haemoglobin and thalassemia Flashcards
when synthesis of haemoglobin occurs and why
during development of RBC, mostly in erythroblast stage, but also reticulocyte stage because RBC have no nucleus or MITOCHONDRIA, so synthesis must occur during RBC development
structure of haemoglobin and where haem and globin produced
2 alpha and 2 beta chains for HbA haem produced in mitochondria- Fe2+ endocytoses into cell as transferrin, and released: synthesis regulated by enzyme ALAS: when too much produce, - feedback occurs globin chains produced in ribosomes in cytosol
haem component- what its made out and what molecules have it
combination of protoporphyrin ring with central Fe atom= Fe combines with oxygen also present in other proteins like myoglobin and peroxidases
globin synthesis- clusters, chains formed and defects DIAGRAM
8 types of globin chains formed by 2 clusters- beta (Chr 11) and alpha (Chr 16) cluster alpha cluster forms embryonic globin chain called azita chain, and alpha chains- azita chains die off after 6 weeks, so embryo reliant on alpha chains- defect of alpha cluster= alpha thalassemia= affects early at embryonic stage beta chains important for foetal and adult globin chains, including delta, gamma- form gamma chains for foetus, then beta chain after birth- defect in beta cluster= beta thalassemia= presents 5 months after birth (as foetus/baby can survive few months with alpha and gamma chains ie foetal haemoglobin)
adult haemoglobins + electrophoresis DIAGRAM
HbA (97%), Hb A2 (alpha and delta-2%) and HbF (alpha and gamma- 1%) in electrophoresis , HbF left of HbA, HbA2 right to HbA
globin structure- secondary and tertiary
secondary structure has helical arrangment, and tertiary forms a sphere, with hydrophilic surface, and hydrophobic core, with a haem pocket (wher O2 can access)
oxy vs deoxyhaemoglobin
higher conc of 2,3 DPG in deoxyhaemoglobin changes shape of globin chains, preventing O2 accessing the haem POCKET
p50 and use
partial pressure of O2 where 50% Hb bound to O2- used to compare affinities of different haemoglobins
factors affecting dissociation curve
HbF, decrease ins 2,3 DPG and increased pH/low CO2a shifts curve to left (higher affinity), opposite and HbS shifts curve to right
2 types of haemoglobinopathies and important point
either due to mutation causing structural change in haemoglobin, or less globin chain synthesiss ie thalassemia HAEM ALWAYS SAME, DEFECTS ONLY DUE TO GLOBIN PART
classification of thalassemia
either by globin type affect (alpha/beta), or by severity (minor/trait= asymptomatic as carrier, intermedia possibly symptomatic, major NEEDS transfusions as both genes mutated)
beta thalassemia- cause, how many genes and prevalence
mutation of beta globin gene= fewer beta globin chains there are 2 beta genes- if heterozygous, you are carrier prevalent in mediterranean coutnries, africa and south asia
inheritance of beta thalassemia
autosomal recessive- if two carriers mate, there is 25% chance of child being a major carriers can either be BB0 or BB+- B+ means it’s partially defective, B0 means no chains can be produced, so child with B0B+ is intermediate, as one gene not COMPLETELY defective
diagnosis of thalassema
full blood count- low MCV, Hb only slgihtly reduced
film- target cell and poikilocytosis (vary in shape eg teardrop): should be hypochromic (greater central pallor due to less haemoglobin) and microcytic (smaller in size), as thalaseemia microcytic
can also see nucleated red blood cells HPLC (electrophoresis)- beta shows raised HbA2 and HbF (normal HbA due to normal alpha chain), alpha difficult as normal HbA2/HbF globin chain analysis- often for alpha thalassemia
featurs of thalasseamia major
hepatosplenomegaly- liver and spleen sense low haemoglobin so enlarge to do more haematopoesis bone marrow do erythroid hyperplasia blood film
clinical features of beta thalassemia and effect of excess iron
fatigue, jaundice (alpha chains without beta more vulnerable to haemolysis), delay in growth/puberty, hepatosplenomegaly, skeletal issues and excess iron excess iron can lead to cardiac and liver failure, as well as endocrine issues with pituitary
causes of death in beta thalassemai
mainly due to cardiac failure from iron overload- also infections and liver disease
treatment of thalassemia major
1st line treatment is regular transfusions and iron chelation (transfusions exacerbate iron overload, so need to reduce it) splenectomy may be needed if transfusion requirement very high, hormone therapy for endocrine issues, hydroxyurea to boost HbF, and bone marrow transplants (only curative treatment)
if thinking of having child, look at partner, and genetic counselling if needed
how transfusions given
must match red cells of donor to patient to prevent immune attack give every 2-4 weeks
managing infection
often infected by organisms that like iron eg yersinia, so prophylaxis ie antibiotics needed
when and how iron chelation therapy given and example
after 10-12 transfusions, eg DFO given via injection newer forms given orally, takes less time to give (3-4 hrs vs 12 hrs)- can also be used in combination
importance of iron chelation, compliance and hwo i
has dramatically increased survival due to complications of iron overload those with lower compliance ( ie don’t want to do it as takes very long )to DFO survive less
side effects of iron chelation
newer forms cause GI symptoms and liver/renal issues DFO can cause skeletal issues, renal issues, and increased infection risk (due to drop in WBC)
monitoring iron overload
serum ferritin (protein that stores iron) liver biopsy (rarely done) hepatic/cardiac MRI- newer form of MRI called R2 MRI looks at liver iron conc
HbH disease and alpha thalassemia
there are 4 alpha globin genes- problems with 3 of them causes HbH disease (intermedia), where shapes are varied, but central pallor not so big as
HPLC for HbH disease
should see random peaks left of HbA peak eg HbH
test what kind of jaundice
conjugated and unconjugated levels
haemolytic uraemic syndrome
most common cause of renal failure in children- dark urine, haemolytic (prehaptic) jaundice, high reticulocyte count (due to haemolysis), red cell fragments in blood film
