Sickle cell anaemia

Question 1

Describe the first description of sickle cell anaemia

Answer 1

‘Peculiar elongated forms of the red corpuscles’

‘Some change in the composition of the corpuscle itself may be the determining factor’

Question 2

What mutation is responsible for sickle cell anaemia

Answer 2

Sickle haemoglobin (HbS) differs from HbA by a single amino acid. The defect is in the β globin chain and results in replacement of glutamic acid at position 6 of the β chain by valine. 3-D models of the deoxyhaemoglobin indicate that the residue at position 6 sits on the surface of the protein. Although glutamate is a highly polar amino acid, the side chain of valine is distinctly nonpolar and this alteration markedly reduces the solubility of deoxyhaemoglobin.

MISSENSE mutation

Question 3

What is important to remember about HbS

Answer 3

In sickle haemoglobin we have two NORMAL alpha chains and two variant beta chains. These are almost identical to normal beta globin but
the AMINO ACID valine rep laces glutamic acid at position 6 of the beta chain.

While Glutamic acid is a polar aminoacid, valine is not and this will inevitably influence the solubility of the molecule and the potential bonds that the globin chains can form.

Question 4

Compare glutamine (HbA) to valine (HbS)

Answer 4

Glutamine is polar and soluble

Whereas valine is non-polar and insoluble

Question 5

Describe the consequences of this mutation for HbS

Answer 5

Deoxyhaemoglobin S is insoluble
HbS polymerises to form fibres - “tactoids”
Intertetrameric contacts stabilise structure

Question 6

Outline the stages in the sickling of red cells

Answer 6

Distortion
· Polymerisation initially reversible with formation of oxyhaemoglobin S

Dehydration (irreversible from now on)

Increased adherence to the vascular endothelium

Question 7

Use 3 words to describe sickled red cells

Answer 7

Rigid - normal red cells should have a biconcave shape - sickle shape and polymerisation makes them less deformable- harder to pass through micro-vasculature
Dehydrated - further concentrates HbS and promotes polymerisation
Adherent - less oxygen delivered to tissues- precipitates to ischaemia and tissue damage

Question 8

Describe the changes that may make the red blood cells more adherent

Answer 8

There are also changes in the red cell membrane, which are not fully understood. The membrane expresses a different profile of adhesion molecules which make the red cells sticky to vascular endothelium.

Question 9

Summarise the population genetics associated with sickle cell anaemia

Answer 9

Distribution matches that of endemic Plasmodium falciparum malaria
Up to 25% Africans (sub-Saharan) and 10% Caribbeans carry sickle gene
Around 300,000 affected births annually worldwide

Question 10

Why has the sickle gene also arisen in different populations

Answer 10

Sickle gene arisen independently in several occasions- based on different haplotypes for beta globin gene- multi-centric origin- selected for by evolution due to protection against malaria

Question 11

Describe the global migration and distribution of the HbS gene

Answer 11

Births/yr
Affected 300,000
HbAS 5.5 million

Patients
US 100,000
Europe 60,000
UK 12-15,000

As migration increase- the number of migrants with HbS has increased- leading to a greater number of origin countries of HbS

Question 12

Summarise the epidemiology of sickle cell disease in the U.K

Answer 12

Prevalence 12000-15000
70% reside in Greater London
350 new births per annum. Most common monogenic disorder
National Haemoglobinopathy Registry (NHR) established 2013. Currently 11,000 SCD patients registered
~ 600 patients at ICHT

Mostly picked up by new born screening

Question 13

Originally, it was not understood why sickling causes such profound clinical problems because it appeared that the normal transit time of red blood cells is sufficient for the red cells to become reoxygenated and for the polymers to be broken down before much sickling takes place. What key feature of sickle cells explains their ability to cause such problems?

Answer 13

The sickle cells are more adherent to the vascular endothelium so they stick to the vessel walls and increase their transit time

This allows more time for the polymerisation to occur

Question 14

What are the sickle cell disorders

Answer 14

Sickle cell anaemia (SS) and compound
heterozygous states e.g. SC, Sb thalassaemia
Genetically simple – Autosomal recessive
Clinically heterogeneous

Question 15

What is the difference between sickle cell disease and sickle cell anaemia

Answer 15

Sickle cell disease = generic term that encompasses all disease syndromes due to sickling

Sickle cell anaemia = homozygous (SS)

Question 16

What is important to remember about SCD

Answer 16

Although sickle cell disease is genetically simple, clinically it is complex with a wide range of symptoms affecting the whole body

Question 17

What are the different sickle cell conditions

Answer 17

Sickle cell disease: sickle cell anaemia βS.βS S
Sickle cell disease: sickle cell / haemoglobin C disease βS.βC S and C
Sickle cell trait βS.βA A and S
Normal βA.βA A

Question 18

Which type of Hb is affected in SCD and why

Answer 18

Only adult Hb is affected because HbF does not have any beta chains. The problems therefore start at 4-6 months or older, after the HbF level decreases and the adult Hb level increases.

Therefore HbF and HbA2 will be normal.

Question 19

What effect does sickling have on the lifespan of RBCs

Answer 19

As the cells are distorted, the body more avidly removes them

They have a lifespan of around 20 days

Question 20

What are the consequences of increased haemolysis

Answer 20

Anaemia

Gallstones

Aplastic Crisis

Question 21

What else is responsible for the anaemia in SCD besided increased haemolysis

Answer 21

There is reduced erythropoietic drive as HbS has a low affinity for oxygen so it delivers the oxygen more effectively to tissues

So hypoxia doesn’t stimulate EPO release from the kidneys as much

Question 22

Why does haemolysis caused increased gallstones

Answer 22

Increased haemolysis means increased release of bilirubin and other red cell breakdown products

These get excreted through the biliary tract and carry a risk of causing gallstones

Question 23

How can SCD lead to aplastic crisis

Answer 23

Aplastic crisis is caused by Parvovirus B19 infection (a common respiratory virus)

The virus infects developing red cells in the bone marrow and blocks their production

This doesn’t have much effect on normal people with a 120-day red cell lifespan

But because the lifespan of red cells in sickle cell disease is so low, a parvovirus infection could cause a steep drop in haemoglobin (anaemia)

Question 24

Describe the consequences of blockages to the micro-vascular circulation

Answer 24

Blockage to microvascular circulation (vaso-occlusion)
Tissue damage and necrosis (Infarction)
Pain
Dysfunction

Question 25

Why is circulation impaired in sickle cell anaemia

Answer 25

As sickled red cells become trapped in the small blood vessels, circulation is impaired and there is damage to multiple organs. In children, infarcts of the small bones of the hands of feet may occur and lead to a painful dactylitis called the “hand-foot“ syndrome and, as a later result, shortening of the digits. In adults, generalised pains are more typical and result from
oxygen deprivation of tissues and avascular necrosis of the bone marrow

Question 26

What is the most common cause of hospital admissions in sickle cell anaemia

Answer 26

Distorted sticky red cells can clog up blood vessels and lead to tissue death. This is called infarction.
It is associateed with severe pain and loss of function.

Pain crisis- due to bone marrow ischaemia – need strong opiods- most common cause of admission to hospital- acute pain crisis

Repeat ischaemic damage= chronic organ damage

Question 27

Describe the consequences of infarction of the spleen

Answer 27

Splenic sequestration/hyposplenism
auto-infarcation- repeptitive infarction damage
The spleen can become engorged and act as a reservoir for the bodies blood supply…the so called sequestration crisis which also requires urgent blood transfusion. As the patients gets older the spleen shrinks and the patients become at risk of death from infections which are normally held in check by splenic activity such as malaria or pneumococcal sepsis.
Suceptible to infections from encapsulated bacteria (which the spleen normally clears)

Question 28

Describe the consequences of infarction on the bones and joints

Answer 28

dactylitis /osteomyelitis/avascular necrosis of the hip

Particularly at risk are the weight bearing femoral head and the fingers.

Osteomyelitis: infection of bone (dead tissue is susceptible to bacterial infection)
Avascular necrosis will result in death of the tissue

Question 29

Describe the consequences of infarction on the skin

Answer 29

chronic/recurrent leg ulcers

Question 30

Describe the pathogensis of vaso-occlusion in sickle cell disease

Answer 30

Polymerisation of HbS (HbS polymers can be seen on X-Ray diffraction)
Trapping in micorvasculature (rigid)
Adherence to endothelium (attraction of other cells- neutrophils)
Vaso-occlusion

Question 31

Describe the relationship between sickle cell vasculopathy and nitric oxide

Answer 31

Cell-free haemoglobin limits nitric oxide bioavailability in sickle cell disease
The free plasma Hb resulting from the haemolysis will scavenge nitric oxide and, hence, deplete the nitric oxide
This takes away the vasodilation effects of nitric oxide, causing vasoconstriction of certain vascular beds (including pulmonary circulation)
Leading to pulmonary hypertension

Question 32

Describe pulmonary hypertension in sickle cell disease

Answer 32

Pulmonary hypertension correlates with the severity of haemolysis
The likely mechanism is that the free plasma haemoglobin resulting from intravascular haemolysis scavenges NO and causes vasoconstriction
Associated with increased mortality

Question 33

Describe the impact of pulmonary hypertension on survival rates in patients with SCD

Answer 33

Pulmonary blood pressure can be measured using the Measurement of tricuspid regurgitant
jet velocity by echocardiography (essentially, the speed of blood moving back over the tricuspid valve)

TRV >2.5m/sec associated with lower survival rates- due to pulmonary hypertension.

Question 34

Outline the effects of the pathogenesis of SCD on the lungs

Answer 34

Lungs
Acute chest syndrome (most common cause of death in adults with SCD)- VASO-OOCLUSIVE CRISIS OF PULMONARY VASCULATURE
Chronic damage
Pulmonary hypertension

Question 35

Outline the effects of the pathogenesis of SCD on the urinary tract

Answer 35

Haematuria (due to papillary necrosis)
Hyposthenuria (inability to control urine concentration – can lead to dehydration)
Renal failure
Priapism (painful erections)

Question 36

Outline the effects of the pathogenesis of SCD on the brain and eyes

Answer 36

Brain:
Stroke and cognitive impairment – affects 8% of SS, most common 2-9yrs.

Macrovasculature- middle cerebral artery- can monitor stroke risk using Doppler studies.

Eyes:
Proliferative retinopathy- similar to that seen in diabetic patients.

Question 37

What is important to remember about the clinical course of SCD

Answer 37

Clinical course variable and unpredictable even within same family

Question 38

Explain the clinical onset of SCD

Answer 38

Symptoms rare before 3-6 months
Onset coincides with switch from fetal to adult Hb
At birth- 80% of Hb is HbF

Question 39

What are the earliest clinical manifestations of SCD

Answer 39

Dactylitis
Splenic sequestration (accumulation of red cells in the spleen leading to a drop in blood count)
Infection (pneumococcal (capsulated))

Question 40

How can we distinguish between sequestration and aplastic crises

Answer 40

Sequestration and aplastic crises can be distinguished by the presence/absence of reticulocytes, but both require urgent transfusion.
Low reitulocytes in aplastic anaemia

The reticulocyte count is raised in a sequestration crisis but in an aplastic crisis it is much lower than normal.

Question 41

Describe the importance of early diagnosis of SCD

Answer 41

Significant reduction 
    in deaths from 
    pneumococcal 
    infection and acute 
    splenic sequestration  

With prophylactic penicillin and education on how to palpate and examine spleen to monitor sequestration of spleen- prevent it getting to advanced stages.

Question 42

What did the PROPS trail show (prophylactic penicillin)

Answer 42

PROPS trial
<3 years
84% reduction 
in pneumococcal
Infection

Question 43

Describe the factors leading to the improvement in the life expectancy in patients with SCD

Answer 43

National Sickle Cell Act
Preventative Penicillin (and new born screening programme)
Hydroxycarbamide treatment
Transfusion for stroke prevention

Question 44

Describe the mortality associated with SCD

Answer 44

In one large survey the median life expectancy for men and women with homozygous sickle cell anaemia was 42 and 48 years respectively and the causes of death were:
21% associated with a painful crisis
14% associated with a chest syndrome
9% associated with renal failure
7% associated with infection
6% perioperative

Question 45

List the sickle emergencies

Answer 45

Septic shock (BP <90/60)
Neurological signs or symptoms (ischaemic in children- mixture of ischaemic and haemorrhagic in adults)
SpO2 <92% on air (hypoxia)
Symptoms/signs of anaemia with Hb <5 or fall >3g/dl from baseline (acute anaemic event)
Priapism >4 hours (medical emergency- if not managed- will lead to permanent erectile dysfunction)

Question 46

Why is hypoxia important to spot in patients with SCD

Answer 46

Hypoxia important to detect- may set up further cycle of further sickling- most commonly due to acute chest syndrome

Question 47

Describe the radiological features of acute chest syndrome

Answer 47

Typically seen as segmental or subsegmental atelectasis/consolidation with a lower lobe predilection, and/or pleural effusion.
A chest radiograph may also show other sequelae from sickle cell disease such as bone infarcts, rib enlargement and cardiomegaly (from anaemia).

Bi-basal changes
Shadowing
Consolidation

Question 48

What is important to remember about acute chest syndrome

Answer 48

Responds well to early intervention- non-invasive respiratory support and exchange transfusion

Question 49

Describe the key features of acute chest syndrome

Answer 49

New pulmonary infiltrate on chest X-ray
 with   Fever
            Cough
            Chest pain
            Tachypnoea

Develops in context of vaso-occlusive crisis
surgery pregnancy

Question 50

Describe the relative incidences of acute chest syndrome in the different sickle cell diseases

Answer 50

Incidence SS>SC>SB+ Thal

Question 51

Describe the statistics associated with acute chest syndrome

Answer 51

Diagnosis often delayed
Mechanical ventilation 15%
Mortality > 18 yr 9%

Question 52

Describe avascular necrosis of the femoral head

Answer 52

Significant disability
Loss of ball and socket shape to joint

Due to ischaemic damage of head of femur
May require hip replacement

Question 53

What are the most common infectious causes of osteomyelitis

Answer 53

1. Salmonella

2. Staphylococcus bacteria

Question 54

Summarise stroke in SCD

Answer 54

Affects 8% SS
Most common 2-9 yrs
Involves major cerebral
vessels

Also involves internal carotid artery.

Question 55

Summarise the features of gallstones in patients with SCD

Answer 55

May present with pain, acute cholecystitis with biliary obstruction and gall stonepancreatitis
Once symptomatic- treatment with laproscopic cholecystectomy is recommended

By 25 years prevalence
of gallstones
50% in SS

Question 56

What genetic modifier can increase the risk of getting gallstones in patients with hereditary haemolytic anaemia (like sickle cell disease)?

Answer 56

Co-inheritance of Gilbert’s syndrome

Question 57

Describe Gilbert’s syndrome

Answer 57

Coinheritance of Gilbert
syndrome(UGT 1A1
TA7/TA7 genotype)
further increases risk

Gilbert- benign variant of BR conjugation- urodine glucornoniside transferase gene (UGT1A1)- in promoter- element with TATA box- required for normal expression- normal 6 TA repeats- extra in gilbert on each allele- TO GIVE 7 TA REPEATS - Caused by an extra TA dinucleotide in the promoter on each chromosome (there are normally 6 TA repeats)

REDUCING EFFICIENCY OF TRANSCRIPTION- REDUCED BR CONJUGATION- REDUCED ENZYME ACTIVITY- INCREASED RISK OF G.S 3-5 FOLD

Question 58

Summarise the laboratory features of SCD

Answer 58

Hb low (typically 6-8 g/dl)
Reticulocytes high (except in aplastic crisis)

Film 	
Sickled cells
Boat cells
Target cells
Howell Jolly bodies

Question 59

Ultimately, what does the area of central pallor reflect

Answer 59

The shape of the RBC

Question 60

What type of inclusion is a Howell-Jolly body

Answer 60

Basophilic

Question 61

Outline the solubility test to check for presence of HbS

Answer 61

In presence of a reducing agent oxyHb converted to deoxy Hb ( reducing agent- sodium diathianite or sodium metabisulfate)
Solubility decreases
Solution becomes turbid
Does not differentiate AS from SS (limitation- so only checks to see if you have one or more sickle traits.

Place against two black lines- won’t be able to see black lines if HbS present (makes the solution more opaque)

Question 62

What is needed for a definitive diagnose of SCD and why

Answer 62

Electrophoresis or high performance liquid
Chromatography (HPLC) separates proteins according
to charge
Electrophoresis – takes advantage of the difference in charge between HbS, HbAS and HbA

Question 63

Describe cellulose acetate membrane Hb electrophoresis

Answer 63

Separates proteins according to charge.
§ You can see homozygous sickle patients have NO HbA and only HbS and a little HbA2.
§ Heterozygous sickle patients have both HbS and HbA.

S travels further to the right than A

In heterozygous state- A band will be thicker (60% of Hb is HbA)

Question 64

Summarise the general measures in the management of SCD

Answer 64

General measures
Folic acid (5mg/day)
Penicillin (by 3 months)
Vaccination (pneumococcoas, meningococcous and haemophilus, also influenzae- consequences more serious- bacterial pneumonia risk
Monitor spleen size (pre-empt the development of acute splenic sequestration)
Blood transfusion for acute anaemic events, chest syndrome and stroke
Pregnancy care (greater risk of maternal obstetric complications and fetal loss)

Question 65

Why do we need to monitor folic acid in SCD

Answer 65

Increased production of RBCs- need adequate folic acid- DNA synthesis

Question 66

Why do we need to monitor spleen size in SCD

Answer 66

Acute splenic sequestration can mean you get an enlarged spleen and often requires prophylactic therapy (against pneumococcal infection), transfusions to correct anaemia and maybe splenectomy.

Question 67

Summarise the management of a painful crisis

Answer 67

PAINFUL CRISIS
Pain relief (opioids)- parenteral- short periods of time to prevent addiction-
Hydration- in pain- may find it hard to take in oral take or i.v fluids
Keep warm
Oxygen if hypoxic (establish cause of hypoxia)

Exclude infection:
Blood and urine cultures
CXR

Question 68

What could be part of the differential for hypoxia in SCD

Answer 68

Acute chest syndrome

SCD patients also at risk of thrombo-embolic episodes so consider pulmonary embolism in differential.

Question 69

Describe the importance of excluding infection in a painful crisis

Answer 69

IF FEBRILE OR INCREASE IN CRP OR OTHER INFLAMMATORY MARKERS- INFECTION SCREEN

If infection is present, antibiotics are needed.

Question 70

List the factors that can trigger a painful crisis

Answer 70

Painful crises triggered by:
Infection
Exertion
Dehydration
Hypoxia
Psychological stress

Question 71

Why do we need to give penicillin prophylactically in SCD

Answer 71

Prophylactic penicillin to prevent some of the infections caused by hyposplenism.

Question 72

Summarise the pain management of a painful crisis

Answer 72

Opioids
- Marked individual variation in response
- Diamorphine most widely used
- Most children receive oral opioid
Individual analgesia protocols
Patient controlled analgesia
Adjuvants – paracetamol, NSAIDs, Pregabalin/Gabapentin

Question 73

Explain the pain management of a painful crisis

Answer 73

Opiate naïve- small doses
;larger doses for more tolerant opiods

Many children managed without opiods- maintain this in adult care
Individual analgesia protocol- doses and nature that are most effective

Patient controlled analgesia- bolus that patient can control themselves- lock out of 20 mins- patient can control dose- allows for lower doses

Pregabalin/Gabapentin - neuropathic pain- feature of prolonged pain crisis

Question 74

Describe the different types of blood transfusion used in the management of SCD

Answer 74

Blood transfusion:
a) top up blood transfusion e.g. if aplastic or sequestration crises.
b) exchange blood transfusion if life threatening/severe disease such as a stroke, or chest crisis. An exchange transfusion aims to reduce the HbS to less than 20%.
NOTE: top-up blood transfusion is NOT a treatment for painful crisis; it will increase blood viscosity and may make the painful crisis worse.

Question 75

What are the current disease modifying therapies for SCD

Answer 75

Transfusion
Hydroxycarbamide (Hydroxyurea)
Haemopoietic stem cell transplantation

Question 76

Describe exchange transfusion

Answer 76

Stroke
Acute chest syndrome

Exchange diffusion
Machine seperates patients blood components by centrifugation- retunrs WBC, platelets, byt changes RBCs- aim to reduce % of HbS below 30
Blood will come from matched donor with normal Hb

Question 77

Describe haemopoietic stem cell transplantation

Answer 77

<16 yr with severe disease
Survival 90-95% Cure 85-90%

Results optimal in cases where there is a matched HLA compatible related donor

Small mortality and risk of loss of fertility with stem cell- myeloablative conditioning
Potential pubertal failure

Question 78

What are the two pharmacological agents available for the induction of HbF

Answer 78

Hydroxyurea

Butyrate

Question 79

Name a drug that is used to induce HbF in sickle cell patients and explain the principle behind this treatment

Answer 79

Hydroxyurea/Hydroxycarbamide
· It is a ribonucleotide reductase inhibitor (cytotoxic)
· It induces the production of red cell in the bone marrow that mainly contain HbF
· So, over time, there will be an increase in the number of red cells that are unable to sickle
· It significantly reduces the frequency of crises
Butyrate also has a similar effect

Question 80

Summarise hydroxyurea

Answer 80

HbF inhibits polymerisation of HbS
Infants with SCD do not usually develop symptoms until > 3 months
Patients with higher HbF levels have fewer complications and improved survival

Question 81

What is the rationale for hydroxyurea in the treatment of SCD

Answer 81

Increases production of baby (fetal) haemoglobin (HbF)
Decreases ‘stickiness’ of sickle red blood cells
Reduces white blood cell production by the bone marrow (higher WBC count associated with worser outcomes)
Improves hydration of red blood cells (reduce conc of HbS-less polymerisation)
Generates nitric oxide which improves blood flow (theoretically beneficial)

Cytotoxic and so need to manage patient closely,

Question 82

Describe the multicentre study of hydroxyurea in SCA

Answer 82

Double blind randomised trial 1992

299 adult patients (HU152 placebo 147)
> 3 painful crises/yr

HU at maximum tolerated dose

Concluded early after 30 months

Crisis rate significantly reduced (44%)
	HU 2.5/yr
	Placebo 4.5/yr

Reduction in
Hospitalisation 58%
Acute chest syndrome 51%
Transfusion 34%

Question 83

Describe the use of hydroxyurea to treat SCA

Answer 83

Commonly used worldwide for both children and adults

Not universally prescribed in the U.K

Question 84

Describe the long-term outlook for hydroxyurea

Answer 84

What is the long term outlook?

17.5 year follow up study 2010

Overall mortality 129/299 (43%)
Never received hydroxyurea 16/44 (36%)
>15 yr treatment with hydroxyurea 0/20

Question 85

Describe the date supporting the use of haematopoietic stem cell transplant for SCD

Answer 85

33 children with HbSS
Age 3-17 years
22 CNS disease
Donors: HLA-matched sibs (n=31) or other related donor (n=2)

Overall survival (OS): 97.0%
Disease-free survival (DFS): 93.9%
aGvHD II-IV: 11.8%
cGvHD: 6.3%

Question 86

What are the indications for haematopoietic stem cell transplant

Answer 86

Indications:
CNS disease
Recurrent severe VOC*
Recurrent ACS*

• if hydroxyurea fails

Question 87

Describe CNS disease

Answer 87

CNS disease
Stroke
Abnormal TCD + silent infarct
Silent infarcts with cognitive deficiency
Abnormal MRA despite transfusions
Abnormal TCD + RBC alloantibodies
CNS disease requiring transfusions with iron overload despite optimal care

Question 88

Describe the limitations of haematopoetic stem cell transplant

Answer 88

Donor availability
18% have unaffected sibling donor
1-2% of children with SCD qualify
Length of Treatment:
2 months as an inpatient
4 months as outpatient
Transplant Related Mortality
Long Term Effects:
Infertility
Pubertal failure
Chronic GvHD
Organ toxicity
Secondary malignancies

Question 89

Describe the potential use of gene therapy for SCD

Answer 89

Lenti-viral vector
Contained modified beta globin gene
Amino acid change at 87- mimics that seen in HbF and responsible for sickling effect seen in HbF
Also provides convenient means of tracking production in RBCs of the variant- will separate from HbA and S in HLPC
Decline in HbA
Total Hb raised to higher level than that normally seen in SCD
Due to production of Hb of trans gene
Converts patient from homozygous state to state akin to sickle cell trait
Requires myeloablative conditioning to enable genetically corrected stem cells to re-populate the bone marrow

Question 90

Describe the use of mAbs in SCD

Answer 90

Inhibits P-selectin (adhesion molecule involved in adhesion of RBC to endothelium)
P-selectin inhibitor Crizanlizumab

45.3% reduction in crisis rate (1.63 vs 2.98)
Median time to 1st crisis 4.07 vs 1.38 mo
2nd crisis 10.32 vs 5.09 mo

Works better at higher dose

Question 91

Summarise the sickle cell trait

Answer 91

HbAS
Normal life expectancy
Normal blood count
Usually asymptomatic
Rarely painless haematuria (PAPILLARY NECLOSIS)
Caution: anaesthetic, high altitude, extreme exertion (SPLENIC INFARCTION) due to sickling of red cells

5.5 million carriers

Question 92

Why does the sickle cell trait need to be identified

Answer 92

However it needs to be identified because certain situations can provoke sickling e.g. anaesthesia, high altitude, air travel in unpressurised planes. All patients from ethnic groups in whom βS occurs should be screened prior to surgery. Sickle trait must also be identified in pregnant women so that their partners can be tested and appropriate counselling given and action taken if necessary.

Question 93

With the sickle solubility test, what must a positive result be confirmed by

Answer 93

A positive result must be confirmed by Hb electrophoresis.

Question 94

Why does the diagnosis require Hb electrophoresis

Answer 94

Definitive diagnosis requires haemoglobin electrophoresis (or an equivalent test) as well as a sickle solubility test. Electrophoresis separates proteins according to their charge; this varies according to the pH at which electrophoresis is carried out. So, at alkaline pH, HbS separates readily from Hb A and F. However, there are some non-sickling haemoglobins (called HbD and HbG) that run with HbS – this is why a sickle solubility test is also needed. In sickle cell anaemia no HbA is detected and there is a variable (5-15%) amount of HbF and a small amount of HbA2. Patients with sickle trait have Hbs A and S (plus small amounts of HbA2 and HbF).

Question 95

What occurs in an attempt to compensate for the shortened life span of RBCs

Answer 95

In an attempt to compensate for the shortened red cell life span there is an increased turnover of red cells and the body’s supply of folic acid can become low.