MEH 9 - Haemolytic Anaemias + Haemaglobinopathies Flashcards
What is the general structure of Hb?
What are haemoglobinopathies?
What are the 2 major kinds of these disorders + their major causes?
- Hb is a tetramer of 4 globin polypeptide chains (2 alpha, 2 non-alpha) + O2 binding haem group (in each globin chain)
- Haemoglobinopathies are defects in globin chain synthesis, typically autosomal recessive disorders.
1) Sickle cell disease - globin gene mutations altering the function/stability/structure of Hb.
2) Thalasseaemias - reduced or absent expression of normal globin chains, due to globin gene mutations, leading to an imbalance in the composition of the tetramer.
Which form of Hb is primarily expressed prior to birth?
Which form commences at birth and steadily becomes dominant?
- Fetal Hb (HbF) which is 2 x alpha, 2 x gamma chains.
- HbA, which is 2 x alpha, 2 x beta chains.
Describe the pathological basis for a/thalassaemia?
- Normally have a 1:1 ratio of alpha to non alpha globin genes (tightly regulated).
- Defects in regulation lead to abnormal expression of the amount of globin genes proteins (alpha globin expression affected in a-thala, beta in b-thala).
What are the 4 types/classifications of a-thalassaemia?
What are these classifications based upon?
- Humans have 4 x a-globin genes, 2 on maternal/paternal chromosome 16. Classification depends on how many of the 4 are deleted.
1) Type 1 - asymptomatic - carrier w/no symptoms
2) Type 2 - a-thalassaemia trait - minimal to no anaemia. Either both genes on one chromosome or one on each deleted.
3) Type 3 - HbH disease - moderately severe - tetramers of B-globin form (called HbH) resulting in microcytic + hypochromic anaemia w/target cells + Heinz bodies.
4) Type 4 - Severe - usually inter-uterine death - excess y-globin forms tetramers in foetus (Hb Bart), unable to delivery oxygen to tissues.
What is B-thalassaemia caused by?
What are the 3 types of B-thalassaemia, their severities and genotype?
- Often by Chr11 gene mutation rather than deletion. B0 = total absence of production, B+ = reduced globin production.
1) B-thalassaemia minor- usually asymptomatic - heterozygous w/1 normal + 1 abnormal gene (B0/B or B+/B)
2) B-thalassaemia intermedia - severe anaemia but doesn’t require regular transfusions - mild homozygous or severe heterozygous.
3) B-thalassaemia major - severe + blood transfusion dependent - homozygous (Bo/Bo or B+/B+)
What would a peripheral blood smear from someone with thalassaemia show?
What other factor also contributes to the defective nature of the red cell during thalassaemia?
- A blood smear would show hypochromic & microcytic red cells. Also anisopoikilocytosis with target cells, nucleated red blood cells + heinz bodies.
- Excess of unaffected globin chains. Hb aggregates get oxidised resulting in premature death of erythroid precursors in bone marrow and excessive destruction of mature red cells in spleen (therefore thalassaemia also a form of haemolytic anaemia).
What are the 4 main consequences of thalassaemia?
1) Extramedullary haemopoiesis - in an attempt to compensate low Hb, causes splenomegaly + hepatomegaly.
2) EPO stimulation due to low oxygen delivery, further contributing to defective RBC production.
3) Iron overload - due to excessive absorption of dietary iron (due to ineffective haemopoiesis) + repeated blood transfusions required to treat anaemia - major cause of premature death.
4) Premature death.
What are the treatment strategies for thalassaemia?
- Red cell transfusions from childbirth
- Holistic care - to pick up and manage complications
- Stem cell transplants - to replace defective RBC production.
What is the cause of sickle cell disease?
What are the potential genotypes an individual can have?
- Autosomal recessive disorder, where glutamic acid is replaced by valine at position 6 on the B-globin gene - Mutant Hb called HbS.
- Heterozygous (HbS) are carriers w/mild asymptomatic anaemia
- Homozygous (HbSS) have severe sickling syndrome
- HbS can also be co-inherited with another abnormal Hb, e.g.: HbC (so HbSC).
When do problems arise in those with sickle cell disease?
What are the symptoms experienced because of this?
- Anaemia usually mild and well tolerated as HbS gives up oxygen readily (compared to HbA).
- Problems arise in low oxygen state - deoxygenated HbS forms polymers that cause red cells to form sickle shape, which occlude small blood vessels.
- Acute chest syndrome, stroke, reduced life expectancy, kidney infarcts, AVN in femoral head etc.
What are haemolytic anaemias?
What are the 2 different ways in which they are caused?
- Haemolytic anaemias are disorders involving abnormal breakdown (haemolysis) of RBC’s in blood vessels (intravascular haemolysis) + spleen (extravascular). When this breakdown exceeds the rate of compensation by bone marrow - anaemia occurs.
1) Inherited - e.g.: Hb defects such as sickle cell or membrane protein defects, e.g.: hereditary spherocytosis or enzymatic defects such as pyruvate kinase or G6PDH deficiency.
2) Acquired - e.g.: autoimmune haemolytic anaemia, severe burns or mechanical damage, e.g.: microangiopathic anaemias.
What are the complications associated with haemolytic anaemia?
Therefore, what are the key laboratory findings from someone with a haemolytic anaemia?
- Accumulation of bilirubin (due to RBC breakdown) causes jaundice + pigment gallstones.
- Overworking of red pulp causes splenomegaly.
- Massive sudden haemolysis can cause cardiac arrest + hyperkalaemia.
- Raised reticulocytes, raised bilirubin + raised LDH
How does mechanical damage result in microangiopathic haemolytic anaemia?
- Sheer stress as cell pass through defective heart valve (e.g.: aortic valve stenosis) - this produces fragments called schistocytes which is a good indicator of the disorder or …
- Cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occurred.
What is the cause of autoimmune haemolytic anaemias?
What are the 2 classifications?
- Autoantibodies binding to red cell membrane proteins after infections.
- Spleen recognises antibody bound cells as abnormal and removes them - causing anaemia.
- Classified as “Warm” (IgG) or “cold” (IgM) based on temp that antibodies react best under in laboratory conditions.
