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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
Bo vs. B+
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
BBo vs. BB vs. BoBo vs. BB+ vs. B+Bo
BBo = TRAIT BB = NORMAL BoBo = MAJOR BB+ = TRAIT BoB+ = INTERMEDIA
27
Order in which you would diagnose thalassaemia?
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 ``` 4. Globin Chain synthesis/ DNA studies o genetic analysis for beta-thalassaemia mutations
28
How can you differentiate between alpha and beta-thalassaemia?
Alpha o NORMAL HbA2 & HbF o +/- HbH Beta o RAISED HbA2 & HbF
29
Characterisits of Beta-thalassaemia Trait?
CARRIER trait - often asymptomatic ``` Diagnosis made by blood film: - HYPOchromic AND - MICROcytic RBCs ``` - RAISED HbA2 & HbF
30
Characteristics of Beta-thalassamia Major?
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
How can you identify Beta-thalassaemia Major on a blood film?
``` o Anaemia o Irregularly contracted cells o HYPOchromic cells o alpha-chain precipitates o Nucleated RBCs ``` o Iron inclusions - PAPPENHEIMER BODIES
32
Clinical presentation of Beta-thalassaemia Major?
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
Clinical features of Beta-thalassaemia?
``` 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
Complications that can follow beta-thalassaemia?
o Cholelithiasis (gallstone formation) o Biliary sepsis o Endocrinopathies o Liver failure
35
What causes most of the clinical complications of beta-thal major?
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
What is the largest cause of death in patient with beta-thal major?
CARDIAC FAILURE
37
Main TWO therapies for beta-thal major?
1. Regular blood transfusions 2. Iron chelation therapy - REMOVAL of iron
38
What are other potential therapies for beta-thal major?
``` o Splenectomy o Supportive medical care o Hormone therapy o Hydroxyurea to BOOST HbF o Bone marrow transplant ```
39
Requirements of transfusions for beta-thal major?
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
If HIGH requirements for transfusions is required for beta-thal major, what else can be considered?
Splenectomy
41
What are patients with a high iron content more prone to?
INFECTIONS i.e. Yersinia & other gram-VE sepsis as the spleen is removed & bacteria thrive of iron overload!
42
When can Iron chelation therapy work?
Start after 10-2 transfusions OR When serum ferritin > 1000mcg/L Audiology & ophthalmology screening prior to starting
43
Potential Iron chelating drugs?
1. DFO - desferrioxamine (only NON-oral route, SC or IV) 2. Deferiprone 3. Deferasirox (has limited clinical exp.)
44
Deferasirox?
(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
Desferrioxamine?
(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
Deferiprone?
(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
Comparison of currently available iron chelators?
ONENOTE!!
48
How can you measure Iron overload in beta-thal major?
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
What is meant by co-inherited beta-thal?
Thalassaemia mutations can be co-inherited with other complications e.g. SCD and beta-thal
50
Co-inherited beta-thal?
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
Alpha-thalassaemia?
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
Problems with beta-thal treatment in developing countries?
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
Screening and prevention of beta-thal?
``` 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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