Haemoglobin and thalassaemia Flashcards
What are the key components of the oxygen dissociation curve?
O2 carrying capacity of Hb at different pO2
x = partial pressure of oxygen
y = HbO2%
Sigmoid shape:
Binding of one molecule facilitates binding of 2nd molecule
P50 = 26.6mmHg
What factors affect the oxygen dissociation curve?
[2,3-DPG]
[H+] - pH
[CO2] in red cells - linked to pH
Structure of Hb
How is a haemoglobin molecule structured?
Haem
4 globin - 2 alpha chains, 2 beta chains
Each chain protects a haem molecule at its centre
What is the function of haemoglobin?
Haem binds reversibly with oxygen
O2 transport
What are the normal variants of haemoglobin?
HbA - a2b2
HbA2 - a2d2
HbF - a2g2
Explain the relationship between globin genes and different types of haemoglobinopathy
8 functional globin chains, arranged in 2 clusters:
b- cluster (b, g, d, e globin genes) on short arm of chr 11
a - cluster (a, z globin genes) on short arm chr 16
Defects in globin chain synthesis = thalassaemia
Explain the genetic basis of thalassaemia
Beta thalassaemia:
Deletion/mutation in b globin gene(s)
Thalassaemia major:
2 abnormal copies of b globin gene
Explain the pathophysiology of thalassaemia
Deletion/mutation in b globin gene(s)
Reduced/absent b globin chain production
What are the clinical features of a/b thalassaemia major?
Both:
Hepatosplenomegaly
Erythroid hyperplasia in bone marrow
Extra-medullary haematopoiesis
Alpha:
Lethal in utero if all 4 alpha globin genes mutated
Survivors usually have 3 alpha globin gene mutations
Beta:
Chronic fatigue
Failure to thrive, delay in growth and puberty, skeletal deformity
Splenomegaly
Iron overload
Jaundice
Severe anaemia usually presents after 4 months
What are the haematological features of beta thalassaemia?
Marked hypochromia Poikilocytosis Basophilic stipling Nucleated RBCs Alpha chain precipitates Iron inclusions Pappenheimer bodies (Perls stain)
How is thalassaemia diagnosed?
Laboratory diagnosis
FBC: microcytic hypochromic indices, increased RBCs relative to Hb
Film: target cells, poikilocytosis but no anisocytosis
Hb EPS/HPLC:
a-thal - normal HbA2 and HbF, +/- HbH
b-thal - raised HbA2 and HbF
Globin chain synthesis/DNA studies
Genetic analysis for B-thal mutations and xmni polymorphism (in b-thal) and a-thal genotype (in all cases)
How is thalassaemia managed?
- Regular blood transfusions
- Iron chelation therapy
- Splenectomy if transfusion requirement is high
- Supportive medical care
- Hormone therapy
- Hydroxyurea to boost HbF
- BM transplant
Explain the structure of globin
Primary
alpha - 141aa
non-a - 146aa
Secondary
75% alpha and beta chains - helical arrangement
Tertiary Approx sphere Hydrophilic surface (charged polar side chains) Hydrophobic core Haem pocket
What is P50
Partial pressure of O2 at which Hb is half saturated with O2
On normal ODC = 26.6 mmHg
Explain cooperativity with regards to oxygen and haemoglobin
Binding of one molecule of oxygen facilitates the binding of a second molecule
What can cause the ODC to shift right?
High [2,3-DPG]
high [H+]
High [CO2]
HbS
All consequences of metabolising tissues
What can cause the ODC to shift left?
Low [2,3-DPG]
HbF
What are the effects of the ODC shifting right?
Easy oxygen delivery
Reduced oxygen affinity
What are the effects of the ODC shifting left?
Give up oxygen less readily
Increased oxygen affinity
Explain thalassaemia intermedia
Present beta globin gene Produces reduced no of globin chains Not totally dysfunctional Varying clinical phenotypes May require episodic blood transfusions
When does thalassaemia major usually present
After 4-6 months of life
When genes switch from gamma to beta
What are the clinical features of beta thalassaemia?
Hepatosplenomegaly Erythroid hyperplasia in bone marrow Extra-medullary haematopoiesis Chronic fatigue Failure to thrive Jaundice Delay in growth and puberty Skeletal deformity Splenomegaly Iron overload
What are some complications of beta thalassaemia?
Cholelithiasis Biliary sepsis Cardiac failure Endocrinopathies Liver failure
What’s the most common cause of death in individuals with beta thalassaemia?
Cardiac death due to iron overload
