sickle cell disease

Question 1

mutation of gene in sickle cell

Answer 1

missense mutation at codon 6 in gene for beta globin chain, where polar soluble glutamate replaced by non polar insoluble valine, forming the SOLUBLE HbS

Question 2

stages of sickling of red cells

Answer 2

distortion where they lose biconvave shape and become RIGID

they DEHYDRATE to concentrate HbS in RBC even more, and are more ADHERENT to endothelium= more ischaemia

Question 3

distribution of sickle gene and epi in UK

Answer 3

mainly africa, mediterranean and middle east

15000 with SCD in UK, mainly in London

Question 4

effect of sickling- anaemia

Answer 4

RBC’s have shorter lifespand than 120 days, so mroe haemolysis= anaemia, gall stones and aplastic crisis (low levels of haemoglobin due to parvovirus infection)

anaemia not only due to shortened lifespan, but also fact that HbS is lower affinity than HbA

Question 5

effec of sickling- tissue damage

Answer 5

blocks microvascular circulation= tissue damage due to infarction, acute pain and organ dysfunction

Question 6

effect of tissue infarction

Answer 6

can damage spleen- increased infection from bacteria

damages bones= dactylitis (swelling in feet and hands= pain) and osteomyelitis (increased risk of fractures)

affects skin due to chronic leg ulcers

Question 7

reason for vasoocclusion

Answer 7

HbS polymers form to cause sickling- they are deformed, adhere more to endothelium and attract WBC, all of which cause occlusion

Question 8

SCD and nitric oxide

Answer 8

haemolysis within blood vessels releases free haemoglobin, which limits NO availability= vasoconstriction= pulmonary hypertension= lower survival rate

Question 9

other effects of SCD- different organs

Answer 9

lungs- pulmonary hypertension and acute chest syndrome (fever, cough, chest pain)

kidney- cannot concentrate urine, blood urine and renal failure

brain- stroke risk

eyes- retinopathy

Question 10

early presentation of SCD

Answer 10

generally asymptomatic before 3-4 months as HbF present, but once it decline, leads to dactylitis, infection and splenic sequestration (spleen enlarges= pooling of blood)

Question 11

what has caused improvement in survival

Answer 11

pencillin prophylaxis and parental education (looks for abnormal abdomen)= reduced deaths from PNEUMOCOCCAL infection and SPLENIC SEQUESTRATION

Question 12

life expectancy in SCD

Answer 12

has improved, but still between 40-50 yrs, mainly due to penicillin and HYDROXYCARBAMIDE

Question 13

sickle emergencies

Answer 13

septic shock (low BP), stroke, low SaO2 and low Hb

Question 14

common conditions in SCD

Answer 14

necrosis of femoral head (due to ischaemia)

osteomyelitis (bone infection)- mostly due to salmonella

stroke- most common in CHILDHOOD

gallstones- those with gilberts syndrome have further increased risk

Question 15

lab features and blood film in SCD

Answer 15

low Hb but high reticulocytes

sickled cells, boat cells, target cells and howell jolly bodies (due to hyposplenism)

Question 16

diagnosis of SCD

Answer 16

can use HBLC (definitive) - trait will band for A and S, disease will have no A and only S

or solubility test- reducing agent converts oxyHb to deoxyHb to decrease solubility, making solution opaque

limitation- doesn’t differentiate between sickle cell trait or disease, so test doesn’t confirm disease

Question 17

general measures for treating SCD

Answer 17

folic acid (needed for DNA synthesis to produce more RBC)

penicillin and vaccination against particularly capsulated bacteria eg pneumococcus

monitor spleen size (prevent splenic sequestration)

blood transfusion for acute anaemic events

pregnancy care (at greater risk of foetal loss)

Question 18

treating painful crisis in SCD

Answer 18

pain relief with opioids eg diamorphine

hydration and keep warm

oxygen for hypoxia

test whether due to infection with culturs and inflammatory markers (CRP)

Question 19

causes of painful crises

Answer 19

infection

dehydration

hypoxia

Question 20

more drastic measures for treatment

Answer 20

blood transfusion eg for stroke and acute chest syndrome

haemopoeietic stem cell transplant

inducing HbF using hydroxyurea/carbamide

Question 21

benefit of hydroxyurea/carbamide

Answer 21

HbF prevents HbS polymerisation= fewer symptoms

also prevents adhesion of RBC, better hydration and produces NO, as well as reducing WBC’s

Question 22

indications for transplant

Answer 22

severe disease, particularly CNS disease (eg stroke), severe vasoocclusive crisis or chest syndrome

Question 23

limitations of transplant

Answer 23

donor availability, length of treatment, and transplant related mortality (3%)

Question 24

use of gene therapy

Answer 24

has been used recently to increase total haemoglobin

Question 25

sickle cell trait

Answer 25

HbAS- usually asymptomatic, but may have painless haematuria, and may feel pain at high altitude/extreme exertion

Question 26

sickle cell anaemia vs sickle cell disease

Answer 26

anaemia relates to only HbSS, the disease relates to heterozygous states as well

Question 27

relation to malaria

Answer 27

molecular change protects against malaria