SCD

Question 1

What is different between HbA and HbS?

Answer 1

A SINGLE aa difference in the beta-chain (missense mutation at codon 6)

Glutamic acid (polar and soluble)
is replaced by
Valine (non-polar and insoluble)

Question 2

What does the aa difference mean for HbS?

Answer 2

It is now INSOLUBLE

HbS polymerises to form fibres - ‘tactoids’
o inter-tetrameric contacts stabilising the structure

Question 3

What are the stages in sickling of RBCs?

Answer 3

RIGID, ADHERENT, DEHDRATED

1. DISTORTION
   o polymerisation initially reversible with formation of oxyHbS
   o BUT is subsequently irreversible
2. DEHYDRATION
3. INCREASED AHDERENCE
   o to vascular endothelium

Question 4

Link between SCD and malaria?

Answer 4

Provides a source of protection from malaria!

Up to 25% Africans and 10% Caribbeans carry the sickle gene!

Question 5

SS?

Answer 5

Sickle cell anaemia (HOMOZYGOUS state)

Question 6

What is encompassed under SCD?

Answer 6

Sickle cell anaemia (SS)
AND
Compound heterozygous states e.g. SC, S-beta thalassaemia

Autosomal recessive

Question 7

What does SCD incorporate?

Answer 7

SS and ALL other conditions that lead to a disease syndrome due to sickling

Question 8

6 overal pathogensis of SCD?

Answer 8

1. Shortened RBC lifespan (leads to haemolysis)
2. Blockage of microvascular circulation
3. Lungs
4. Urinary Tract
5. Brain
6. Eye

Question 9

Shortened RBC lifespan & SCD?

Answer 9

Leads to haemolysis!

o Anaemia - partly due to reduced erythropoietic drive as HbS is a LOW AFFINITY Hb

o Gallstones - co-inheritance of Gilbert syndrome further increases risk (affect bilirubin conjugation)

o Aplastic crisis - Parvovirus B19

Question 10

Blockage to microvascular circulation & SCD?

Answer 10

1. INFACRTION!
   o spleen - hyposplenism (capsulated bac. can attach more)
   o bones/joins -
   
   • dactylitis (inflammation of bone)
   • avascular necrosis (e.g. of femoral)
   • osteomyelitis (infection of bone e.g. salmonella)
     o skin - ulcerations
2. PAIN
3. DYSFUNCTION

Question 11

Lungs & SCD?

Answer 11

1. Acute - acute chest syndrome
2. Chronic - Pulmonary hypertension
   o Correlated w. severity of haemolysis
   o Free plasma Hb from haemolysis scavenges NO and causes vasoconstriction

Question 12

Urinary tract & SCD?

Answer 12

o Haematuria - due to papillary necrosis

o Renal failure & Hyposthenuria
- impaired [urine]

o Priapism

Question 13

Brain & SCD?

Answer 13

o Stroke
o Cognitive impairment

Affects 8% of SS, most common 2-9years old

Question 14

Eyes & SCD?

Answer 14

o Proliferative retinopathy!

Question 15

When do the clinical presentations of SCD start?

Answer 15

3-6 months after birth

This is as the switch to adult HbA from fetal has NOT occurred yet!

Question 16

What are the clinical presentations of the early manifestations of SCD?

Answer 16

o Dactylitis

o Splenic sequestration
- undergoes enalrgement leading to cooling of blood volume & anaemia

o Infection (pnuemococcal normally)

Question 17

What else can trigger painful SCD crises?

Answer 17

Infection
Exertion
Dehydration
Hypoxia - due to acute chest syndrome
Psychological stress

Question 18

Laboratory features of SCD?

Answer 18

1. Hb LOW (6-8 g/dl)
2. Reticulocytes (immature RBCs) HIGH
   - EXCEPT in aplastic crisis

3. Film
 o Sickled cells
 o Boat cells
 o Target cells
 o Howell Jolly bodies

Question 19

2 step process to diagnose SCD?

Answer 19

1. SOLUBILITY test

2. Electrophoresis (HPLC)

Question 20

Solubility test?

Answer 20

To diagnose SCD

1. In presence of reducing agent, oxyHb is converted to deoxyHb
2. Solubility deceases & solution becomes turbid

Question 21

What is an issue with the Solubility test and diagnosing SCD?

Answer 21

Does NOT differentiate between AS & SS

AS - sickle cell trait
SS - homozygous state

Question 22

What test can you do after the Solubility test to differentiate?

Answer 22

Electrophoresis (HPLC)

Separates proteins according to charge

Question 23

How can you differentiate between AS and SS using elecrophoresis?

Answer 23

Homozygous state:
o have NO HbA
o HAVE HbS
o LITTLE HbA2

Heterozygrous state:
o have BOTH HbS & HbA

Question 24

General measurement measures for people with SCD?

Answer 24

o Folic acid

• anaemia
• required for DNA synthesis due to the increase in RBCs

o Penicillin (prophylaxis)
 - splenic dysfunction

o Vaccination

• splenic dysfunction
• agaisnt capsulated bac. & influenza

o Montior spleen size

o Blood transfusion
- for acute anaemic events, chest syndrome & stroke

o Pregnancy care

Question 25

Why must you monitor spleen size when managing SCD?

Answer 25

Splenic dysfunction Acute splenic sqeuestration can mean you get an enlarged spleen! Often requires: o phrophylactic therapy (against pneumococcal infection) o transfusions (to correct anaemia) o MAYBE splenectomy

Question 26

How should you manage if someone has a painful crisis?

Answer 26

o Pain relief - opioids - Diamorphine widely used - variation in inidividual response - patient-controlled analgesia o Hydration o Keep warm o O2 if hypoxic MUST exclude infection so do: - blood & urine cultures - CXR

Question 27

Current disease-modifying therapies for SCD?

Answer 27

1. Exchange transfusion o Stroke o Acute chest syndrome 2. Haematopoietic stem cell transplantation o from sibling HLA or other haplo-identical individuals o <16 years with SCD o Survival rate = 90-95% o Cures in around 85-90% 3. Induction of HbF o HYDROXYUREA/hydroxycarbimide o Butyrate

Question 28

Why is treatment of SCD with hydroxyurea (hydroxycarbamide) good?

Answer 28

Induces HbF production! HbF INHIBITS polymerisation of HbS - that's why infants with SCD do NOT usually develop symptoms until >3months Patients with HIGHER HbF have: o fewer complications o improved survival

Question 29

Rationale behind the use of hydroxyurea (hydroxycarbamide)?

Answer 29

``` o Increases HbF o Decreases 'stickiness' of SRBCs as reduces polymerisation - reduces ADHESION o Reduces WBC production by bone marrow o Improves hydration of RBCs o Generates NO - improves blood flow ```

Question 30

Characterisitcs of AS (sickle cell trait?)

Answer 30

HbAS o Normal life expectancy o Normal blood count o Usually asymptomatic - rarely painless haematuria (due to papillary necrosis) Take caution w. anaesthetic use, high altitude and extreme exertion

Question 31

Sickle cell anaemia includes both HbSS and HbSC | True/False

Answer 31

FALSE Applies specifically to the homozygous state so HbSS Sickle cell disease encompasses all sickle cell disorders

Question 32

Sickling is due to a change in the a globin chain | True/False

Answer 32

FALSE Beta-globin

Question 33

The molecular alteration is a deletion which protects against malaria True/False

Answer 33

FALSE NOT a deletion - missense (point) mutation so alters an aa changing the biophysical property of the resulting Hb

Question 34

Sickle Hb makes red cells less deformable True/False

Answer 34

TRUE

Question 35

Clinical manifestations may start in utero because b-globin is part of fetal Hb True/false

Answer 35

FALSE HbF is compsoed of ALPHA and GAMMA CHAINS so is NOT affected by

Question 36

Osteomyelitis is the name given to inflammation of a digit | True/false

Answer 36

FALSE Osteomyelitis is a BONE infection Digit inflammation is DACTYLITIS

Question 37

Women with HbSS have a normal life expectancy True/false

Answer 37

FALSE Better than males BUT still NOT normal

Question 38

Chest crises may be fatal True/false

Answer 38

TRUE MOST COMMON cause of death!

Question 39

Solubility tests are used to confirm sickle cell anemia if screening tests are positive True/false

Answer 39

FALSE Will ONLY identify for Sickle Hb presence so will NOT show if have sickle cell trait OR disease (anaemia)

Question 40

If a lady with HbAS has a partner with HbSS she should be offered genetic counselling True/false

Answer 40

TRUE