Haemolyti Anaemias An Haemoglobinpathies Flashcards
Overarching definition of thalassaemia
Reduced rate of synthesis of normal alpha or beta globin chains. More frequently present in south Asian, middle or Far Eastern. Alpha globin chain on chromosomes 16 and beat globin chain on chromosome 11
How does thalassaemia cause anaemia
Normally have a 1;1 ratio of alpha and beta globin chains but in thalassaemia have different amounts. This leads to the chain in excess forming aggregates and an imbalance in the b/a tetramer meaning less haemaglobin present for oxygen transport.
How many of each globin chain in haemoglobin and on which chromosomes are they found
2 beta (found on chromosome 11) and 2 alpha (found on chromosome 16) BUT have 4 globin genes coding for the 2 alpha chains (2 from each parent). 2 from each parent
What is beat thalasaemia minor
Where one of the beta globin chains has a mutation. Causes microcytosis but total level of blood is normal as bone marrow responds by producing more RBC. Only time get anaemia is during pregnancy or a persistent infection
What is beta thalassaemia major
Synthesis of globin chains is totally absent due to both having a mutation. Need blood transfusion for 1st couple moths of life because cant produce HbA to replace HbF due to lack of beta globin chains
What happens when all 4 genes are deleted of lost during alpha thalassaemia
Death in Utero. Cant survive
What happens if only 1 of alpha genes is deleted in alpha thalassaemia
It’s silent. Patients are asymptomatic without anaemia
What is haemoglobin H disease.
Where 3 alpha globin genes aren’t functional. Leads to severe microcytosis, anaemia, haemolytic and splenomegaly
What happens when 2 globin genes are deleted. Normal alpha thalasaemia
Minimal anaemia but shows microcytosis and hypochromia
Differences between thalassaemia major, intermedia and minor
Major- transfusion dependant
Intermedia - require transfusion intermittently
Minor- require no transfusion
Consequences of thalassaemia
Extramedullary haemopoesis- making RBC outside of bone marrow. Results in splenomegaly, hepatomegaly (because making RBC here) and haemopoesis in the bone cortex which can impair growth
Also less o2 = EPO = more defective red cells = iron overload.
Overall reduced life expectancy
Treatment of thalasaemia
Transfusions
Iron chelation (bind to iron so excess of it doesn’t cause harm)
Folic acid
Immunisation (becomes immunocompromised due to overactive spleen)
Stem cell trasnsplantation (v rare)
Pre conception counselling holistic care
What is sickle cell disease
Common Hb variant is HbS found often in west Africans. Gives resistance to malaria. Also can have sick-b-thalasaemia, HbS/C or HbS/E. HbS has uncharged valine instead of charged glutamic acid.
What happens to RBC with HbS at low oxygen
Polymerise deforming it to a sickle shape. After repeated episodes of this cell loses elasticity and fails to return to normal shape when normal oxygen levels return
4 consequences of sickle cell formation
Vaso-occlusive episodes- sickle cells get trapped and blocks capillaries causing pain
Anaemia- sickle cells undergo early haemolytic due to suckling
Jaundice- (and gallstones) due to increased bilirubin
Splenic atrophy - due to splenic infarction due to vasooclussion. This can lead to increased risk towards encapsulated bacteria
Sickle cell treatment
Haemopoetic stem cell transplantation
Folic acid
Hydroycarbomide - increase Hb
Red cell exchange
Inherited causes of haemolytic anaemia
Glycolysis defect - pyruvate kinase deficiency limits ATP production
Penthouse p pathway - G6PDH deficiency leads to oxidative damage
Membrane protei e.g herdiatary spherocytosis
Haemoglobin defect e.g sickle cell
Acquired causes of haemolytic anaemia
Mechanical damage - microangiopathic anaemia
Antibody damage - autoimmune haemolytic anaemia
Oxidant damage - exposure to chemicals
Heat damage - severe burns
Enzymatic damage - snake venom
How can mechanical damage cause miroangiopathic haemolytic anaemia
Red cells are damaged by physical trauma. May be due to cells being damaged by shear stress as the pass through defective heart valve e.g in aortic valve stenosis
Disseminated intracapsular coagulation - bleeding and clotting occur at same time which means RBC damaged by vessel laden with fibrin strands (due to increased activation of coagulation cascade.
What are the shape of red blood cells present after mechanical damage
Schistocytes - red blood cell fragments almost
What causes immune haemolytic anaemia
Infection, lymphoproliferative disorders e.g leukaemia or reactions to drugs e.g cephalosporins
What do warm autoimmune haemolytic anemia’s cause
React best in warm temps. Antibodies (IgG) recognise epitomes on RBC membrane. Macrophages in spleen recognise them once antibody has bound and remove cell or nibble bit off = spherocytosis. Causes splenomegaly because spleen does extra
What happens during cold autoimmune haemolytic anaemia
IgM autoantibodies recognise red cell epitopes. Bind best at cooler temps e.g in fingertips. Bind causing agglutinate which blood capillaries causing ischeamic conditions causing numb finger (or other distal parts of body). When get back into warmer space IgM falls off BUT may have created hole in membrane or macrophage might recognise it in spleen and destroy the cell
What causes anaemia in a pyruvate kinase defiancey
Pyruvate kinase needed to catalyse final step in glycolysis. Since RBC lack mitochondria glycolysis is only ATP supply. Without it K+/Na+ atp dependant pump doesn’t work and red cells lose K+ to plasma. Water follows down conc gradient and cell shrinks and dies
What causes anaemia in a G6PDH deficiency
It’s rate limiting enzyme of lentos phosphate pathway which produced NADPH. Need NADPH to protect against oxidative stress and maintaining levels of glutathione. This is RBC only source and therefore in infection or exposure to medication RBC are under threat from oxidative stress and phagocytosis in the spleen. = jaundice.
Mutations which cause hereditary spherocytosis
Spectrin - links plasma membrane to actin cytoskeleton
Ankyrin - links integral membrane protein to spectrin-actin cytoskeleton
Band 3 - involved in linkage of cytoskeleton to plasma membrane
Protein 4.2 - regulated association of protein 3 with ankyrin
Why are the 4 previously mentioned protein important in membrane structure
Facilitate vertical interaction between cytoskeleton and plasma membrane. Disruption of this would reduce membrane surface area Because membranes is unsupported resulting in a spherocyte.
How do spherocytes cause anaemia
Spherocytes are un-flexible and become trapped and damaged as they pass through spleen reducing their life span by haemolysis.
Symptoms of some one with hereditary spherocytosis
Jaundice, splenomegaly and Howell-jolly bodies seen. Mild patients don’t require treatment but those with more severe may need splenectomy as spherocytes no longer lasted by spleen
