Lecture 8 (Part 1) - Haemoglobinopathies Flashcards
State 2 types of haemoglobinopathies
- Abnormal globin chain synthesised: sickle cell
- Reduced/absent expression of normal globin chain: thalassemia
[globin gene mutation results in reduced expression]
Types of Hb in adults? What chromosome is α gene and β gene?
- HbA (2α, 2β) - 95%
- HbA2 (2α, 2d) - 3%
- HbF (2α, 2g)- <1%
(replaced 3-6 months of age to HbA)
- α gene is Chr16, β Chr11
(globin proteins from diff genes form diff tetramers)
Which population is thalassemia more prevalent? Hence, what should we be cautious of?
**α:non-a usually 1:1 (normal), thalassemia messed up
- More prevalent in South Asian, Mediterranean, Middle East
- Important to be aware of ethnicity for prenatal counselling
4 stages of thalassemia that range in severity from asymptomatic to deadly. Name each stage and explain the mechanism behind for a-thalassemia
(Chr16)
(no of α-globin chains deleted is the number)
- Silent carrier state (asymptomatic)
- α-thalassemia trait (mild/no anaemia) –> results in hypochromic/microcytosis in RBC
- Haemoglobin H (HbH) disease (moderately severe) –> result in microcytic, hypochromic, target cells/codocytes (RBC w bullseye in middle) & Heinz bodies
- Hydrops fetalis (intrauterine death) —> all 4 α deleted. Excess y-globin tetramers formed (?) (called Hb Barts) –> X deliver O2
3 stages of thalassemia that range in severity from asymptomatic to deadly. Name each stage and genetics behind B-thalassemia
(Chr11. Often due to gene mutation)
- B-Thalassemia minor/trait (asymptomatic/mild anaemia) –> heterozygous with 1 normal/abnormal gene
- B-thalassemia intermedia (severe anaemia) –> heterozygous –> mild variants of homo. (B+)
[most common]. some hetero (B+/B0), both hetero (B0/B+) - B-thalassemia major (transfusion-dependant, manifests 6-9 months after birth) –> homozygous B0/B0 or B+/B+
[B+ is reduction, B0 is absence]
What is genetic basis of HbH?
- 3 mutated a-globin chains
- blood film will show microcytic and hypochromic anaemia with the presence of target cells and Heinz bodies.
What will blood smear show in thalassemia?
- Hypochromic and microcytic RBC (due to low Hb)
- Anisopoikilocytosis: frequent target cells and Heinz bodies
What is the effect of thalassemia on excess unaffected globin chain
- Forms insol. aggregates w a chains
- Hb aggregates –> oxidised –> premature death of erythroid precursor –> excessive destruction in spleen (splenomegaly) –> haemolytic anaemia
Consequences of thalassemia
- Extramedullary haemopoiesis: to compensate for reduced RBC
- Results in splenomegaly, hepatomegaly and expansion of haemopoiesis into bone cortex
- Impairs growth –> short stature, swelling of bones - Reduced O2 delivery –> stimulation of EPO (kidney) –> more defective RBC
- Iron overload: leads to premature death
- Excessive absorption of dietary iron due to ineffective haemopoiesis
- Repeated blood transfusions - Reduced life expectancy
Suggest treatments for thalassemia
- Red cell transfusion + iron chelating tablets (delay iron overload - deferoxamine)
- Folic acid - support erythropoiesis
- Immunisation (pancytopenia results in lower immunity)
- Holistic care (cardiology, endocrinology): manage complications
- Counselling: at risk couples
- Stem cell transplant
What is sickle cell disease? What is the Hb formed? Diff btw heterozygous and homozygous ppl?
- Autosomal recessive disease resulting from mutation of B-globin gene
- GAG codon changed to GTG, glutamic acid –> valine
- HbS (can also be co-inherited with another abnormal Hb, e.g HbC –> cause sickling)
- Heterozygous = carrier/mild symptoms, HbSHbS = severed anaemia
Which population has higher prevalence of sickle cell and why?
- West African population
- Confers protection against malaria
- Heterozygous individual, mild/asymptomatic –> some RBC sickled –> parasite X divide in
When do sickle cell RBC become problematic and why?
- Anaemia usually mild as HbS readily gives up O2 (>HbA)
- But in low O2 state, deoxygenated HbS polymerise –> sickle shape –> revert to normal when O2 ⬆️
- Irreversible sickled cell, less deformable –> occlusion in RBC
Consequences of sickle cell formation are?
- Sickle cell form occlusion in small capillaries –> recurrent acute pain, stroke, chronic kidney disease, joint pain from avascular necrosis
- Anaemia –> sickle cell haemolysis (20-30 day lifespan)
- Jaundice (& gallstones) –>⬆️bilirubin
- Splenic atrophy due to splenic infarction –> ⬆️risk of infection (Streptococcus pneumonia, Streptococcus meningitidis)
- Acute chest syndrome –> ⬇️life expectancy
What are the 3 patterns sickle cell disease present in clinic?
- Vaso-occlusive –> painful bone crises/organ or spleen
- Aplastic –> bone marrow X work (triggered by parvovirus)
- Haemolytic anaemia
- End point is organ damage due to hypoxia or acute thromboses
What are the treatments for sickle cell?
- Folic acid
- Hydroxycarbamide (increases HbF )
- Red cell exchange
State 2 types of haemolytic anaemia and list examples for each
- Inherited HA:
- Pyruvate kinase deficiency
- G6PDH deficiency
- Hereditary spherocytosis
- Sickle Cell - Acquired HA:
- Mechanical dmg (microangiopathic anaemia)
- Oxidant dmg
- Heat dmg
What are lab findings of a person w HA?
- ⬆️reticulocytes (BM tries to compensate)
- ⬆️bilirubin
- ⬆️LDH (red cells)
What are the complications associated w HA?
- Splenomegaly –> compensate for fall in Hb
- Sudden haemolysis from incompatible blood transfusions –> cardiac arrest due to lack of O2 to cells & hyperkalaemia (release of contents of RBC)
- Jaundice: ⬆️bilirubin –> discoloration of sclera and skin, urine dark
- Pigment gallstones (bilirubin & Ca salts)
3 types of inherited defects in RBC structure are H.Spherocytosis, H. Eliptocytosis, H. Pyropoikilocytosis. Desc each and structure
- Sphrerocytosis: spectrin, ankyrin, band 3, protein 4.2 defect –> cell less flexible, dmg easily
[splenectomy is done to prevent more deformed RBC] - Eliptocytosis: (eclipse shape RBC) spectrin defect most common
- Pyropoikilocytosis: spectrin defect, abnormal sensitivity to heat
What is the anaemia due to acquired dmg? When does it occur? What forms?
- Microangiopathic HA from mechanical dmg
- Occurs from:
i) shear stress as cells pass through defective heart valve (aortic valve stenosis), cells dmg forced thru narrowed opening
ii) Increased activation of clotting cascade –> cells snag on fibrin strands
[Disseminated intravascular coagulation]
iii) Heat dmg
iv) Osmotic dmg - Schistocytes (fragment of RBC) formed
What is autoimmune HA? Cause? Result in?
- Autoantibodies bind to RBC membrane proteins –> spleen recognise –> remove
- Cause: infection or cancer of lymphoid system
- RBC lifespan reduced causing anaemia
What is the antibodies involved in AI HA?
- Warm, IgG: Macrophages destroy/nibble RBC –> spherocytes
- Cold, IgM:
i) Bind to RBC distal part of body (fingertips), cause agglutination & block small capillaries
ii) Cause numb fingers, pallor, blue discoloration - When RBC circulate to warmer, IgM falls off and agglutination disappears
Why is direct Coombs’ test relevant for AI HA?
- Detect antibodies or complements bound to RBC surface
- Patient RBC mixed w anti-human globulin antibody
- If RBC have antibodies, globulin will attach to them –> RBC clump –> cfm AI
A 23 year old man with Sickle Cell Disease is prescribed penicillin.
What is the primary reason for prescribing this drug in this patient?
- To compensate for hyposplenism (due to vaso-occlusion)
- ⬆️risk of infection
