haemoglobin 3: sickle cell anaemia

Question 1

what genetic mutation causes sickle cell anaemia?

Answer 1

missense mutation at codon 6 of gene for B globin chain

Question 2

what changes in the primary structure happen as a result of the mutation?

Answer 2

valine replaces glutamic acid (glu = polar & soluble, valine = non-polar & insoluble)

Question 3

why are the cells sickle shaped?

Answer 3

HbS polymerises and forms fibres called tactoids -> intertetrameric contacts stabilise structure

Question 4

what are some properties of sickle cells?

Answer 4

rigid, increased adherence to vascular endothelium, dehydrated

Question 5

what is the epidemiology of SCD in the UK?

Answer 5

12-15k, most common monogenic disorder

Question 6

what is the difference between sickle cell anaemia and sickle cell disease?

Answer 6

anaemia = SS homozygous genetic condition 
SCD = all conditions that lead to cell becoming sickled eg SC, SB-thalassaemia

Question 7

how does the lifespan of a sickle cell differ from that of a normal cell?

Answer 7

very short (10-20 days)

Question 8

what happens as a result of the changed lifespan of a sickle cell?

Answer 8

haemolysis causes: anaemia, gall stones, aplastic crisis (parvovirus B19 arrests development of red cells in bone marrow)

Question 9

why does sickle cell result in anaemia?

Answer 9

increased haemolysis & lower affinity of HS for haemoglobin -> reduced erythropoietic drive

Question 10

what happens as a result of the changed shape of a sickle cell?

Answer 10

vaso-occlusion -> tissue damage & necrosis (infarction), pain, dysfunction

Question 11

what are the consequences of tissue infarction?

Answer 11

hyposplenism, dactylitis, avascular necrosis, osteomyelitis, chronic/reccurent leg ulcers

Question 12

how does sickle cell cause pulmonary hypertension?

Answer 12

release of haemoglobin from haemolysis scavenges NO from endothelium -> causes vasoconstriction -> pulmonary hypertension

Question 13

what is the overall pathogenesis of sickle cell anaemia?

Answer 13

lungs: acute chest syndrome, chronic lung damage, pulmonary hypertension
urinary tract: haematuria, hyposthenuria, renal failure, priapism
brain: stroke, cognitive impairment
eyes: proliferative retinopathy

Question 14

what are the early presentations of sickle cell disorders?

Answer 14

dactylitis, splenic sequestration (increased size of spleen -> pooling of blood, anaemia), infection (s pneumoniae)

Question 15

when do symptoms start to appear?

Answer 15

after 6 months (rare before 3-6 months) - onset coincides with switch from foetal to adult Hb synthesis

Question 16

what are some examples of sickle emergencies?

Answer 16

septic shock (BP <90/60), neurological symptoms, SpO2 <92% (on air), acute anaemic event (with Hb <5 / fall >3mg/dl from baseline), priapism >4hr

Question 17

what is a common cause of joint pain in SCD?

Answer 17

osteomyelitis caused by salmonella

Question 18

stroke:

Answer 18

common in children 2-9, often arises from middle cerebral artery & intracranial internal carotid artery

Question 19

gallstones:

Answer 19

by 25, 50% of SS patients have gallstones, coinheritance of gilbert syndrome increases risk 3-5x

Question 20

what are the laboratory features of SCD?

Answer 20

low Hb (6-8g/dl)
increased reticulocytes
film: sickled cells, boat cells, target cells, howell-jolly bodies

Question 21

how does a solubility test work?

Answer 21

in presence of reducing agent oxyHb -> deoxy Hb -> solubility decreases -> solution becomes turbid HOWEVER does not differentiate AS from SS

Question 22

how can a definitive SS diagnosis be made?

Answer 22

electrophoresis & high performance liquid chromatography (HPLC) separates proteins by charge

Question 23

what general measures can be taken to manage SCD?

Answer 23

folic acid, prophylactic penicillin, vaccination (against capsulated bacteria), spleen size monitoring, blood transfusion for acute events, pregnancy care

Question 24

how can crises be managed?

Answer 24

pain relief (opioids), hydration, warmth, oxygen if hypoxic, exclude infection

Question 25

how can pain be managed?

Answer 25

opioids (marked individual variation in response, diamorphine most widely used), patient controlled analgesia, adjuvants (paracetamol, NSAIDs, pregabalin/gabapentin)

Question 26

what are the current disease-modifying therapies for SCD?

Answer 26

exchange transfusion, haemopoietic stem cell transplantation (<16yo with severe disease, survival 90-95%, cure 85-90%), induction of HbF (hydroxyurea, butyrate)

Question 27

how can hydroxyurea be used to treat SCD?

Answer 27

increases production of HbF (which inhibits polymerisation of HbS), decreases stickiness of sickle cells, reduces WBC production by bone marrow, improves hydration of red cells, generates nitric oxide which improves blood flow

Question 28

what are the indications for HSCT?

Answer 28

CNS disease, reccurent severe VOC, recurrent ACS

Question 29

what are the limitations of HSCT?

Answer 29

donor availability (18%have unaffected sibling donor), length of treatment (2 months as inpatient, 4 months outpatient), transplant related mortality, long term effects (infertility, pubertal failure, chronic GvHD, organ toxicity, secondary malignancies)

Question 30

overview of sickle trait:

Answer 30

HbAS, normal life expectancy, normal blood count, usually asymptomatic, rarely painless haematuria BUT caution: anaesthetic, high altitude, extreme exertion