Sickle Cell Disease

Question 1

Normal haemoglobin

Answer 1

-4 globin chains, 4 haem molecules

-Normal adult
=HbA>95%: 2a, 2b chains
=HbA2 2-3%: 2a, 2d chains
=HbF <1%: 1a, 2g chains

-Foetal: mainly HbF, switch to HbA occurs at 3-6 months of life

Question 2

Genetic abnormalities in sickle cell disease

Answer 2

-Single nucleic acid substitution GAG->GTG in beta globin gene beta->beta 3 (point mutation)
-Glutamic acid to valine
-Autosomal recessive!

-Hb AA=normal
-Hb AS= carrier (African, malaria protection), only symptomatic if severely hypoxic
-Hb SS= sickle cell disease, symptoms don’t develop until 4-6 months when abnormal HbSS molecules take over from fetal haemoglobin

-HbSC and HbS/ beta thalassemia also sickling disorders

Question 3

Effect on beta haemoglobin chain

Answer 3

-Normal haemoglobin exists as monomers in cell, even when deoxygenated
-Haemoglobin S polymerises and forms crystals when deoxygenated at low oxygen
-sickle cells are fragile and haemolyse; they block small blood vessels and cause infarction

Question 4

How do we detect haemoglobin S?

Answer 4

-Haemoglobin electrophoresis
-High performance liquid chromatography

Question 5

Effect on red blood cells

Answer 5

-Normal: flexible biconcave disc, retain shape= pass through small capillaries
-Polymerises and clumps= sickle shape, more easily damaged in small vessels, small vessel occlusion
=clinical complications

Question 6

What increases sickling?

Answer 6

-Hypoxia
-Infection
-Acidosis
-Cold
-Low levels of HbF
=Higher levels are protective

Question 7

Chronic haemolytic anaemia

Answer 7

-Hb -70g/L (60-80)
-Jaundice, elevated bilirubin (increased cell breakdown)
-Reticulocytosis (bone marrow produces more immature red cells- polychromatic)

Question 8

Sickle cell complications

Answer 8

-Acute vaso-occlusive bony pain (blockage of capillaries= infarction)
-Acute organ VOC
-Sequestration- liver or spleen
-Chronic end-organ damage

Question 9

Types of sickle cell crises

Answer 9

-Thrombotic, ‘vaso-occlusive’, ‘painful crises’
-Acute chest syndrome
-Anaemic
=Aplastic
=Sequestration
-Infection

Question 10

Describe thrombotic crises

Answer 10

-also known as painful crises or vaso-occlusive crises
-precipitated by infection, dehydration, deoxygenation (e.g. high altitude)
-painful vaso-occlusive crises should be diagnosed clinically - there isn’t one test that can confirm them although tests may be done to exclude other complications
-infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain

Question 11

Describe acute chest syndrome

Answer 11

-vaso-occlusion within the pulmonary microvasculature → infarction in the lung parenchyma
-dyspnoea, chest pain, pulmonary infiltrates on chest x-ray, low pO2
-management
=pain relief
=respiratory support e.g. oxygen therapy
=antibiotics: infection may precipitate acute chest syndrome and the clinical findings (respiratory symptoms with pulmonary infiltrates) can be difficult to distinguish from pneumonia
=transfusion: improves oxygenation
-the most common cause of death after childhood

Question 12

Describe aplastic crises

Answer 12

caused by infection with parvovirus
sudden fall in haemoglobin
bone marrow suppression causes a reduced reticulocyte count

Question 13

Describe sequestration crises

Answer 13

sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
associated with an increased reticulocyte count

Question 14

Painful vaso-occlusive crises

Answer 14

-Present with dactylitis
-Managed with analgesics
-Commonest manifestation of sickle cell disease requiring hospital assessment and admission.
-The pain can be extremely severe and should be addressed urgently, with patients triaged as high priority and contact should be made with the on-call Haematology team.

Question 15

Assessment of painful vaso-occlusive crises

Answer 15

-Routine Investigation (*Urgent requests)
=FBC, reticulocytes *
=Group & screen (state on form that patient has Sickle Cell Disease. Request full red cell phenotype if new patient)
=Urea, creatinine electrolytes *
=LFT’s, LDH
=Baseline pulse oximetry ON AIR
=Haemoglobin electrophoresis in NEW patients only

-If indicated
=Blood cultures
=Viral serology
=Urine dipstick + MSU
=Throat swab

-Additional Investigations
=If there are chest signs or temperature >38o: – Chest X-ray
=If O2 sats on air < 94% – Arterial gases on air
=If there are abdominal signs: – Chest X-Ray, Abdominal X-ray and amylase
=Appropriate microbiological specimens (sputum, stool, wound, etc.)
=Note: Patients on Desferrioxamine (DFO), admitted with diarrhoea/abdominal pain, should have blood and stool screened for Yersinia and the DFO stopped

Question 16

Management of painful vaso-occlusive crises

Answer 16

-Management is supportive (i.e. conservative) unless there are indications for exchange transfusion.

=Acute cerebro-vascular event
=Acute chest syndrome
=Multi-organ failure

-The aim of treatment is to break the vicious cycle of sickling, hypoxia and acidosis leading to more sickling — all exacerbated by dehydration.
-Prompt treatment of painful crises can reduce suffering and prevent further sickle related complications.
-Analgesia should be given within 30 minutes of the patient presenting.

-Principals of management
=Effective analgesia
=Hydration
=Oxygenation
=Antimicrobials – prophylactic or therapeutic if pyrexial
=Ongoing assessment of analgesic efficacy
=Blood transfusion (do not rapidly reduce percentage of HbS containing cells, severe anaemia)/ exchange transfusion if neurological complications (rapidly reduce percentage of HbS)

Question 17

Analgesia in management of crises

Answer 17

-Aim is to achieve safe, effective analgesia whilst avoiding IV opiates if possible.
-Patients with end stage renal failure, consider alternative opiate e.g. Fentanyl
-Some patients will have individualised pain protocols which should be referred to if available

=Mild/mod: Paracetamol 1g QDS, Ibuprofen 400mg/ diclofenac 50mg, dihydrocodeine 60mg, reassess after 30 mins
=Mod/severe: morphine 5-10mg s/c stat or oromorph 5-10 mg stat, reassess 20-30 mins post dose and titrate with pain
=If persisting: morphine 5-10mg s/c or oromorph, consider addition of MST 1mg/kg 12 hourly, hourly observations
==Persisting still: consider alternative to morphine (fentanyl, oxycodone), consider PCA, consult hospital pain team
==If pain controlled: stop morphine s/c, change to oromorph, continue MST and reduce after further 24 hours

Question 18

Notes of pain management

Answer 18

-Paracetamol and NSAIDS should be used in addition to opiates as required, as they have a synergistic effect
-All patients will have different analgesic requirements and many know what they have required to achieve pain relief in the past. Analgesia should be titrated with pain
-Patients should be monitored every 30 mins until pain is controlled and patient is stabilised and every 2 hours thereafter
-Monitoring must include pain, sedation, vital signs, respiratory rate, O2Saturation
-Naloxone should be available for reversal of sedation and/or respiratory depression (RR<12/min)
-Pethidine is not recommended because of risk of seizures at high doses

Question 19

Additional therapies for painful crises

Answer 19

-Antipruritic: Hydroxyzine 25 mg bd po
-Antiemetics: e.g. Cyclizine 50 mg tds
-Laxatives if opioid analgesia is to continue
-Folic acid 5mg od
-Prophylactic Low Molecular Weight Heparin
-Prophylactic antibiotics (usually penicillin V 250mg bd)

Question 20

Fluids in painful crises

Answer 20

-Adequate fluid intake is essential
-Patients should be encouraged to drink at least 3 litres of water-based fluids per 24 hours
-Every patient must have a fluid balance chart which should be completed by the nursing staff or by the patient (if able)
-Intravenous or ng fluids may be required if the patient is unable to tolerate oral fluids

Question 21

Oxygen in painful crises

Answer 21

-Oxygen saturations on air should be monitored regularly
-Many patients have a symptomatic benefit from Oxygen therapy, and it should be prescribed and be available whatever the oxygen saturations (even if>98%) if the patient requests
-Oxygen saturations on air should be >94%
-If oxygen saturations on air <94% Call haematologist
-Check Arterial Blood Gases (ABGs) on air
-Administer humidified oxygen at 2-4 L/min by mask or nasal cannulae
-Increase frequency of observations to hourly or more frequently if clinical picture dictates
-Arterial Blood Gases: Consider a diagnosis of Acute Chest Syndrome if worsening hypoxia

Question 22

Infection and antimicrobials in painful crises

Answer 22

-If apyrexial continue prophylactic antibiotics: Penicillin V 250 mg bd po (Erythromycin 250mg bd po if allergic)
-If temperature greater than 38C, undertake blood cultures/septic screen and commence Co-amoxiclav (Unless penicillin allergic) for 5 days. Prophylactic antibiotics should be stopped
-If patient is on Hydroxycarbamide (Hydroxyurea), check FBC urgently and stop the Hydroxycarbamide if the platelet count <100x109/l, reticulocytes<100x109/l or neutrophils <1x109/l

-Consider:
=Pneumococcal sepsis (especially if not taking prophylaxis and not vaccinated)
=Gram negative sepsis
=Lower respiratory tract infection
=Urinary tract infection
=Osteomyelitis
=Malaria if travelled recently
=Parvovirus B19 if low reticulocyte count
=Yersinia if on DFO and have diarrhoea

Question 23

Examples of end organ damage

Answer 23

-Brain
=Thrombosis or haemorrhage
=Paralysis
=Sensory deficits
=Death

-Lung
=Acute chest syndrome
=Pulmonary hypertension
=Pneumonia

-Penis
=Priapism (painful prolonged unwanted erections)

-Heart failure

-Splenic atrophy (increased risk of infection)

-Haematuria
-Renal Failure

Question 24

Long-term sickle cell management

Answer 24

-Hydroxyurea
=increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes
-NICE CKS suggest that sickle cell patients should receive the pneumococcal polysaccharide vaccine every 5 years