CSI - Murewa Abebi and Sickle Cell disease

Question 1

Symptoms: vision loss

Answer 1

• angiogenesis proliferating retinopathy
• sickle cells accumulate within the micro vessels in the retina increasing the pressure and damaging the vessels
• sickle cell ischaemia releases chemokines to stimulate the growth of new blood vessels to maintain oxygen to retina

Question 2

symptoms: bone crises

Answer 2

• reduced blood flow to the bone marrow due to sickling within blood vessels leading to microvascular occlusion
• inadequate blood flow to the bone tissue leads to oxygen deprivation and prolonged ischaemia leads to infarction causing avascular infarction and osteonecrosis

Question 3

symptoms of sickle cell disease: strokes

Answer 3

• ischaemic stroke as the cerebral artery is blocked resulting in oxygen deficiency
• silent strokes are asymptomatic and occur due to sickling in smaller blood vessels within the brain
• haemorrhagic stroke: aneurysmal bleed in the cerebral arteries due to angiogenesis as the collaterals are easily borken
• blockage and ischaemia releases selectins damaging blood vessels and increasing susceptibility of sickling further reducing oxygen supply to respiring tissues

Question 4

other symptoms of sickle cell (6)

Answer 4

• sickle cell anemia (erythrocyte/haemoglobin deficiency)
• jaundice is due to excess bilirubin due to haemolysis
• pain crises, shortness of breath, strokes
• splenomegaly - enlarged spleen due to higher proportion of foetal haemoglobin
• acute crisises (pain in hand joints
• chronic - gall stones, kidney damage

Question 5

how can you diagnose sickle cell? (3)

Answer 5

• electrophoresis
• sickle cell solubility test
• screening

Question 6

diagnosis of sickle cell disease: screening

Answer 6

• pregnant women are screened for the trait
• genetic counselling is offered for couples who are both heterozygous for the disease, allowing them to make an informed decision
• new-borns are screened using haemoglobin isoelectric focussing (Hb IEF) by taking a heel-prick sample of blood

Question 7

diagnosis of sickle cell: electrophoresis of sickle cell disease

Answer 7

• AFSC control involved
• there is an intense band in the HbS region (greater concentration) and a lower concentration of Hb
• HbF band is more prevalent due to compensatory mechanism
• valine is uncharged whereas glutamate is so HbS is further away from the anode

Question 8

treatment of sickle cell disease (4)

Answer 8

• blood transfusions
• treating crises
• hydroxycarbamide
• gene therapy

Question 9

preventing triggers of a vaso-occlusive crisis (3)

Answer 9

• avoid cold weather as it leads to stimulated vasoconstrictions which narrow blood vessels and lead to increased susceptibility of clotting and blockage
• avoid strenuous exercise as it leads to decreased deoxygenation of haemoglobin leading to conformational change triggering sickling
• dehydration

Question 10

Why is blood transfusions used to treat sickle cell?

Answer 10

• used to treat sickle cell anemia
• however, multiple tranfusions may lead to hemosiderosis (damgaging liver, heart, pancreas and other organs) and lead to diabetes

Question 11

How can you treat crises?

Answer 11

• pain associated with sickle cell can be treated with painkillers (ibuprofen and aspirin)
• severe pain can be treated using opiods (morphine)
• keeping hydrated, keeping warm
  AVOIDING AREAS OF HIGH ALTITUDES AND LOW OXYGEN LEVELS

Question 12

How can you treat sickle cell using a bone marrow transplant?

Answer 12

• removes mutated haemopoetic stem cells which then generates functioning erythrocytes without the mutated gene
• procedure is only available to patients severely suffering from the disease, are young and have a matched sibling

Question 13

How can you treat sickle cell using gene therapy?

Answer 13

• modified sterile viral vectors are used to insert the functional gene with in the HSCs
• restriction endonucleases are used to catalyse the hydrolysis of phosphodiester bonds between adjacent nucleotides to remove the dysfuncional gene and replace using a functioning gene using ligases

Question 14

Pathophysiology of sickle cell: genetic changes

Answer 14

• there is a base substitution in the gene for the B-polypeptide chain of haemoglobin at codon number 6
• the amino acid changes from a charged glutamate to an uncharged valine

Question 15

Pathophysiology of sickle cell: haemoglobin (HbS)

Answer 15

• haemoglobin consists of 2 alpha and 2 beta chains (tetrameter)
• if the Betachains are altered, this forms Haemoglobin (HbS)
  -HbS is insoluble at low partial pressures (in its deoxygenated form) and crystallizing forming a sickle cell shape
• deformation of erythrocyte causes vascular occlusion leading to sickle cell anaemia
• HbS occurs when one or two copies of an abnormal B globin gene are inherited

Question 16

Pathophysiology of sickle cell: HbS mechanism

Answer 16

• deoxygenation causes haemoglobin molecules to undergo conformational changes - the amino acids interact through hydrophobic interactions
• exposed hydrophobic surface area causes the haemoglobin molecule to be associated with each other
• haemoglobin molecules polymerise into fibres, due to valine interlocking protrusion
• haemoglobin molecules accumulate together forming rigid polymers
  this distorts the cell, changing the shape - THIS IS SICKLING

Question 17

What is the effect of acidosis?

Answer 17

decreases the affinity of the erythrocyte to oxygen

Question 18

what is the effect of low-flow vessels?

Answer 18

this increases the deoxygenation time

Question 19

What are the amino acid in HbA vs HbS?

Answer 19

• HbA - alanine, leucine (hydrophobic) and glutamate (hydrophilic)
• HbS - alanine, leucine and valine (hydrophobic)