Haemoglobin and Thalassaemia Flashcards
Explain the Function of Haemoglobin
To transport Oxygen from lungs to tissues, Co2 from tissues to lungs
Determines shape of erythrocytes
Explain the overalls structure of Haemoglobin
2 parts:
- Haem molecule with centrally bound iron
- Globin chains (4 per Hb molecule, mostly 2 each (2a2ß, 2a2x etc.)
Usually form spheres
Where is Haem synthesised?
What is required for this?
Haem is synthesised in the Mitochondrium
It requires Iron (ususally Fe2+) and protoprophyrin that together form feroprotoprophyrin
Explain the genetic origin of the globin chain
Various combinations of two chains possible to give rise to different form of Haemoglobin but overall
Two clusters
- Beta-cluster (in chormosome 11) –> loci for ß, gamma, delta, epsilon chains
- Alpha cluster (on chromosome 16) –> loci for alpha and zeta chains
Explain the different presence of Haemoglobin chains in different stages of life
- Up to 7 Weeks–> Zeta chains present , zeta Hb
- Pre-birth (up to 6 month after birth) –> HbF consisting of 2a2gamma
- In adulthood (and from 6month after birth on)
- mainly HbA--> 2a2ß but also
- HbF<0.8%
- HbA2 (2a2delta) <3%
Why do symptoms of ß-thalassaemia and sickle cell disease normally occur after 3-6 month of life?
Because that is the time when ß-globin chains are fist produced (where defects are implemented)
Before HbF is more present (no ß chains)
What does complete alpha thalassaemia normally result in (all 4 loci)?
It normally results in fetal death
–> used from 7 Weeks of fetal development onwards–> fatal if not working at all
What is the secondary and tertiary structure of haemoglobin?
Secondary: Mainly Helical (75%)
Tertiary: sperical shape wiht haem pockets
Explain the ODC
What is P50 in the Oxygen Dissociation curve?
What is it used for?
P 50= (partial pressure of O2 at which Hb is half saturated with O2) 26.6mmHg
–> used to compare the different binding affinities of Hb chains
What is thalassaemia?
Defects in globin chain synthesis
What different types of Haemoglobinopathies are there?
Structural variants of haemoglobin
or
Defects in globin chain synthesis (thalassaemia)
How can you classify thalassaemia?
- Globin type affected
- alpha thalassaemia
- beta thalassaemia
- Clinical severity
- minor “trait”–> usually asymptomatic carrier
- intermedia –> non-transfusion dependant
- major –> diffusion dependant
How many genes encode for the ß-globin chain?
How does this effect thalassaemia?
There are 2 genes coding for thalassaemia
- if one is affected: carrier, traid thalassaemia
- if both are affected: symptomatic thalassaemia
How does the Intermedia thalassaemia differ from the major thalassaemia?
There are many many mutations in the ß globin chain genes with different severities
In Major: two defect genes with severe mutation are inherided
In intermdia: two defect genes with either less severe mutation or one with severe, one with less severe mutation are inherited
What is thalassaemia?
How is it inherited
Single gene defect in the ß globin chains causing a reduced or absent production of ß-globin
It is an autosomal recessive condition
How would you diagnose someone you’d suspect to have thalassaemia?
-
FBC
- Microcytic Hypochromic
- Increased RBCs relative to Hb
-
Film
- Target cells,
- poikilocytosis
- no anisocytosis
-
Hb EPS / HPLC
- in a-thal: Normal HbA2 & HbF, +/- HbH (not enough for diagnosis)
- in b-thal: Raised HbA2 & raised HbF
- Globin Chain synthesis/ DNA studies
- Genetic analysis for β-thalassaemia mutations and XmnI polymorphism (in β-thalassaemias) –> just in some cases
- α-thalassaemia genotype (in all cases)
What is the clinical presentation of someone with thalassaemia major?
- Severe anaemia usually presenting after 4 months
- Hepatosplenomegaly —> due to extra-medullar haematoppisis (also can be seen in enlarged mandible + forehead if not managed)
- Blood film shows gross hypochromia, poikilocytosis and many NRBCs
- Bone marrow - erythroid hyperplasia
What are the signs and symptoms of someone having ß thalassaemia?
- Chronic fatigue (anaemia)
- Jaundice (increased haemolysis)
- Delay in growth and puberty
- Skeletal deformity
- Splenomegaly
- Iron overload
What are the main complications in someone with thalassaemia?
- Cholelithiasis and biliary sepsis –> Infections
- Cardiac failure (main cause of death)
- Endocrinopathies –> due to occlusion of endocrine glands
- Liver failure
How do you treat someone with Thalassaemia Major?
Main Ways
- Regular blood transfusions (every 2-4 weeks)
- ideally with phenotyped red cells
- Iron chelation therapy (to prevent iron overload)
- Start after 10-2 transfusions or when serum ferritin >1000 mcg/l
- Splenectomy
- Supportive medical care (e.g. vaccinations)
- Hormone therapy (in endocrine problems)
- Hydroxyurea to boost HbF
- Bone marrow transplant (in severe cases, balance risk to profit)
Explain the relationship between infections and thalassaemia
Patients are more prone to infections because
- •Yersinia
•Other Gram negative sepsis thrive in iron-rich environents
- Splenectomy –> reduces immune system
How are the iron levels in a patient measured?
Serum ferritin
Liver biopsy (rarely done right now)
Cardiac or hepatic T2 MRI
Which drugs might be used as iron chelation therapy?
What are their advantages and disadvantages?
What is the HbH Disease?
It is a intermidia form of a thalasssemia with three alpha chians mutated
How would be blood film of someone with ß-Thalassemia trait look like?
- Microcytosis
- hypochromia and
- occasional cells showing basophillic stippling
How would the blood film in someone wiht ß-Thalasemia major look like?
The peripheral blood film will show
- extreme hypochromia
- microcytosis and
- poikilocytosis
Might show
- Howell Jolly bodies and
- nucleated RBC’s will be present as a result of splenectophy and a hyper plastic bone marrow.
+ Inclusion bodies
- , Alpha globin precipitates and pappenheimer bodies
