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Year 2 - MCD - Haematology > Sickle cell Disese > Flashcards

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)
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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

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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
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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

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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
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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
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7
Q

Inheritance of SCD

A
  • autosomal recessive

- clinically heterogenous

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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
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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

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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
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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
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12
Q

Pathogenesis - Lungs

A
  • Acute chest syndrome (most common cause of death in adults with SCD)
  • Chronic damage
  • Pulmonary hypertension
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13
Q

Pathogenesis - urinary tract

A
  • Haematuria (papillary necrosis)
  • Impaired concentration of urine (hyposthenuria)
  • Renal failure
  • Priapism
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14
Q

Pathogenesis - brain

A
  • Stroke (abnormalities in the large cerebral arteries)

- Cognitive impairment

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15
Q

Pathogenesis - eyes

A
  • proliferative retinopathy
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16
Q

Clinical course of SCD

A
  • variable and unpredictable even within same family!
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17
Q

Why might you give penicillin profylaxis?

A

a study showed that there was an 84% reduction in pneumococcal infection in SCD children

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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
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19
Q

Priapism

A

persistent and painful erection of the penis.

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20
Q

What is common in a CSD chest x-ray?

A
  • acute chest syndrome
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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%
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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
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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
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24
Q

Laboratory features of SCD

A
  • Hb low (typically 6-8 g/dl)
  • Reticulocytes high (except in aplastic crisis)
  • abnormal blood film
25
Q

Blood film in SCD

A
  • Sickled cells
  • Boat cells
  • Target cells
  • Howell Jolly bodies
26
Q

How do you diagnose SC disorders?

A
  • solubility test
  • Electrophoresis (definitive diagnosis)
  • chromomatography (HPLC) -> separates proteins according to charge -> (definitive diagnosis)
27
Q

Solubility test for the diagnosis of SCD

A
  • 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
Q

Management of SCD - general measures

A
  • 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
Q

How do you manage painful crisis in SCD?

A
  • Pain relief -> analgesia (opioids) -> only use for a short time
  • Hydration
  • Keep warm
  • Oxygen if hypoxic
  • Exclude infection: Blood and urine cultures, CXR.
30
Q

What triggers painful crises?

A
  • Infection
  • Exertion
  • Cold
  • Dehydration
  • Hypoxia
  • Psychological stress
31
Q

Pain management in SCD

A
  • 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
Q

What is the most widely used pain med (opioid) in SCD?

A

Diamorphine

33
Q

Other ways to manage SCD

A
  • 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
Q

Current disease-modifying therapies for SCD

A
  • Transfusion
  • Hydroxycarbamide (Hydroxyurea)
  • Haemopoietic stem cell transplantation
35
Q

Hydroxyurea in treatment of SCD

A

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
Q

Hydroxyurea - what is the rationale?

A
  • 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
Q

Indications for HSCT

A
  • CNS disease
  • Recurrent severe VOC*
  • Recurrent ACS*

(* = if hydroxyurea fails)

38
Q

CNS disease in SCD

A
  • 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
Q

New approaches in SCD treatment

A
  • gene therapy (CD34+ cells)

- Crizanlizumab

40
Q

Sickle cell trait

A
  • 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
Q
  1. Sickle cell anaemia includes both HbSS and HbSC

- > True/False?

A

FALSE

-> it applies to the homozygous state SS

42
Q
  1. Sickling is due to a change in the a globin chain

- > True/False

A

FALSE

-> beta globin defect

43
Q

The molecular alteration is a 3. 3. deletion which protects against malaria
True/False?

A

FALSE

-> its a missence mutation but yes it protects from malaria

44
Q
  1. Women with HbSS have a normal life expectancy

- > True/false?

A

FLASE

Life expectancy is significantly reduced
However better than males

45
Q
  1. Solubility tests are used to confirm sickle cell anemia if screening tests are positive
    - > True/false?
A

FALSE

-> will only identify the presence of HbS (sickle Hb) does not differentiate between trait and SCA

46
Q
  1. Clinical manifestations may start in utero because b-globin is part of fetal Hb True/false
A

FALSE

foetal haemoglobin is alpha and gamma chains

47
Q
  1. Osteomyelitis is the name given to inflammation of a digit True/false?
A

False

osteomyelitis is bone infection, inflammation of digits is dactylics.

48
Q
  1. Chest crises may be fatal

True/false?

A

True

most common cause I adult SCD

49
Q

Haemoglobin S

A
  • Deoxyhaemoglobin S is insoluble
  • HbS polymerises to form fibres: “tactoids”
  • Intertetrameric contacts stabilise structure
50
Q

SCA vs SCD

A
  • SCA refers to the homozygous form SS

- SCD is a generic term for all sickling disorders that come in different forms.

51
Q

Early presentation of SCD

A
  • 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
Q

Dactylitis

A

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
Q

Splenic sequestration

A

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
Q

Avascular Necrosis

of the Femoral Head

A
  • Causes severe disability

- may require joint replacement

55
Q

What bacteria most commonly cause osteomyelitis in SCD?

A
  • salmonella osteomyelitis

- streptococcal infection is next most common

56
Q

HPLC

A

high performance liquid chromatography

57
Q

Limitations of HSCT

A
  • 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
Q
  1. Sickle Hb makes red cells less deformable - true/flase?
A

TRUE

59
Q
  1. If a lady with HbAS has a partner with HbSS she should be offered genetic counselling - true/false?
A

TRUE

-> autosomal recessive, clear genetic risk of having a child with SCD (50%)

Year 2 - MCD - Haematology (11 decks)

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