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MCD - haematology > The haemoglobin molecule and thalassaemia > Flashcards

The haemoglobin molecule and thalassaemia Flashcards

1
Q

What are the two gross components of haemoglobin and where are they synthesised?

A

haem - mitochondria

globin - ribosomes

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2
Q

Schematic of synthesis of haemoglobin.

A

(not in sofia)

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3
Q

Outline the structure of haem

A

Combination of protoporphyrin ring with central iron atom.

Iron usually ferrous (Fe2+) - binds reversibly with oxygen.

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4
Q

Which enzyme in mitochondria is responsible for haem synthesis?

A

ALAS.

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5
Q

How many functional globin chains are there?

A

8

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6
Q

How are globin chains arranged? Where are these located? Which functional globin chains does each contain?

A

Clusters.

b- cluster (b, g, d and e globin genes) on the short arm of chromosome 11

a- cluster (a (a1 and a2) and z globin genes) on the short arm of chromosome 16

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7
Q

How are different globin chains expressed over the course of life?

A

zeta and eta expressed very early, drop to zero after 6 weeks.

alpha and gamma rise as zeta and eta fall and then predominate during foetal development.

gamma drops as birth approaches and drops to zero by 42 weeks (post natal)

beta rises and as gamma drops.

alpa and beta predominate throughout adult life.

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8
Q

Where is globin synthesised over the course of life.

A

Yolk sac –> liver and spleen (liver predominates) –> bone marrow for adult life.

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9
Q

What are the normal adult haemoglobin phenotypes? Which chains do they contain? How common are they?

A

Hb A - a2b2. 96-98%

HbA2 - a2d2. 1.5-3.2%

Hb F - a2g2. 0.5-0.8%

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10
Q

Explain the primary, secondary and tertiary structure of globin.

A

Primary - 141AA for alpha. 146AA for non alpha.

Secondary - 75% alpha and beta chains in helical arrangement.

Tertiary - approximate sphere, hydrophilic surface, hydrophobic core, haem pocket.

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11
Q

What effect does 2,3-DPG have on oxygen binding?

A

Favours oxygen disassociation - haem less able to access oxygen

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12
Q

explain the sigmoid shape of the oxygen dissociaiton curve.

A

Cooperative binding - binding of one molecule facilitates the second molecule binding.

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13
Q

How is P50 defined and what is its value?

A

PP of O2 at which half of Hb is saturated with O2 - 22.6mmHg

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14
Q

Oxygen dissociation curve.

What shifts do changes in pH, 2,3-DPG, HbF, HbS cause?

A
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15
Q

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

A
  • Concentration of 2,3-DPG
  • H+ion concentration (pH)
  • CO2in red blood cells
  • Structure of Hb
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16
Q

How might you shift the Hb dissociation curve to the left or right?

A

Right -

  • High 2,3-DPG
  • High H+
  • High CO2
  • HbS

Left -

  • Low 2,3-DPG
  • HbF
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17
Q

What causes haemoglobinopathies?

A

Structural variants of haemoglobin,

defects in globin chain synthesis.

18
Q

How is thalassaemia classified?

A

According to the globin type affected and the clinical severity -

minor trait

intermedia

major

19
Q

How does beta thalassaemia arise?

A

Deletion of mutation in beta globin gene.

Reduced/absent production of beta globin chains

20
Q

How is beta thalassaemia inherited?

A

recessive mendelian.

21
Q

How can thalassaemia be diagnosed?

A

Abnormalities in FBC - Microcytic Hypochromic indices and Increased RBCs relative to Hb

Blood film - target cells present, poikilocytosis (high RBC variation) but no anisocytosis (little variation in size)

Hb electrophysiology study/HPLC -

alpha thalassaemia - normal HbA2 and HbF, variable HbH

beta thalassaemia - raised HbA2, raised HbF.

Globin chaun synthesis/DNA studies -

beta thalassaemia - genetic analysis for B thalassaemia mutations and Xmnl polymorphism

alpha thalassaemia - genetic analysis for alpa thalassaemia genotype.

22
Q

What causes thalassaemia major?

A

•Carry 2 abnormal copies of the beta globin gene

23
Q

What are the consequences of thalassaemia major? When does it present clinically?

A
  • Severe anaemia, incompatible with life without regular blood transfusions
  • Clinical presentation usually after 4-6 months of life
24
Q

What characteristics might RBCs in a beta thalassaemia patient have?

A

alpha chain precipitates.

Pappenheimer bodies.

25
Q

Outline the clinical presentation of thalassaemia major.

A
  • Severe anaemiausually presenting after 4 months
  • Hepatosplenomegaly
  • Blood film shows gross hypochromia, poikilocytosis and many NRBCs
  • Bone marrow - erythroid hyperplasia
  • Extra-medullary haematopoiesis
26
Q

Outline some clinical features of beta thalassaemia major.

A
  • Chronic fatigue
  • Failure to thrive
  • Jaundice
  • Delay in growth and puberty
  • Skeletal deformity
  • Splenomegaly
  • Iron overload
27
Q

What complications can arise from beta thalassaemia major?

A
  • Cholelithiasis and biliary sepsis
  • Cardiac failure
  • Endocrinopathies
  • Liver failure
28
Q

What are the major causes of death in beta thalassaemia patients?

A

–Cardiac disease - due to iron overload 71%

–Infections 12%

–Liver disease 6%

–Other causes 11%

(out of 240 thalassaemia major patients born in italy between 1960 and 1984)

29
Q

How is beta thalassaemia major treated?

A
  • Regular blood transfusions
  • Iron chelation therapy
  • Splenectomy
  • Supportive medical care
  • Hormone therapy
  • Hydroxyurea to boost HbF
  • Bone marrow transplant
30
Q

How frequently are transfusions given? If transfusion requirement is high what treatment option is considered?

A

2-4 weekly.

Splenectomy.

31
Q

How is infection risk managed?

e.g. for Yersinia and other gram- species.

A

prophylaxis in splenectomised patients - immunisation and antibiotics.

32
Q

When is iron chelation therapy given?

A

Started after 10-12 transfusions of when serum ferritin >1000mcg/l.

Audiology and opthalmology screening prior to starting.

33
Q

Table comparing iron chelators.

A
34
Q

How is deferasirox administered? How large is its dose?

What are its side effects?

A

–Oral

–Dose 20-40mg/kg

–SE: rash, GI symptoms, hepatitis, renal impairment

35
Q

How is desferrioxamine administered? How large is the dose given? What are the side effects?

A

–Sc infusion 8-12 hours 5-7 days per week (or IV 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

36
Q

How is deferiprone administered? How large is the dose? What are the side effects?

A

–Oral

–Dose 5-100 mg/kg/day

–Effective in reducing myocardial iron

–SE: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy

37
Q

Table comparing iron chelators.

A
38
Q

How is iron overload monitored?

A

•Serum ferritin

–>2500 associated with significantly increased complications

–Acute phase protein

–Check 3 monthyif transfused otherwise annually

  • Liver biopsy (rarely)
  • 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 cardicdisease

–Check annually or 6monthly if result >20

39
Q

What are the features of alpa thalassaemia?

A
  • Deletion or mutation in aglobin gene(s)
  • Reduced or absent production of aglobin chains
  • Affects both foetusand adult
  • Excess bandgchains form tetramers of HbHand Hb Bartsrespectively
  • Severity depends on number of aglobin genes affected
40
Q

How is alpa thalassaemia classified?

A

Alpha+

Alpha0

HbH

Hb Barts

as more alpha chains are lost.

41
Q
A

MCD - haematology (6 decks)

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