haemoglobinpathies and haemolytic anaemias Flashcards
What is sickle cell anaemia and how does it affect haemoglobin
- sickle cell anaemia HbS is an autosomal recessive disease.
- caused by the point mutation to uncharged valine from charged glutamic acid.
- It makes Haemoglobin more prone to polymerisation at low oxygen tension leading to the formation of long twisted haemoglobin polymers that can result in the deformation of the red blood cell. this is reversible however repetitive sickling can lead to permanent change.
what is a haemolytic anaemia
they result from the abnormal breakdown of red blood cells in vessels( intravascular haemolysis) or the spleen ( extra vascular hemolysis.
what is the main consequence of chronic haemolytic anaemia
shortness of breath
fatigue
accumulation of bilirubin , leading to jaundice and associated risk of complications like gallstones.
what test do we use to test for autoimmune haemolytic anaemias
the direct Coombs test, it is used to detect antibodies or complement bound to the surface of red blood cells.
isolated red blood cels are incubated and anti human globulin is put on them. a positive test will agglutinate. the antihuman antibodies from links between the red blood cells by binding to the human antibodies on the RBC’s
To be able to classify haemolytic anaemias into acquired and inherited types, and explain the underlying causes in each division
Inherited haemolytic anaemias are due to defective genes, examples are : glycolysis defects like pyruvate kinase deficiency which limits ATP production.
G6PDH deficiency which leads to oxidative damage.
Hereditary spherocytosis which affects the membrane protein
Haemoglobin defects like sickle cell anaemia
Acquired Haemolytic anaemias are due to damage to cells. examples are :
Mechanical damage like microangipathic anaemia
Antibody damage ( autoimmune haemolytic anaemia)
Oxidant damage
Heat damage e.g severe burns
Enzymatic damage e.g snake venom.
what chromosome are the a-globin genes found on?
chromosome 16
what chromosome are the b-globin genes found on?
chromosome 11
what is a haemoglobinopathay
inherited disorders where expression of on or more of the glib chains of haemoglobin is abnormal. typically autosomal recessive.
there are two categories:
abnormal haemoglobin variants: due to a mutation in the genes for aloha or beta globin chains that alter the stability/function of the haemoglobin. (sickle cell)
thalassemias are caused by reduced or absent expression of alpha or beta globin chains. this leads to a reduced level of haemoglobin rather than an abnormal haemoglobin.
what are the types of haemoglobin chains
fetal (F) A2/Y2 (alpha and gamma)
Adult (A) A2/B2 (alpha and beta)
and( A2) A2/D2 ( alpha and delta)
they exist as an adaptive response to variations in oxygen requirements.
where are the globin genes encoded? and what controls the expression of the different genes.
chromosome 16 (alpha) and 11(beta) . locus control regions regulate the expression of the different genes, this is what allows you to go from having fetal haemoglobin to adult haemoglobin
what is alpha thllasaemia?
where the alpha globin gene is affected. disrupting the ratio of alpha to non alpha globin chain proteins. this can cause issues in both the relative and absolute amounts of the globin chain proteins. it is more prevalent in Far East populations.
what is the clinical consequence of having 3 deletion in the alpha globin genes
three or more deletions lead to Haemoglobin H disease, which is moderately sever. if there are exactly 3 deletions there will still be some production of alpha globin.
the consequence is microcytic hypo chromic anaemia with target cells and Heinz bodies(irreversibly denatured haemoglobin attached to the erythrocyte cell membrane)
how does the amount of alpha globin genes deleted affect the severity of alpha thallasaemia
1 deletion: silent carrier state- symptomatic.
2 deletion: alpha thalassemia trait- minimal or no anaemia - could be both alpha genes on one chromosome deleted or one on each- causes microcystosis and hypochromia in RBC’s. very similar to B-thalassemia minor
3 deletions - haemoglobin H disease: moderately severe. tetramers of B-globin form resulting microcytic, hypochomic anaemia with target cells and Heinz bodies. resembling B-thalassemia intermedia
what causes sickle cell anaemia
a mutation of glutamic acid in the sixth position to valine.
HbS readily gives up oxygen better than
in low oxygen conditions the HbS polymerises and forms a sickle shaoe this is reversible short term blur repetitive sickling cycles can lead to irreversible sickled RBC’s and this occulusions in small blood vessels
what are the three types of clinical pattern
vaso-occulusive episodes to occlusion of small capillaries due to sickle cells being trapped.
- painful bone crises
- acute chest chest syndrome
-chronic kidney diseases
-joint problems from vascular necrosis
-strokes
Aplastic( often triggered by parvovirus)
Haemolytic
End-organ damage occurs as a result of acute thrombosis or o2 deprivation.
splenic atrophy due to splenic infarction with an associated susceptibility to infection by encapsulated bacteria such as streptococcus pneumoniae and streptococcus meningitidis.
what does occlusion in small blood vessels lead to
Retinopathy
Splenic atrophy
Avascular necrosis (e.g femoral head )
Acute chest syndrome
Stroke
Osteomyelitis
Skin ulcers
Kidney infarcts
Priaprism.
what is the clinical consequence of having 3 deletion in the alpha globin genes
three or more deletions lead to Haemoglobin H disease, which is moderately sever.
the consequence is microcytic hypo chromic anaemia with target cells and Heinz bodies(irreversibly denatured haemoglobin attached to the erythrocyte cell membrane)
what is the severity and the genotype of someone with Beta thalassemia major
they are homozygous recessive, the inability to produce HbA the patient will have severe microcytic and hypochromic anaemia the anaemia is severe, they are transfusion dependant.
these symptoms manifest between 6-9 months after birth as synthesis switches to from HbF to HbA.
excessive extra medullary haemopoeisis wil occur in an attempt to keep up with haemolysis there for they will have abnormal skills.
- hepatosplenomegaly
- iron overload( due to transfusions causing build up in the liver spleen and bone marrow)
what is iron overload and what are associated risk factors
iron overload is when there is an accumulation of iron in the body.. initially iron is stored in the liver spleen and bone marrow. excessive iron levels can lead to iron being stored in the heart, pancreas, joints and skin.
excess iron can damage these organs.
excessive blood transfusions ( 20 units) , alcohol consumption
alcohol consumption ( can also damage the liver.it supresses hepcidin. hepcidine reduces the iron entry to plasma from absorptive duodenal cells so alcohol increases iron entry to the blood).
