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Year 2 - MCD Haem > Hb Molecule & Thalassaemia > Flashcards

Hb Molecule & Thalassaemia Flashcards

1
Q

Normal [Hb]?

A

120-165g/L

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2
Q

When does the synthesis of Hb begin?

A

During development of RBC
o begins in pro-erythroblast

65% erythroblast stage
35% reticulocyte stage

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3
Q

What makes up Hb?

A

Haem - synthesised in mitochondria (transferrin/iron is the core)

Globin - synthesised in ribosomes

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4
Q

What happens if excess Haem is produced?

A

Delta-ALA is the regulatory step of haem manufacture

Provides -ve feedback!

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5
Q

Step by step process of the synthesis of Hb?

A

A. HAEM

  1. Transferrin transports the ferrous to the RBC
    - OR the ferrous is liberated from the ferritin molecules
  2. Glycine, B6 + Succinyl CoA = DELTA-ALA
  3. Delta-ALA undergos moderations outside the mitochondria
  4. Passes back in as PROTO-PORPHYRIN
  5. Proto-porphyrin goes on to form HAEM which binds to the globins

B. GLOBINS

  1. AA used in ribosomes to create GLOBIN CHAINS

C. HAEMOGLOBIN

  1. Haem + globin chains associate
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6
Q

Properties of Haem?

A

o Also contained in OTHER PROTEINS
e.g. myoglobin, cytochromes, catalases etc.

o Haem is the SAME in ALL MOLECULES
- only the globin (chains) change

o Haem is the combination of:
- proto-porphyrin ring + central ferrous
= ferro-proto-porphyrin

o Synthesised mainly in mitochondria
- main enzyme being ALAS

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7
Q

Properties of globin?

A

8 FUNCTIONAL globin chains!
- arranged in 2 CLUSTERS

  1. BETA-cluster
    o beta, gamma, delta and epsilon
    o encoded on chr11 - on SHORT arm (p-arm)
  2. ALPHA-cluster
    o alpha and zeta
    o encoded on chr16 - on SHORT arm (p-arm)
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8
Q

Explain the Globin gene expression and how it switches for the ALPHA-CLUSTER

A

ONENOTE!!

o Alpha-globin is made relatively EARLY (prenatal) and stays HIGH throughout

o Zeta-globin is OPPOSITE to alpha
- it levels starts to DROP after 8 weeks

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9
Q

What does the globin gene expression mean for ALPHA-CLUSTER is alpha-globin deficient?

A

Starts pre-natal!

Very bad for fetus - can often lead to embryonic death

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10
Q

Explain the Globin gene expression and how it switches for the BETA-CLUSTER

A

ONENOTE!!

o Beta-globin is OPPOSITE to gamma
- starts to become dominant AFTER birth

o Gamma-globin is OPPOSITE to beta

  • dominant PRE-NATAL
  • still produced for a bit post-natal before dropping

o Delta-globin is made mid-natal and remains LOW forever

o Epsilon-globin is SAME as zeta-globin
- it levels starts to DROP after 8 weeks

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11
Q

What does the globin gene expression mean for BETA-CLUSTER deficient?

A

Presents later on as baby can surivive!!

o during utero as only producing GAMMA-globin
- when expect beta to be produced, would then see this abnormality i.e. Beta thalassemia

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12
Q

HbA vs. HbA2 vs. HbF?

A

HbA - alpha2 beta2
o MOST COMMON
o 96-98%

HbA2 - alpha2 delta2
o 2ND most common
o 1.5-3%

HbF - alpha2 gamma2
o LEAST common
o 0.5-0.8%

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13
Q

1o, 2o and 3o structure of Globin?

A

1o

  • Alpha is 141aa
  • Non-alpha is 146aa

2o
- 75% alpha & beta chains are HELICAL arrangement

3o

  • approx. sphere
  • hydrophilic surface = hydrophobic core
  • haem pocket
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14
Q

When does Hb have the highest affinity for oxygen?

A

When the binding is LOOSE (cooperativity)

i.e. MORE O2 = GREATER BINDING of O2

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15
Q

What is released by MUSCLE CELLS to increase the dissociation of O2?

A

2,3 DPG

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16
Q

p50 in terms of O2?

A

Partial pressure of O2
at which
Hb is HALF SATURATED with O2

26.6mmHg

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17
Q

Explain the Hb-ODC if it is more left vs. more right?

A

If LEFT:
o O2 is binding MORE readily
o i.e. give up O2 less easily

If RIGHT:
o O2 is binding LESS readily
o i.e. give up O2 easily

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18
Q

What does the NORMAL position of the Hb-ODC depend on?

A

o [2,3-DPG]

o [H+] i.e. pH

o CO2 in RBCs

o Hb structure

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19
Q

Properties of Hb-ODC if RIGHT-SHIFT?

A

HIGH:
o [2,3-DPG]
o [H+]
o CO2

Hb Structure = HbS!!

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20
Q

Properties of Hb-ODC if LEFT-SHIFT?

A

LOW:
o [2,3-DPG]

Hb Structure = HbF!!

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21
Q

Haemoglobinopathies?

A

Genetic disorder

Characterised by a either
o DEFECT of GLOBIN CHAIN SYNTHESIS (e.g. thalassaemia)
OR
o Structural variants of Hb

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22
Q

What is the most common inherited single gene disorder worldwide?

A

Haemoglobinopathies

23
Q

How is thalassaemia classified?

A
  1. GLOBIN type affected
  2. Clinical severity
    o Minor or ‘TRAIT’
    o Intermedia
    o Major
  3. 4 ALPHA clusters in total
    o alpha1 and alpha2 on each chr16
    o ONLY 2 beta clusters
24
Q

How is beta-thalassaemia inherited?

A

Autosomal recessive

DELETION or MUTATION in Beta-globin gene(s)

o reduced OR absent production of beta-globins

25
Q

Bo vs. B+

A

Bo = DELETION of one beta-globin encoding gene

B+ = MUTATION of one beta-globin encoding gene

B+ is LESS SEVERE (can still produce SOME beta-globin chains)

26
Q

BBo vs. BB vs. BoBo vs. BB+ vs. B+Bo

A

BBo = TRAIT

BB = NORMAL

BoBo = MAJOR

BB+ = TRAIT

BoB+ = INTERMEDIA

27
Q

Order in which you would diagnose thalassaemia?

A
  1. FBC
    o Microcytic Hypochromic indices
    o Increased RBCs relative to Hb
2. Film
 o Target cells
 o Poikilocytosis (shape change)
BUT
 o NO anisocytosis (unequal size)
3. Hb EPS / HPLC
 o alpha-thal 
   - NORMAL HbA2 & HbF
   - +/- HbH
 o beta-thal
   - RAISED HbA2 & HbF
  1. Globin Chain synthesis/ DNA studies
    o genetic analysis for beta-thalassaemia mutations
28
Q

How can you differentiate between alpha and beta-thalassaemia?

A

Alpha
o NORMAL HbA2 & HbF
o +/- HbH

Beta
o RAISED HbA2 & HbF

29
Q

Characterisits of Beta-thalassaemia Trait?

A

CARRIER trait - often asymptomatic

Diagnosis made by blood film:
 - HYPOchromic
AND
 - MICROcytic
RBCs
  • RAISED HbA2 & HbF
30
Q

Characteristics of Beta-thalassamia Major?

A

Carry 2 abnormal copies of the BETA-globin gene

o SEVERE anaemia
o required regular blood transfusions
o Clinically presents after 4-6months of life

31
Q

How can you identify Beta-thalassaemia Major on a blood film?

A 
o Anaemia
o Irregularly contracted cells
o HYPOchromic cells
o alpha-chain precipitates 
o Nucleated RBCs

o Iron inclusions - PAPPENHEIMER BODIES

32
Q

Clinical presentation of Beta-thalassaemia Major?

A

o SEVERE anaemia (presents after 4months)

o Hepatosplenomegaly (liver & spleen)

o Blood film
- gross hyochromia, poikilocytosis, many NRBCs (nucleated)

o Bone marrow - erythroid hyperplasia

o Extra-medullarly haematopoiesis

33
Q

Clinical features of Beta-thalassaemia?

A 
o chronic fatigue
o failure to thrive
o JAUNDICE
o Delay in growth & puberty
o Skeletal deformity e.g. expasion of frontal & maxillary bone (face)
o Splenomegaly
o Iron overload
34
Q

Complications that can follow beta-thalassaemia?

A

o Cholelithiasis (gallstone formation)
o Biliary sepsis
o Endocrinopathies
o Liver failure

35
Q

What causes most of the clinical complications of beta-thal major?

A

IRON OVERLOAD

Achieved in 2 ways:

  1. Non-transfusion dependent iron overload
    - ineffective erythropoiesis
    - SO iron excess is NOT utilised
  2. Transfusion iron overload
    - many transfusions lead to this
36
Q

What is the largest cause of death in patient with beta-thal major?

A

CARDIAC FAILURE

37
Q

Main TWO therapies for beta-thal major?

A
  1. Regular blood transfusions
  2. Iron chelation therapy
    - REMOVAL of iron
38
Q

What are other potential therapies for beta-thal major?

A 
o Splenectomy
o Supportive medical care
o Hormone therapy
o Hydroxyurea to BOOST HbF
o Bone marrow transplant
39
Q

Requirements of transfusions for beta-thal major?

A

o Phenotypes RBCs
- match the donot cells to the RBCs for match

o Pre-transfusion aim is Hb 95-100g/L
o Regular transfusion 2-4weekly

40
Q

If HIGH requirements for transfusions is required for beta-thal major, what else can be considered?

A

Splenectomy

41
Q

What are patients with a high iron content more prone to?

A

INFECTIONS

i.e. Yersinia & other gram-VE sepsis

as the spleen is removed & bacteria thrive of iron overload!

42
Q

When can Iron chelation therapy work?

A

Start after 10-2 transfusions
OR
When serum ferritin > 1000mcg/L

Audiology & ophthalmology screening prior to starting

43
Q

Potential Iron chelating drugs?

A
  1. DFO - desferrioxamine (only NON-oral route, SC or IV)
  2. Deferiprone
  3. Deferasirox (has limited clinical exp.)
44
Q

Deferasirox?

A

(Exjade)

o Oral
o Dose is 20-40mg/kg (ONCE DAILY)
o Half-life is 12-16hours
o Excreted faecal route

SE
Rash, GI symptoms, hepatitis, renal impairment

45
Q

Desferrioxamine?

A

(Desferal - DFO)

o SC/IV infusion
o Dose is 20-50mg/kg
o 8-12 hours, 5days/week
o Half-life if 20-30mins
o Excreted in urine or faecal route
o Long-established!
o Vit C!

SE
Vertebral dysplasia, pseudo-rickets, genu valgum, retinopathy, increased infection risk

46
Q

Deferiprone?

A

(Ferriprox)

o Oral
o Dose 5-100mg/kg/day
o Effective at reducing myocardial iron
o RECENT!

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

47
Q

Comparison of currently available iron chelators?

A

ONENOTE!!

48
Q

How can you measure Iron overload in beta-thal major?

A
  1. Serum ferritin
    o >2500 associated w. increased complications
    o Acute phase protein
    o check 3monthly if transfused otherwise annually
  2. Liver biopsy
    o RARELY performed
    o Iron overload might NOT be uniform in liver
  3. MRI T2 cardiac and hepatic
    o <20ms increased risk of impaired LF function
    o check annually OR 3-6monthly is cardiac dysfunction
  4. Ferriscan (R2 MRI)
    o NON-invasive
    o NOT affected by inflammation or cirrhosis
    o <3mg/g normal
    o >15mg/g associated w. cardiac disease
    o check annually OR 6monthly is result >20
49
Q

What is meant by co-inherited beta-thal?

A

Thalassaemia mutations can be co-inherited with other complications

e.g. SCD and beta-thal

50
Q

Co-inherited beta-thal?

A

o Sickle Beta-thalassaemia

o HbE beta-thalassaemia

  • very common in SEA
  • clinically variable in expression SO can be as severe as beta-thal major
51
Q

Alpha-thalassaemia?

A

o DELETION or MUTATION in alpha-globin chains
- SO reduced OR absent production of it

o Affects BOTH fetus and adult
- alpha is in ALL globin variants

o Excess BETA & GAMMA chains
- form tetramers of HbH (beta excess) and HbBarts (gamma excess)

o Severity depends on number of alpha-globin genes affected

52
Q

Problems with beta-thal treatment in developing countries?

A

o Lack of awareness & experience of health care providers
o Availability of blood
o Cost and compliance with iron chelation therapy
o Cost of bone marrow transplants

53
Q

Screening and prevention of beta-thal?

A 
o counselling and health education
o extended family screening
o pre-marital screening
o discourage marriage betw. relatives
o antenatal testing
o pre-nantal diagnosis (CVS)

Year 2 - MCD Haem (11 decks)

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