Sickle cell Disese Flashcards
1
Q
The sickle gene mutation
A
- Missense mutation at codon 6 of the gene for b globin chain
- Glutamic acid replaced by Valine (polar+soluble -> non-polar+insoluble)
2
Q
Red cell effects of SCD
A
Stages in sickling of red cells:
- Distortion
- Polymerisation initially
reversible with formation
of oxyHbS
- Subsequently irreversible
- Dehydration
- Increased adherence to
vascular endothelium
-> rigid, adherent + dehydrated
3
Q
Where is SCD most common?
A
- Africa
- also common in Mediterrean, Middle East and India
- selected for in evolution due to Malaria protective properties
- Up to 25% Africans (sub-Saharan) and 10% Caribbeans carry sickle gene
4
Q
How common is SCD?
A
- Around 300,000 affected births annually worldwide
- UK: 12-15,000 affected patients, 60 000 in Europe, 100 000 in the US
5
Q
Epidemiology of SCD in UK
A
- 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
6
Q
Sickle cell disorders
A
- Sickle Cell Anaemia: homozygous form SS
- There are heterozygous disorders as well such as “Haemoglobin SC disease” or “Haemoglobin S-beta thalassemia”
- these disorders are autosomal recessive
- they are clinically heterogenous -> even family members present with different severity
7
Q
Inheritance of SCD
A
- autosomal recessive
- clinically heterogenous
8
Q
Pathogenesis
A
- Shortened red cell lifespan (-> haemolysis that leads to Anaemia; Gall Stones; Aplastic Crisis (Parvovirus B19))
- Anaemia partly due to a reduced erythropoietic drive as haemoglobin S is a low affinity haemoglobin
- Blockage to microvascular circulation (vaso-occlusion)
- > Tissue damage and necrosis (Infarction), Pain, Dysfunction
9
Q
Consequences of tissue infarction
A
Spleen
- hyposplenism - spleen undergoes autoinfarction as a consequence of repetitive ischaemic damage and makes patients more susceptible to infection by capsulated bacteria e.g. pneumococcus.
Bones/Joints (acute painful crisis in children)
- dactylitis - avascular necrosis - predisposes to osteomyelitis
Skin
- chronic/recurrent leg ulcers
10
Q
relationship between free Hb and NO
A
- Cell-free haemoglobin limits nitric oxide bioavailability in sickle cell disease
- can lead to pulmonary hypertension
11
Q
Pulmonary hypertension
A
- 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
- patients with SCD and PH probably have a worse prognosis
12
Q
Pathogenesis - Lungs
A
- Acute chest syndrome (most common cause of death in adults with SCD)
- Chronic damage
- Pulmonary hypertension
13
Q
Pathogenesis - urinary tract
A
- Haematuria (papillary necrosis)
- Impaired concentration of urine (hyposthenuria)
- Renal failure
- Priapism
14
Q
Pathogenesis - brain
A
- Stroke (abnormalities in the large cerebral arteries)
- Cognitive impairment
15
Q
Pathogenesis - eyes
A
- proliferative retinopathy
16
Q
Clinical course of SCD
A
- variable and unpredictable even within same family!
17
Q
Why might you give penicillin profylaxis?
A
a study showed that there was an 84% reduction in pneumococcal infection in SCD children
18
Q
What are some emergencies in SCD?
A
- Septic shock (BP <90/60)
- Neurological signs or symptoms
- SpO2 <92% on air (Hypoxia!)
- Symptoms/signs of anaemia with Hb <5 or fall >3g/dl from baseline
- Priapism >4 hours
19
Q
Priapism
A
persistent and painful erection of the penis.
20
Q
What is common in a CSD chest x-ray?
A
- acute chest syndrome
21
Q
Acute chest syndrome
A
- New pulmonary infiltrate on chest X-ray (with: Fever, Cough, Chest pain, Tachypnoea)
- Incidence SS>SC>S-beta+ Thal
- Develops in context of vaso-occlusive crisis
- more common after surgery and in pregnancy
- Diagnosis often delayed
- require mechanical ventilation: 15%
- Mortality > 18 yr 9%
22
Q
Stroke im SCD
A
- Affects 8% SS
- Most common in childhood!!! peak at 2-9 yrs of age
- Involves major cerebral
vessels - more common in SS than in other forms of SCD
23
Q
Gall stones in SCD
A
- By 25 years prevalence
of gallstones is 50% in SS
- Coinheritance of Gilbert syndrome (UGT 1A1 TA7/TA7 genotype) further increases risk - can lead to gallstone pancreatitis
24
Q
Laboratory features of SCD
A
- Hb low (typically 6-8 g/dl)
- Reticulocytes high (except in aplastic crisis)
- abnormal blood film
25
Blood film in SCD
- Sickled cells
- Boat cells
- Target cells
- Howell Jolly bodies
26
How do you diagnose SC disorders?
- solubility test
- Electrophoresis (definitive diagnosis)
- chromomatography (HPLC) -> separates proteins according to charge -> (definitive diagnosis)
27
Solubility test for the diagnosis of SCD
- In presence of a reducing agent oxyHb converted to deoxy Hb
- Solubility decreases
- Solution becomes turbid
- Does not differentiate AS from SS (doesn't differentiate trait from homozygous stain)
28
Management of SCD - general measures
- Folic acid
- Penicillin (at about 3m of age)
- Vaccination (incl. influenza because the consequences can be more serious e.g. pneumonia, not because they are more prone to the infection)
- Monitor spleen size
- Blood transfusion for acute anaemic events, chest syndrome and stroke
- Pregnancy care (greater risk of obstetric complications and foetal loss)
- pain management
- Exchange transfusion (Stroke
Acute chest syndrome)
- Haemopoietic stem cell transplantation <16 yr with severe disease -> Survival 90-95% Cure 85-90%;
- Induction of HbF: Hydroxyurea, Butyrate
29
How do you manage painful crisis in SCD?
- Pain relief -> analgesia (opioids) -> only use for a short time
- Hydration
- Keep warm
- Oxygen if hypoxic
- Exclude infection: Blood and urine cultures, CXR.
30
What triggers painful crises?
- Infection
- Exertion
- Cold
- Dehydration
- Hypoxia
- Psychological stress
31
Pain management in SCD
- 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
32
What is the most widely used pain med (opioid) in SCD?
Diamorphine
33
Other ways to manage SCD
- Exchange transfusion: Stroke, Acute chest syndrome
- Haemopoietic stem cell transplantation: <16 yr with severe disease; Survival 90-95%; Cure 85-90%;
- Induction of HbF (Hydroxyurea, Butyrate)
34
Current disease-modifying therapies for SCD
- Transfusion
- Hydroxycarbamide (Hydroxyurea)
- Haemopoietic stem cell transplantation
35
Hydroxyurea in treatment of SCD
Hydroxyurea / hydroxycarbimide increases the amount of HbF in the blood -> less sickle cells!
- 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
36
Hydroxyurea - what is the rationale?
- Increases production of baby (fetal) haemoglobin (HbF)
- Decreases ‘stickiness’ of sickle red blood cells
- Reduces white blood cell production by the bone marrow
- Improves hydration of red blood cells
- Generates nitric oxide which improves blood flow -> metabolised to NO
37
Indications for HSCT
- CNS disease
- Recurrent severe VOC*
- Recurrent ACS*
(* = if hydroxyurea fails)
38
CNS disease in SCD
- 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
39
New approaches in SCD treatment
- gene therapy (CD34+ cells)
| - Crizanlizumab
40
Sickle cell trait
- HbAS
- Normal life expectancy
- Normal blood count
- Usually asymptomatic
- Rarely painless haematuria
- Caution: anaesthetic, high altitude -> may develop some vasoocclusive symptoms, extreme exertion -> e.g. in hot conditions with dehydration, e.g. in military training deaths have occurred
=> overall a benign condiiton
41
1. Sickle cell anaemia includes both HbSS and HbSC
| - > True/False?
FALSE
-> it applies to the homozygous state SS
42
2. Sickling is due to a change in the a globin chain
| - > True/False
FALSE
-> beta globin defect
43
The molecular alteration is a 3. 3. deletion which protects against malaria
True/False?
FALSE
-> its a missence mutation but yes it protects from malaria
44
7. Women with HbSS have a normal life expectancy
| - > True/false?
FLASE
Life expectancy is significantly reduced
However better than males
45
9. Solubility tests are used to confirm sickle cell anemia if screening tests are positive
- > True/false?
FALSE
-> will only identify the presence of HbS (sickle Hb) does not differentiate between trait and SCA
46
5. Clinical manifestations may start in utero because b-globin is part of fetal Hb True/false
FALSE
foetal haemoglobin is alpha and gamma chains
47
6. Osteomyelitis is the name given to inflammation of a digit True/false?
False
osteomyelitis is bone infection, inflammation of digits is dactylics.
48
8. Chest crises may be fatal
| True/false?
True
most common cause I adult SCD
49
Haemoglobin S
- Deoxyhaemoglobin S is insoluble
- HbS polymerises to form fibres: “tactoids”
- Intertetrameric contacts stabilise structure
50
SCA vs SCD
- SCA refers to the homozygous form SS
| - SCD is a generic term for all sickling disorders that come in different forms.
51
Early presentation of SCD
- symptoms are rare before 3-6 months of age
- onset coincides with switch from foetal to adult Hb synthesis
- early manifestations include: dactylics, splenic sequestration, infection - S. pneumonia
52
Dactylitis
Dactylitis is inflammation of a digit (either finger or toe) and is derived from the Greek word dactylos meaning finger. The affected fingers and toes swell up into a sausage shape and can become painful.
53
Splenic sequestration
Splenic sequestration is a problem with the spleen that can happen in people who have sickle cell disease. Splenic sequestration happens when a lot of sickled red blood cells become trapped in the spleen. The spleen can enlarge, get damaged, and not work as it should.
54
Avascular Necrosis
| of the Femoral Head
- Causes severe disability
| - may require joint replacement
55
What bacteria most commonly cause osteomyelitis in SCD?
- salmonella osteomyelitis
| - streptococcal infection is next most common
56
HPLC
high performance liquid chromatography
57
Limitations of HSCT
- 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
```
58
4. Sickle Hb makes red cells less deformable - true/flase?
TRUE
59
10. If a lady with HbAS has a partner with HbSS she should be offered genetic counselling - true/false?
TRUE
-> autosomal recessive, clear genetic risk of having a child with SCD (50%)
