9- Haemoglobinopathies & Haemolytic Anaemias

Question 1

• define what haemoglobinopathies are. What 2 disease types can they lead to and what is the effect of the mutation?
• what are the 3 types of Hb? When do they commence/ and cease? And what is the reason for diff types
• what is Hb? Structure?

Answer 1

• haemoglobinopathies=defects in globin chain synthesis, inherited disorders that are normally autosomal recessive. eg thalassaemia (globin mutation causes structure/function/stability of Hb) and sickle cell (globin gene mutation causes reduced expression of some globin proteins)
• HbA 95% in adults, commences after birth, HbF main form just before birth, HbA2 3%, adaptive response to variations in O2 requirements.
• tetramer of 4 globin polypeptide chains: 2 alpha, 2 beta. Each globin chain has a haem w iron

Question 2

• what chromosome is the alpha globin gene complex on, what chromosome for beta globin gene?
• how many alpha and how many beta genes do humans have?

Answer 2

• alpha= chromosome 16, beta= chromosome 11

- 4 alpha (1 from mum 1 from dad), 2 beta (1 on each chromosome)

Question 3

• how are thalassaemias caused? what’s the difference between alpha and beta thalassaemia?
• which ethnic groups are they more common in?
• name the 4 types of disease an individual w alpha thalassaemia can have. why is it 4? Describe each
• name the 3 types of disease an individual w beta thalassaemia can have. why is it 3? Describe each.

Answer 3

• defects in regulation of expression of globin genes (not 1:1) so abnormalities in both relative & absolute amounts of globin chain proteins. Beta globin chain affected= beta thalassaemia, alpha globin chain affected= alpha thalassaemia.
• people from south Asian, Mediterranean, Middle East (beta) or Far East (alpha)
• 4 diseases=humans have 4 globin chains so number of globin chains deleted denotes severity. 1 chain deleted= silent carrier state, asymptomatic, carrier w no symptoms. 2 chains deleted= alpha thalassaemia trait, minimal or no anaemia, either x2 genes on one chromosome 16 or x1 from each c16, can cause microcytosis and hypochromia in RBCs, resembles beta thal. Minor. 3 chains deleted= Hb H disease, moderately severe, deformed Hb tetramers (called Hb H chains) cause microcytic hypochromic anaemia w target cells and Heinz bodies, resembles beta thal. intermedia. 4 chains deleted= hydrophobic fetalis, severe- usually results in prenatal death, Hb Bart formed that is unable to deliver O2 to tissues so death
• beta= 3 diseases bc 3 different genes (B=normal, B+=reduced globin production, B0=no globin production). 1)beta thalassaemia minor/trait= usually asymptomatic or mild anaemia, genotype is [B,B0 or B,B+]. 2)beta thalassaemia intermedia=severe anaemia but not bad enough to need transfusions, like Hb H disease, genotype is [B+,B+ or B0, B+ ]
  3) beta thalassaemia major= severe, transfusion dependant anaemia, starts 6-9 months after birth as we switch from HbF -> HbA, genotype is [B0, B0 or B+, B+]

Question 4

• what would you see in a peripheral blood smear of someone w severe thalassaemia? what effect is there on Hb?
• what are the consequences of thalassaemia in general and beta specifically?
• what are the treatments for thalassaemia?

Answer 4

• hypochromic, microcytic RBCs due to low Hb, anisopoikilocytosis w lots of target cells, Heinz bodies and nucleated RBCs.
• excess of unaffected chains aggregate ie Hb aggregates & gets oxidised causing premature erythroblastosis death (a form of haemolytic anaemia) in BM so ineffective erythropoiesis, spleen over destroys RBCs so reduces their lifespan
• extramedullary haemopoeisis causes splenomegaly, hepatomegaly, expansion of bones of face etc, reduced O2 delivery causes stimulation of erythropoietin to make more defected RBCs, iron overload, reduced life expectancy
• beta specifically=accumulation of insoluble alpha globin aggr. that result in cell death, fewer mature RBCs leave BM & those that do are microcytic and hypochromic, spleen destroys those and this causes anaemia, increased iron not being used in erythropoiesis means iron overload that must be treated by blood transfusion, anaemia means more EPO released by kidney, extramedullary haemopoeisis causes skeletal deformities.
• red cell transfusions from childhood, iron chelation, folic acid to help w erythropoiesis, immunisation, holistic care as they’re Perone to complications, stem cell transplants in some.

Question 5

• what is sickle cell disease? what gene causes and what types are there, which is the most common?
• describe the disease pathway, what is a sickle cell crisis
• give the 3 types of crises
• give symptoms of sickle cell

Answer 5

• autosomal recessive, mutation of beta globin gene, GAG -> GTG switching glutamic acid to valine
• this defective Hb is called HbS. Types= HbS,Hb is a heterozygous carrier & asymptomatic, HbSS= homozygous, most common cause of severe sickling syndrome. HbS is v common in W.Africa as it protects against malaria
• the anaemia is usually mild and okay as HbS readily gives up O2 compared to HbA BUT problem comes in a low O2 state when deO2 HbS forms polymers causing RBCs to become sickle shaped, irreversible ones are less deformable so can’t be flexible in BVs therefore cause an occlusion and stick together.
• crisis =when the sickle cells cause a blockage in a small BV causing immense pain. 1) vase-occlusive= most common, painful bone crises 2) aplastic=often triggered by parvovirus 3) haemolytic
• retinopathy, splenic atrophy, a vascular necrosis eg femoral head, acute chest syndrome, stroke

Question 6

• what are haemolytic anaemias?where do they happen? what lab findings are there?
• give inherited and acquired reasons for haemolytic anaemia.
• what signs and symptoms are there?
• describe 3 inherited defects in red cell membrane structure
• give the name for the anaemia describing mechanical damage of RBCs (acquired). give reasons.

Answer 6

• abnormal breakdown of RBCs, can happen in BVs (intravascular haemolysis) or spleen and rest of RES (extra vascular haemolysis), BM can only compensate so much, anaemia will develop if rate of destruction> rate of production.
• inherited= (defective gene) glycolysis defect (eg pyruvate kinase deficiency causes lack of ATP for RBCs), pentose phosphate pathway defect (NADPH drops therefore RBCs more prone to oxidative damage), membrane protein (eg hereditary spherocytosis), Hb defect (sickle cell). Acquired= mechanical damage, Ab damage (autoimmune haemolytic anaemia), oxidant damage (exposure to chemicals), heat damage, enzymatic damage.
• raised reticulocytes (as BM attempts to compensate), raised bilirubin (breakdown of haem), raised LDH (RBCs rich in this enzyme)
• accumulation of bilirubin causes jaundice, pigment gallstones, splenomegaly, massive sudden haemolysis can cause cardiac arrest & hyperkalaemia
• hereditary spherocytosis=spherical RBCs, cells less flexible, ankyrin, spectrin, protien 4.2 or Band 3 defects disrupt RBC shape. Hereditary eliptocytosis=elliptical shape, spectrin defect most common. Hereditary pyropoikilocytosis=spectrin defect, severe form of hereditary elliptocytosis
• called microangiopathic haemolytic anaemias, sheer stress as cells pass through stenosed valve, cells snagging on fibrin strands on small vessels where clotting cascade is active eg disseminated intravascular coagulation, heat damage or osmotic damage, forms schistiocytes

Question 7

• what causes autoimmune haemolytic anaemias?
• what are they classified as?
• how does that then contribute to anaemia?

Answer 7

• caused by autoantibodies binding to RBC membranes, can result from infections or cancers.
• classified as warm (IgG) or cold (IgM) based on temps antibodies react best at under lab conditions
• spleen then recognises antibody bound cells as abnormal and removes them & reduced lifespan of RBCs causes anaemia.