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RRY2HAEM > The Haemoglobin Molecule and Thalassemia > Flashcards

The Haemoglobin Molecule and Thalassemia Flashcards

1
Q

What are the different types of globin chain proteins?

A

Alpha, Beta, Gamma, Delta (and embryonic- epsilon and zeta)

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2
Q

State the three different haemoglobins that are present in the human body.

A

HbA – alpha + beta = 95%
HbA2 – alpha + delta = 1-3.5%
HbF – alpha + gamma = trace .7%

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3
Q

Describe how affinity of haemoglobin changes with oxygen binding and how this helps its role of oxygen transport.

A

The more oxygen binds, the greater the affinity of the haemoglobin for oxygen.
This is good because if deoxyhaemoglobin has a low affinity for oxygen(as no oxygen is already bound), it will only pick up oxygen if the oxygen saturation is very high (i.e. in the lungs) so it will not take up oxygen in the metabolically active tissues where the oxygen saturation is low and where the tissues need oxygen.
Similarly, oxyhaemoglobin has a high affinity for oxygen so it will only give up oxygen in environments where the oxygen saturation is very low (i.e. respiring tissues that need oxygen)

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4
Q

State 3 factors that can shift the oxygen dissociation curve to the right.

A

Increase in 2,3-DPG
Increase in [H+]
CO2 (hypercapnia)

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5
Q

What effect do HbS and HbF have on the oxygen dissociation curve?

A

HbS has a lower affinity for oxygen than HbA so it shifts the ODC to the right
HbF has a higher affinity for oxygen than HbA so it shifts the ODC to the left

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6
Q

What is special about alpha globin genes?

A

There are TWO alpha globin genes from each parent so there are FOUR alpha globin genes in total.

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7
Q

Which globin chains are present in early embryonic life but are switched off after about 3 months gestation?

A

Zeta and epsilon

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8
Q

Which globins are present in foetal haemoglobin?

A

Alpha

Gamma

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9
Q

When are the genes coding for the globin in foetal haemoglobin switched off?

A

It is decreased towards birth and in the first year after birth.
After 1 year of life, the normal adult pattern of haemoglobin synthesis would have been established.

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10
Q

Which globin chains are present in HbA2?

A

Alpha

Delta

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11
Q

On which chromosomes are the two globin gene clusters and which genes are present in each cluster?

A 
Chromosome 16 – ALPHA cluster 
 TWO alpha genes  
 Zeta gene  
Chromosome 11 – BETA cluster 
 Beta gene  
 Gamma gene 
 Delta gene  
 Epsilon gene
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12
Q

What is thalassemia?

A

Disorders in which there is a reduced production of one of the two types of globin chains in haemoglobin leading to imbalanced globin chain synthesis

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13
Q

How is thalassemia classified in terms of clinical severity?

A

Minor: Thalassemia trait = asymptomatic carrier common variant with little clinical significance

Intermediate: Thalassemia intermedia
somewhere in between
can require transfusions or not

Major: Transfusion dependent – Thalassemia Major = fatal without transfusion

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14
Q

What is the outcome of alpha thalassemia major?

A

Fatal in utero because alpha globin is needed to make HbF (alpha + gamma)

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15
Q

Clinical presentation of thalassemia major?

Clinical features

A

a. Severe anaemia presenting at 4 months leading to Chronic fatigue
b. Failure to thrive
c. Jaundice
d. Hyperactive bone marrow
e. Delay in growth and puberty
f. Extramedullary haematopoiesis

g. Skeletal deformity (bone marrow expansion due to extramed haematopoiesis causing the distinctive facial features)
h. Hepatosplenomegaly
i. Iron overload (patients with thalassaemia absorb more iron in GI tract)

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16
Q

Which 2 types of abnormal haemoglobin can result due to Alpha thalassaemia

A

Haemoglobin H and Hb barts

Lack of Alpha chain forms tetramers of Beta chains instead of 2 alpha and beta= HbH

Same but tetramer of gamma chain= Hb barts

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17
Q

What is beta thalassemia major? Describe how the disease progresses.

A

Severe defect in both beta globin chains
The foetus will have no problem in utero because they have normal functioning HbF (which doesn’t need beta globin)
At around 2-3 month after birth, you get a transition from HbF to HbA
At this time the baby will become profoundly anaemic.
They will need life-long transfusions from this point onwards.

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18
Q

State some features of thalassemia trait.

A

This the carrier state of thalassemia.
They may be mildly anaemic but they can also be normal.
Usually have a LOW MCH and LOW MCV

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19
Q

Summarise the laboratory diagnosis of Thalassemia

A 
Start simple:
-	FBC 
-	Film 
Complex tests:
-	Hb electrophoresis/ HPLC 
-	DNA studies eg PCR to look at genes for globin chains
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20
Q

What types of mutation cause alpha thalassemia and beta thalassemia?

A

both can be caused by deletion or point mutation in the respective alpha/beta globin gene

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21
Q

Which ethnic groups have a high prevalence of thalassemia?

A 
Chinese 
South-east Asian 
Greek 
Turkish 
Cypriot
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22
Q

Laboratory diagnosis: What features would you see when looking at FBC of thalassemia?

A
  • Poikilocytosis (no anisocytosis)
  • Target cells
  • Hypochromasia
  • Nucleated RBC
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23
Q

What are the consequences of regular blood transfusions used to treat beta thalassemia major?

A

Iron overload: Chronic transfusion has been associated with iron accumulation. There’s not enough transferrin to bind to all the iron, the unbound iron can catalyse production of reactive oxygen species which can damage the liver (cirrhosis), heart (cardiac failure), endocrine organs (hypopituitarism, hypothyroidism, diabetes) etc.
Also increases chance of infection.

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24
Q

Name three iron chelator drugs that can be used to treat iron overload.

A

Desferrioxamine (DFO/desferal)
Deferiprone
Deferasirox

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25
Q

What are the key indicators when monitoring the iron overload in the management of thalassemia patients

A
  1. Serum ferritin (but not that accurate as it is also an ACP that rises in inflammation etc)
  2. Cardiac and hepatic MRI to measure iron levels in heart and liver

Liver biopsy used to be done but not anymore

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26
Q

Laboratory diagnosis: What features would you see when looking at Blood film of thalassemia?

A

target cells
poikilocytosis (different shape)
NO anisocytosis(different size)
Microcytic and hypochromic (relate this to the FBC card earlier)

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27
Q

Laboratory diagnosis:

What is the most definitive test for thalassemia

A

DNA studies - PCR, sanger sequencing etc

Most alpha thalassemias are diagnosed this way because they are quite hard to diagnose (HPLC gives normal HbA2 and HbF)

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28
Q

Complications of thalassemia

A 
Cholelithiasis (gallstones)
Biliary sepsis
Cardiac failure
endocrinopathies
liver failure
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29
Q

Treatments for thalassemia major (minor usually asymtomatic)

A

Main treatments:

  • Regular blood transfusions
  • Iron chelation therapy (remove XS iron)

Other treatments:

  • Splenectomy (patients may have splenomegaly due to extramedullary hematopoiesis)
  • Supportive medical care for cardiac, liver problems
  • Hormone therapy, iron overload can cause hypogonadism
  • Hydroxyurea to boost HbF production
  • Bone marrow transplant
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30
Q

Why are thalassemia patients prone to infection? What can be done to reduce the chances?

A

They tend to have iron overload and there are pathogens that thrive on iron especially gram - bacteria like YERSINIA

Also, thalassemia patients could have splenectomy due to splenomegaly via extramedullar haematopoiesis which is an important immune organ.

to prevent this, immunisation in splenectomised patients is good. (prophylaxis)

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31
Q

Main concern for management of thalassemia patients

A

infection and monitor iron overload

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32
Q

What are:
Sickle b thalassemia
HbE b thalassemia

A

Sickle b thal:
inherits one sickle allele from one parent and b thal allele from the other parent
NB sickle allele is also a mutation on the beta globin gene. So this disease is basically inheriting two different faulty beta globin alleles from the 2 parents

HbE b thal:

  • Single point Mutation in beta chain, forming HbE which is an abnormal haemoglobin
  • Reduced synthesis of functional beta chain leads to beta thalassemia
33
Q

Mature rbc do not have

A

nuclues or mitochondria

34
Q

Synthesis of haemoglobin : how much in eryhthroblast stage and reticulocyte stage

A

65% erythroblast stage

35% reticulocyte stage

35
Q

Strucgure of haemolgobin a

A

4 chains– 2 a, 2 b– type of chains may alter with different haemoglobin
Haem group in centre with central iron ion– ferrous form fe2+

36
Q

Structure of haemolgobin a

A

4 chains– 2 a, 2 b– type of chains may alter with different haemoglobin
Haem group in centre with central iron ion– ferrous form fe2+

37
Q

Where is haem synthesised

A

Mitochondria

38
Q

Where is globin synthesised

A

Ribosomes

39
Q

How is iron transported into the cell

A

Bound to transferrin, transferrin iron complex is endocytosed by vesciles and transported to mitochondria.

40
Q

Enzyme that regulates synthesis of haem and where is it located

A

Delta ALA
– Negative feedback step

Located in mitochondria

41
Q

List 5 proteins in which haem can also be in apart from haemoglobin

A

Myoglobin, cytochromes, peroxidases, catalases, tryptophan

42
Q

What makes up haem component

A

Protoporphyrin ring with central iron atom– ferroportoporphyrin

43
Q

Synthesis of globin-8 FUNCTIONAL GLOBIN CHAINS ARRANGED IN A AND B CLUSTER-
list B cluster– which chromosome and which arm

and a cluster– which chromosome and which arm

A

B cluster- B, Gamma, Delta, Epislon globin genes located on short arm of chromosome 11

A cluster- A1 , a2 and zeta globin genes on the short arm of chromosome 16

44
Q

which gene will

A

Foetus and adult

45
Q

Which stage of life will the chromosome 16 genes be responsible for

A

Embryo

46
Q

Which globin from the alpha cluster is the first to be produced

A

Zeta globin chains– produced after conception, but also production stopped 7 weeks of gestation– embroygenic

47
Q

a globin chain is produced when and until

what happens if this isnt functioning properly

A

Pregestation and even through adult life

embryonic death

48
Q

Which globin from the beta cluster is the first to be produced

form what type of haemoglobin

A

gamma globin chain

foetal haemoglobin

49
Q

When does gamma globin chain begin to tail off and which globin chaintakes over its place

A

Gamma globin starts to tail off few weeks postpartum and B globin chain starts to increase

50
Q

When does gamma globin chain begin to tail off and which globin chaintakes over its place

A

Gamma globin starts to tail off few weeks postpartum and B globin chain starts to increase

51
Q

Primary globin structure

A

a 141 AA

Non a 146 AA

52
Q

Secondary globin structure

A

75% a and B chains- helical arrangement

53
Q

Tertiary globin structure

A

Approximate sphere
Hydrophilic surface (charged polar side chains), hydrophobic core
Haem pocket

54
Q

How many globin chains in haemoglobin and ho many oxygens can haemoglobin bind to

A

4 globin chains

4 oxygens

55
Q

Phenomenon in which oxygen binding becomes easier after first

A

Postive cooperativity

56
Q

p50

2,3 DPG role
which cells can high levels be found

A

when Hb is half saturated with O2

Promote deoxygenated state– high levels found in metabolic cells

57
Q

What 4 factors does normal position of curve depend on

A

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

58
Q

Left shift means? Vv

A

Greater affinity, less readily donating
REDUCED CONCENTRATIONOF 2,3 DPG
INCREASED pH

Right shift– less affinity, more readily donating oxygen
INCREASED 2,3 DPB
DECREASED pH

59
Q

Haemoglobinopathies– 2 types are?

A

Structural variants of haemoglobin

Defects in globin chain synthesis – thalassaemia

60
Q

2 different ways of Classifying thalassaemia

A

Globin type affected

Clinical severity-
Minor trait– asymptomatic
Intermediate– can require or not require transfusions
Major– require transfusions

61
Q

B Thalassaemia caused by

A

Deletion or mutation in B globin gene

Results in reduced or asbsent porduction of B globin chain

62
Q

Prevalence of B thalassaemia

A

Mainly in Mediterranean countries, Arabina peninusla, Iran, Indian subcontinent, Africa, Southern China, South East Asia

63
Q

Inheriting pattern of B thalassaemia

A

Autosomal Recessive mendelian

BB^0= Trait
BB=Normal
B^0B^0= Major
B+ (Able to produce some betaglobin)
BB+-- tRIAT
B+B^0--BThal Intermedia
64
Q

Thalassaemia major cause

A

Carry 2 abnormal copies of the beta globin gene

65
Q

Thalassaemia Requires

A 
regular blood transfusions
Iron chelation therapy
Splenectomy
Supportive medical care
Hormone therapy
Hydroxyurea to boost HbF
Bone marrow transplant
66
Q

When do you present

A

Clinical presentation usually after 4-6 months of life

67
Q

Other complications of B thalassaemia

A

Cholelithiasis and biliary sepsis
Cardiac failure
Endocrinopathies
Liver failure

68
Q

How are transfusions carried out

A

Phenotyped red cells
Regular transfusion 2-4 weekly
If high requirement consider splenectomy

69
Q

Mangement of infection

A

Yersinia
Other Gram negative sepsis

Prophylaxis in splenectomised patients – immunisation and antibiotics

70
Q

Iron chelation therapy

ALL 3 CAN BE USED IN COMBINATION

A

Start after 10-2 transfusions or when serum ferritin >1000 mcg/l
Audiology and ophthalmology screening prior to starting

Deferasirox (Exjade)
Oral
SE: rash, GI symptoms, hepatitis, renal impairment

DFO
Long-established
SE: vertebral dysplasia, pseudo-rickets, genu valgum, retinopathy, high tone sensorineural loss, increased risk of Klebsiella and Yersinia infection
Compliance-- parenteral adminsitration
Vitamin C

Deferiprone (Ferriprox)
Oral
Effective in reducing myocardial iron
SE: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy

71
Q

Monitoring of iron overload

A

Serum ferritin
-Acute phase protein

Liver Biopsy- Rare
T2 cardiac and hepatic MRI

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

72
Q

HbE B Thalassaemia common where

A

Common combination in South East Asia

73
Q

Clinical Variation>

A

Clinically variable in expression can be as severe as B thalassaemia major

74
Q

Alpha Thalassaemia

A

Deletion or mutation in a globin gene(s)
Reduced or absent production of a globin chains
Affects both foetus and adult
Excess Band Gamma chains form tetramers of HbH and Hb Barts respectively
Severity depends on number of a globin genes affected

75
Q

Thalassaemia carrier

A

Thalassaemia minor / trait
Carry a single abnormal copy of the beta globin gene
Usually asymptomatic
Mild anaemia

76
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

77
Q

Screening and Prevention

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)
78
Q

Haemoglobinopathies offer protection against

A

Malaria– make it hard for the parasite to enter rbc

79
Q

Lab diagnosis of B thalassaemia

A

FBC– Full blood count– Microcytic Hypochromic indices

Increased RBCs relative to Hb

Film- Target cells, poikilocytosis but no anisocytosis

Hb EPS / HPLC
A-thal- Normal HbA2 & HbF, +/- HbH (LOSS OF 3 A GLOBIN GENES YOU MAY SEE ABRNOMAL HAEMOGLOBIN VARIANCE.
IF YOU LOSE ALL 4- INCOMPATIBLE FOR LYF)
B-thal- Raised HbA2 & raised HbF

Globin Chain synthesis/ DNA studies
Genetic analysis for β-thalassaemia mutations and XmnI polymorphism (in β-thalassaemias) and α-thalassaemia genotype (in all cases)

RRY2HAEM (10 decks)

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