CPS 1 SICKLE CELL DISEASE Flashcards
Describe the causes + risk factors of SCD
- Inherited genetic disease
- Affects primarily people of African descent
- Disorder affecting beta globin chain of pigment haemoglobin present in RBC (therefore, abnormal haemoglobin molecules, so abnormal rbc, so sickle cell)
- Multisystem disorder
Normal Red Blood Cells
- Biconcave, disc-shaped cells
- Anucleate
- Larger than capillary lumen
- Highly flexible
- Squeezes to travel through capillary, then un-squeezes to regain normal shape
- Life span - 120 days in circulation before removed
- Removed + Recycled by reticuloendothelial system (spleen)
Describe haemoglobin function
- Transport O2 from lungs to tissues for metabolism
- Transport CO2 from tissues to lungs for excretion + binding of H+ ions + maintenance of pH
- Hb binds o2 in lungs + unbinds (releases) to tissues
NEEDS TO HAVE ABILITY TO BIND + UNBIND in reversible manner.
Describe haemoglobin structure
- Quaternary protein structure
- Tetramer - 4x polypeptide globin chains with 4 haem ions (Fe2+) in poryphrin rings (each chain has central haem group which consists of porphyrin ring)
- Oxygen binds to Fe2+ to form oxyhaemoglobin
Each Hb binds 4 oxygen molecules
Chemical structure of single haem molecule
State different types of haemoglobin
HbA - 2x alpha +2x beta - adult haemoglobin
HbA2 - 2x alpha and 2x delta - also found in adults but lower quantity
HbF - 2x alpha and 2x gamma - foetal haemoglobin. Produced by new borns till 6 months. HbF decreases now, HbA production increases
Each type has different affinity for O2 (due to different structure)
Affinity - attraction between haemoglobin + oxygen molecule
Higher affinity - higher attraction between haemoglobin +oxygen
How does haemoglobin have the ability to bind and unbind to O2 in a reversible manner?
- Haemoglobin undergoes conformational change during O2 uptake + release
- Haemoglobin is a neurotic molecule - exists in two different states
- T (tense): low O2 areas. Low oxygen affinity (gives up O2 more easily to tissues)
- R (relaxed): high O2 areas. High oxygen affinity (found in lungs, o2 conc higher, haemoglobin quickly picks up o2) - Hb molecule oscillates between these two states
Describe the process of cooperative binding within haemoglobin molecules
- Hb in T form. Difficult to bind first O2
- First O2 binds. Hb relaxes.
- Binding of successive O2 easier
- All 4 binded, Hb is in R state. Fully saturated
Dissociation works in similar way
Dissociasion of first O2 from Hb is difficult
However, once first O2 dissociates, makes it easier for rest to dissociate - cooperative dissociation
FOCUS ON DIAGRAM SHOWING T STATE + R STATE
Diagram showing Hb in T state and R state
Oxyhaemoglobin Dissociation Curve
Oxyhaemoglobin Dissociation Curve
- Initially flat - binding of first oxygen molecule difficult
- Steepens rapidly - First O2 binds. Hb relaxes. Binding of successive O2 easier (pO2 rises)
- Plateau - All 4 binded, Hb is in R state. Fully saturated
Typical % of O2 Saturation in Lungs
Factors affecting O2 saturation
Dissociation curve can shift to left / right
SCD shifts curve to right
Foetal Hb shifts curve to left. HbF must have higher affinity for O2 in order to attain it from maternal circulation. HbF competing with HbA within mother for O2, therefore, needs higher affinity
Pathophysiology / Mechanisms of disease for SCD
- Production of abnormal haemoglobin (HbS)
- Autosomal Recessive (both parents must be carriers HbAS
- Carriers partially protected against malaria - malaria parasite dislikes sickle cells (carriers more common in Africa, because sickle cell trait offers protection against malaria, so, trait has been positively selected for in regions where malaria is common e.g. Africa)
Describe SCD transmission
- HbAS - sickle cell trait (carrier, no symptom, unless exposed to extreme low levels of O2)
- HbSS - sickle cell anaemia (homozygous genotype, patient with disease!)
- HbSc - combined heterozygosity for HbS + HbC (sickle cell disorders occur in heterozygous states with other Hb variants
How is HbS produced?
HbS - abnormal haemoglobin
- Single base mutation affecting beta globin chain
(Adenine nucleotide changed to thymine. This results in the substitution of glutamic acid to valine) - Change of one amino acid changes haemoglobins solubility
- Glutamic acid: hydrophillic, attracted to water, more soluble
- Valin: Hydrophobic, repels water, insoluble - Change in solubility makes HbS less water soluble and more hydrohobic
- Creates sticky pockets so molecules clump together into
strands - HbS molecules polymerise when oxygen levels are low
- Sickle cells are rigid + inflexible (compared to highly flexible, normal RBC, this is where the issue is)
- The above is initially reversible but eventually becomes irrervsible (polymerised sickled T state in tissues which are poor in O2 can change into un-polymerised biconcave R state in lungs which are rich in O2. But, constant switching back and forth damages + causes severe strain RBC membrane which results in permanent sickling
- Permanently sicked RBC are defective. Removed by spleen at faster rate than usual
Sickle Blood Film
Pay attention
Difference between normal + sickle cells.
Elongated crescent shape
State 2 consequences of SCD
- Chronic haemolysis (RBC breakdown) - leads to aneamia
rbc only last 10-20 days opposed to normal 120 days - Vaso-occlusion (Vessel blockage) - sickled RBCs cause obstruction of circulation. Abnormally shaped RBCs cannot flow through vessels as well as normal shaped ones. (Due to reduced flexibility + elongated shape when sickled) - SEVERE PAIN
Define anaemia
Reduction in Hb below reference level (based on age + sex)
State different types of Jaundice
- Pre-hepatic - excess RBC breakdown (due to SCD)
- Hepatic - liver fails (cirrhosis)
- Post-hepatic - bile outflow obstructed (gallstones)
