SCD Flashcards
What is different between HbA and HbS?
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)
What does the aa difference mean for HbS?
It is now INSOLUBLE
HbS polymerises to form fibres - ‘tactoids’
o inter-tetrameric contacts stabilising the structure
What are the stages in sickling of RBCs?
RIGID, ADHERENT, DEHDRATED
- DISTORTION
o polymerisation initially reversible with formation of oxyHbS
o BUT is subsequently irreversible - DEHYDRATION
- INCREASED AHDERENCE
o to vascular endothelium
Link between SCD and malaria?
Provides a source of protection from malaria!
Up to 25% Africans and 10% Caribbeans carry the sickle gene!
SS?
Sickle cell anaemia (HOMOZYGOUS state)
What is encompassed under SCD?
Sickle cell anaemia (SS)
AND
Compound heterozygous states e.g. SC, S-beta thalassaemia
Autosomal recessive
What does SCD incorporate?
SS and ALL other conditions that lead to a disease syndrome due to sickling
6 overal pathogensis of SCD?
- Shortened RBC lifespan (leads to haemolysis)
- Blockage of microvascular circulation
- Lungs
- Urinary Tract
- Brain
- Eye
Shortened RBC lifespan & SCD?
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
Blockage to microvascular circulation & SCD?
- 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
- PAIN
- DYSFUNCTION
Lungs & SCD?
- Acute - acute chest syndrome
- Chronic - Pulmonary hypertension
o Correlated w. severity of haemolysis
o Free plasma Hb from haemolysis scavenges NO and causes vasoconstriction
Urinary tract & SCD?
o Haematuria - due to papillary necrosis
o Renal failure & Hyposthenuria
- impaired [urine]
o Priapism
Brain & SCD?
o Stroke
o Cognitive impairment
Affects 8% of SS, most common 2-9years old
Eyes & SCD?
o Proliferative retinopathy!
When do the clinical presentations of SCD start?
3-6 months after birth
This is as the switch to adult HbA from fetal has NOT occurred yet!
What are the clinical presentations of the early manifestations of SCD?
o Dactylitis
o Splenic sequestration
- undergoes enalrgement leading to cooling of blood volume & anaemia
o Infection (pnuemococcal normally)
What else can trigger painful SCD crises?
Infection Exertion Dehydration Hypoxia - due to acute chest syndrome Psychological stress
Laboratory features of SCD?
- Hb LOW (6-8 g/dl)
- Reticulocytes (immature RBCs) HIGH
- EXCEPT in aplastic crisis
3. Film o Sickled cells o Boat cells o Target cells o Howell Jolly bodies
2 step process to diagnose SCD?
- SOLUBILITY test
2. Electrophoresis (HPLC)
Solubility test?
To diagnose SCD
- In presence of reducing agent, oxyHb is converted to deoxyHb
- Solubility deceases & solution becomes turbid
What is an issue with the Solubility test and diagnosing SCD?
Does NOT differentiate between AS & SS
AS - sickle cell trait
SS - homozygous state
What test can you do after the Solubility test to differentiate?
Electrophoresis (HPLC)
Separates proteins according to charge
How can you differentiate between AS and SS using elecrophoresis?
Homozygous state:
o have NO HbA
o HAVE HbS
o LITTLE HbA2
Heterozygrous state:
o have BOTH HbS & HbA
General measurement measures for people with SCD?
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
Why must you monitor spleen size when managing SCD?
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
How should you manage if someone has a painful crisis?
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
Current disease-modifying therapies for SCD?
- Exchange transfusion
o Stroke
o Acute chest syndrome - 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% - Induction of HbF
o HYDROXYUREA/hydroxycarbimide
o Butyrate
Why is treatment of SCD with hydroxyurea (hydroxycarbamide) good?
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
Rationale behind the use of hydroxyurea (hydroxycarbamide)?
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
Characterisitcs of AS (sickle cell trait?)
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
Sickle cell anaemia includes both HbSS and HbSC
True/False
FALSE
Applies specifically to the homozygous state so HbSS
Sickle cell disease encompasses all sickle cell disorders
Sickling is due to a change in the a globin chain
True/False
FALSE
Beta-globin
The molecular alteration is a deletion which protects against malaria
True/False
FALSE
NOT a deletion - missense (point) mutation so alters an aa changing the biophysical property of the resulting Hb
Sickle Hb makes red cells less deformable
True/False
TRUE
Clinical manifestations may start in utero because b-globin is part of fetal Hb
True/false
FALSE
HbF is compsoed of ALPHA and GAMMA CHAINS so is NOT affected by
Osteomyelitis is the name given to inflammation of a digit
True/false
FALSE
Osteomyelitis is a BONE infection
Digit inflammation is DACTYLITIS
Women with HbSS have a normal life expectancy
True/false
FALSE
Better than males BUT still NOT normal
Chest crises may be fatal
True/false
TRUE
MOST COMMON cause of death!
Solubility tests are used to confirm sickle cell anemia if screening tests are positive
True/false
FALSE
Will ONLY identify for Sickle Hb presence so will NOT show if have sickle cell trait OR disease (anaemia)
If a lady with HbAS has a partner with HbSS she should be offered genetic counselling
True/false
TRUE
