inherited Hb disorders Flashcards
describe the structure of Hb
tetrameric complex of globin chains
each globin chain is associated with a haem group
each haem group carries a single atom of iron
haem groups carry oxygen
in adults the main Hb type is HbA which is 2 alpha chains and 2 beta chains (2 genes encode alpha chain on chromosome 16 and 1 gene encodes beta chain on chromosome 11)
what common variations of Hb structure exist ?
HbF is found in the fetus. This is made of 2 alpha chains and 2 gamma chains and switches to adult Hb within the first year of life.
HbA2 is a variant made of 2 alpha and 2 delta chains
how are Hb disorders classified?
into qualitative and quantitative disorders
qualitative - changes to the globin chain amino acid sequence that results in variant Hbs eg. sickle cell disease
quantative - complete or partial reduction of globin chain production eg. thalassaemia
what is sickle cell disease and what are the genetic variations?
autosomal recessive condition which is a genetic polymorphism that results in substitution of the amino acid valine for glutamic acid at position 6 of the beta globin chain.
HbSS - homozygous - both alleles are mutated giving sickle cell disease so they only make HbS haemaglobin which is 2 alpha chains and 2 S chains
HbAS - heterozygous - only one allele is mutated so they are a carrier for sickle cell disease meaning they make both HbA and HbS
what are the advantages and disadvantages of being a carrier for sickle cell disease?
advantages - evolutionary advantages which gives protection against falciform malaria.
disadvantages - it is useually asymptomatic with a normal life expectancy however it may be associated with renal disease, splenic infarction, increased risk of thromboembolism, pregnancy complications and sickling under extreme physiological stress. There is also the risk of giving sickle cell disease to the offspring
what are the advantages and disadvantages of being a carrier for sickle cell disease?
advantages - evolutionary advantages which gives protection against falciform malaria.
disadvantages - it is useually asymptomatic with a normal life expectancy however it may be associated with renal disease, splenic infarction, increased risk of thromboembolism, pregnancy complications and sickling under extreme physiological stress. There is also the risk of giving sickle cell disease to the offspring
what populations are at risk of sickle cell disease?
- african / carribean heritage
- middle eastern herritage
- south asian herritage
outline the pathophysiology of sickle cell disease
HbS has the potential to polymerase when in the deoxyhaemaglobin state (no oxygen attatched) which alters the structure of the RBCs and they will appear sickled on a blood film. This reduces the deformability of RBCs and results in vaso-occlusion. There is also a decreased lifespan of RBCs due to haemolysis. (haemolysis can cause jaundice and pigmented gallstones). There is a compensatory increase in RBC production which can cause reticulocytosis and folate deficiency.
outline the acute presentation of sickle cell disease
vaso-occlusive crisis - this is the occlusion of small blood vessels by sickled RBCs. This may be precipitated by temperature change, infection, stress, pregnancy etc. It can be painful and has varying intensity but is often severe
acute chest syndrome - this occurs when the pulmonary vasculature becomes occluded. It causes chest pain, rib pain, tachypnoea, cough, hypoxia, fever and there may be evidence of consolodation or pulmonary infiltrates on CXR. patients at high risk are those who are inpatients for a vaso-occlusive crisis, are pregnant or are post partum and it has a risk of recurrance.
stroke - infarct or haemorrhage
acute splenic sequestation - sickling in spleen
acute hepatic sequestation - sickling in liver
priapism - erectile dysfunction
growth delay
infections - septacaemia, menningitis, UTI, osteomyelitis. Causes hyposplenism so at particular risk of encaspsulated organisms such as pnuemococcus, menigiococcus and haemophillus
how is an acute vaso-occlusive crisis treated?
analgesia
fluids
oxygen
low molecular weight heparin
how is acute chest syndrome treated?
this is an emergency so needs to be recognised early
immediate cross match urgent critical care review respiratory support - 02, CPAP, ventillation general support - fluids, physio etc tranfusion - top up or exchange
outline the chronic presentations of sickle cell disease
renal - concentration defect, CKD
lungs - chronic sickle lung
strokes - infarct or haemorrhage
cardiac - cardiomegaly, right heart failure, pulmonary hypertension
eyes - retinopathy
hepatobiliary - gallstones
leg ulcers
avascular necrosis of femoral heads
erectile dysfunstion seccondary to priapism
how is chronic sickle cell disease managed?
- education
- psychological support
- primary / seccondary prevention
- screening - children have transcranial dopplers to assess risk of stroke and adults have echocardiography for pulmonary hypertension
- management of established complications
specific interventions
- folic acid
- analgesia
- infection management - prophylactic antibiotics, vaccinations
- blood transfusion
- hydroxycarbamide - in patients with severe reccurent painful crisis or acute chest crisis. reduced HbS and increases fetal Hb.
how are blood transfusions given in sickle cell disease? what are the risks?
top up transfusion
exchange transfusion
regular transfusion programmes - eg. to prevent stroke in children identified at risk from transcranial doppler screening
it is risky and should always be discussed with a specialist
- alloimmunisation
- haemolytic transfusion reaction
- transfusion associated infections
- iron overload in chronic transfusion
- hyperviscosity
what is alpha thalassaemia?
a reduction in production of alpha globin chains causing a lack of HbA and a relative increase in production of beta and gamma Hb chains causing an increase in abnormal varients of Hb
autosomal recessive inheritence of 2 genes (4 alleles)
this produces unstable red cells which causes ineffective haematopoeisis and haemolysis leading to anaemia
