding (cooperativity)
  • P 50 (partial pressure of O2 at which Hb is half saturated with O2) 26.6mmHg
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19
Q

p50

A

(partial pressure of O2 at which Hb is half saturated with O2) 26.6mmHg

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20
Q

cooperative binding

A
  • Binding of one molecule facilitate the second molecule binding (cooperative binding)
  • due to changes in the structure of the molecule
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21
Q

What shift the ODC to the left?

A
  • high pH
  • HbF
  • low 2,3 DPG

=> give up oxygen less readily

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22
Q

What shifts the ODC to the right?

A
  • low pH
  • HbS
  • high 2,3 DPG
  • high CO2

=> easy O2 delivery

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23
Q

What does the normal position of the Hb-O2 dissociation curve depend on?

A
  • Concentration of 2,3-DPG
  • H+ ion concentration (pH)
  • CO2 in red blood cells
  • Structure of Hb
24
Q

Haemoglobinopathies

A
  • Structural variants of haemoglobin
    or
  • Defects in globin chain synthesis (thalassaemia)
25
Q

Thalassemias

A
  • Genetic disorders characterized by a defect of globin chain synthesis
  • Most common inherited single gene disorder worldwide
26
Q

What disease is Thalassemia linked to in a way?

A
  • It is common in areas with malaria.

- Haemoglobinopathies offer protection against Malaria

27
Q

How can you classify thalassemia?

A
  • Globin type affected (e.g. Beta-thalassemia)
  • Clinical severity
    • minor / “trait” (usually asymptomatic but able to pass on offspring)
    • intermediate (wide spectrum)
    • major (cannot survive without regular transfusions)
28
Q

Beta thalassemia - what is the defect?

A
  • Deletion or mutation in b globin gene(s)

- Reduced or absent production of b globin chains

29
Q

Where is beta thalassemia prevalent?

A

mainly Mediterranean countries (Greece, Cyprus, Southern Italy), Arabian peninsula, Iran, Indian subcontinent, Africa, Southern China, South-East Asia

30
Q

Inheritance of thalassemia

A
  • recessive
  • autosomal
  • mutations vary in phenotype and severity

=> classic mendelian

31
Q

Lab diagnosis of Thalassemia

A
  • FBC - Full blood count abnormalities -> Microcytic Hypochromic indices, Increased RBCs relative to Hb
  • Film: target cells, poikilocytosis but no anisocytosis -> size uniform but different shapes + morphologies
  • Hb Electrophoresis / HPLC -> a-thalassemia normal HbA2 and HbF +/- HbH; beta thalassemia: raised HbA2 and raised HbF
  • globin chain synthesis / DNA studies
32
Q

Thalassemia Major

A
  • Carry 2 abnormal copies of the beta globin gene
  • Severe anaemia, incompatible with life without regular blood transfusions
  • Clinical presentation usually after 4-6 months of life
    = transfusion dependant Thalassemia
33
Q

What does a blood film in beta thalassemia major look like?

A

The peripheral blood film will show extreme hypochromia, microcytosis and poikilocytosis.
Often Howell Jolly bodies and nucleated RBC’s will be present as a result of splenectophy and a hyperplastic bone marrow.

In Beta thalassaemia major two forms of inclusion bodies may be seen, Alpha globin precipitates and pappenheimer bodies. .

34
Q

Clinical presentation of thalassemia major

A
  • Severe anaemia usually presenting after 4 months
  • Hepatosplenomegaly - due to extramedullary haematopoiesis (in the liver and the spleen, these organs go back to producing RBCs)
  • Blood film shows gross hypochromia, poikilocytosis and many NRBCs
  • Bone marrow - erythroid hyperplasia
  • Extra-medullary haematopoiesis
35
Q

Symptoms and signs of thalassemia major

A
  • Chronic fatigue
  • Failure to thrive
  • Jaundice
  • Delay in growth and puberty
  • Skeletal deformity
  • Splenomegaly
  • Iron overload
36
Q

Other complications of thalassemi major

A
  • Cholelithiasis and biliary sepsis
  • Cardiac failure
  • Endocrinopathies
  • Liver failure

=> these are associated with iron overload.

37
Q

What are the major causes of death in thalassemia patients?

A
  • cardiac disease (most common)
  • infections (2nd most common)
  • liver disease
  • other causes
38
Q

Treatment of Thalassemia major

A
  • Regular blood transfusions
  • Iron chelation therapy
  • Splenectomy (in splenectomy and if transfusion requirement is high but also has complications such as thromboembolisms)
  • Supportive medical care
  • Hormone therapy
  • Hydroxyurea to boost HbF
  • Bone marrow transplant
39
Q

Transfusions in beta-thalassemia

A
  • Phenotyped red cells
  • Aim for pre-transfusion Hb 95-100g/L
  • If high requirement, consider splenectomy
  • start ASAP
  • 2-4x/week
40
Q

How often are transfusions given in beta thalassemia?

A
  • Regular transfusion 2-4 weekly
41
Q

Iron Chelation therapy

A
  • Start after 10-2 transfusions or when serum ferritin >1000 mcg/l
  • Audiology and ophthalmology screening prior to starting
  • increased survival!!
42
Q

What are problems with compliance to chelation theerapy?

A
  • s.c.
  • regular (infusion over 12h)
  • interferes with social life

-> now oral options available

43
Q

What are the 3 common iron chelation drugs?

A
  • DFO (s.c., i.v.)
  • deferiprone (oral, 3x/d)
  • deferasirox (oral, 1x/d)
44
Q

Deferasirox (Exjade)

A
  • Oral
  • Dose 20-40mg/kg
  • SE: rash, GI symptoms, hepatitis, renal impairment
  • iron chelation
45
Q

Desferrioxamine (Desferal)

A
  • Long-established
  • s.c. infusion 8-12 hours 5-7 days per week (or I.V. in cardiac iron overload)
  • Dose 20-50 mg/kg/day
  • SE: vertebral dysplasia, pseudo-rickets, genu valgum, retinopathy, high tone sensorineural loss, increased risk of Klebsiella and Yersinia infection
  • Compliance
  • Vitamin C
  • iron chelation
46
Q

Deferiprone (Ferriprox)

A
  • Licensed 1999
  • Oral
  • Dose 5-100 mg/kg/day
  • Effective in reducing myocardial iron
  • SE: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy
  • increased susceptibility to developing infection -> weekly blood counts recommended whilst on therapy
  • also side effects: zinc deficeincy? rewatch
47
Q

Deferiprone (Ferriprox)

A
  • Licensed 1999
  • Oral
  • Dose 5-100 mg/kg/day
  • Effective in reducing myocardial iron
  • SE: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy
  • increased susceptibility to developing infection -> weekly blood counts recommended whilst on therapy
  • also side effects: zinc deficeincy, and atropathy?
48
Q

Combined therapy (chelation)

A
  • any 2 of these drugs can be used in combination
  • different combinations are used in clinical practice
  • advantage: you can limit the toxicity of the drugs by limiting the dose of the drugs in the combination
49
Q

Comparison

A

see PP slide!

50
Q

Monitoring iron overload

A
  • Serum ferritin
    >2500 associated with significantly increased complications
    Acute phase protein
    Check 3 monthy if transfused otherwise annually
  • Liver biopsy
    Rarely performed
  • T2* cardiac and hepatic MRI
    <20ms – increased risk of impaired LF function
    Check annually or 3-6monthly if cardiac dysfunction
- Ferriscan – R2 MRI
Non-invasive quantitation of LIC
Not affected by inflammation or cirrhosis
<3mg/g normal
>15mg/g associated with cardic disease
Check annually or 6monthly if result >20
51
Q

Synthesis on Hb

A
  • diagram on PP!
  • Transferrin enters the cell -> Fe goes to Ferritin or enters the mitochondrion
  • transferrin enters the circulation again
  • Fe is used to make haem
  • Aminoacids -> Ribosomes form a2b2 chains
  • a2b2 chains combine with haem to make Hb
52
Q

What infections are common in beta thalassemia?

A
  • yersinia
  • other gram-ve sepsis
  • prophylaxis in splenoctomised patients - immunisation and antibiotics
  • some of these organisms thrive on iron which makes thalassemia patients susceptible due to the iron rich environment
53
Q

Alpha Thalassemia

A
  • Deletion or mutation in a globin gene(s)
  • Reduced or absent production of a globin chains
  • Affects both foetus and adult
  • Excess beta and gamma chains form tetramers of HbH and Hb Barts respectively
  • Severity depends on number of alpha globin genes affected
54
Q

Thalassemia carrier

A
  • Also known as Thalassaemia minor / trait
  • Carry a single abnormal copy of the beta globin gene
  • Usually asymptomatic
  • Mild anaemia
55
Q

HbH disease

A
  • has a haemolytic element to it with microcytosis, anisoocytosis poikilocytosis and “puddling” of haemoglobin within the RBC.
56
Q

Problems Associated with Treatment in Developing Countries

A
  • Lack of awareness of the problems
  • Lack of experience of health care providers
  • Availability of blood
  • Cost and compliance with iron chelation therapy
  • Availability of and very high cost of bone marrow transplant
57
Q

Screening and prevention of thalassemia

A
  • 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)

Year 2 - MCD - Haematology (11 decks)

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