Sickle cell disease Flashcards
What is the inheritance pattern for Sickle cell disease?
autosomal recessive
Describe the 4 variants of sickle cell pathologies?
Sickle cell anaemia (e.g. HbSS): inheritance of two abnormal sickle genes (one paternally and one maternally).
Sickle cell disease (e.g. HbSC): inheritance of one abnormal sickle gene and a second haemoglobin variant of the beta chain that causes sickling. For example, haemoglobin C.
Sickle cell trait (e.g. HbS): inheritance of one abnormal sickle gene (either paternally or maternally). Also known as a sickle carrier.
Sickle-thalassaemia (e.g. HbSβ0): inheritance of one abnormal sickle gene and one abnormal thalassaemia gene (e.g. alpha or beta). Severity depends on the thalassaemia gene inherited.
What is haemoglobin composed of?
composed of four globin chains and four heme molecules, which are the actual oxygen-binding structures that contain iron.
What are the 6 types of heamoglobins?
HbA: two alpha, two beta (95-98% in adults)
HbA2: two alpha, two delta (2-4% in adults)
HbF: two alpha, two gamma (foetal haemoglobin: 0.8-2% in adults)
HbS: two alpha, two sickle (abnormal beta)
Gower: two zeta, two epsilon (embryonic haemoglobin)
Portland: two zeta, two gamma (embryonic haemoglobin)
On which chromosome are the genes for the development for alpha globulins? Which other globin chains are coded for on this chromosome?
Alpha globin gene cluster: located on chromosome 16. Contains the embryonic globin genes zeta and two copies of the alpha globin gene (alpha-1 and alpha-2).
On which chromosome are the genes for the development for beta globulins? Which other globin chains are coded for on this chromosome?
Beta globin gene cluster: located on chromosome 11. Contains the embryonic globin gene epsilon, fetal globin genes and the adult beta and delta globin genes.
What is the difference between the amount of alpha and beta globulin genes inherited?
four alpha globin genes and two beta globin genes. With the alpha genes, two are inherited paternally and two inherited maternally. With the beta globin genes, one is inherited from each parent.
Why is there a high prevalence of sickle cell disease in Africa? (speculated reason)
speculated to be due to a survival advantage for heterozygous carriers (i.e. one normal gene and one sickle gene) in malarial regions.
When do symptoms of sickle cell disease begin to develop and why?
symptoms usually begin in the second half of the first year (after 6 months) of life when the levels of foetal haemoglobin normally begin to fall.
What is the genetic mutation responsible for sickle cell disease?
point mutation in the beta-globin gene located on chromosome 11
glutamic acid to be converted to valine.
What is the meaning of the term compound heterozygous?
Inheritance of sickle haemoglobin alongside another haemoglobin variant is referred to as compound heterozygous (e.g. HbSC). This refers to the presence of two or more different recessive alleles.
How do sickle cell cause vessel occlusion?
sickle haemoglobin polymerises at low oxygen tension, which distorts its shape and leads to vessel occlusion.
Describe the pathophysiology of sickle cell disease
- formation of sickle-shaped red blood cells
- occur due to polymerisation of sickle haemoglobin when placed under low oxygen tension
- damages red blood cells leading to chronic haemolysis and clustering that results in occlusion of blood vessels
- Haemolysis shortens the lifespan of red blood cells to ~10-20 days compared to 120 days
- vaso-occlusion causes tissue ischaemia (inadequate blood supply) that leads to infarction (tissue death from ischaemia).
The sickle process is increased by which factors?
- low oxygen levels,
- dehydration
- concurrent illness (e.g. infections)
- cold exposure
- acidosis
What are the consequences of vaso-occlusion? (8)
Acute painful episodes (i.e. painful crisis)
Acute chest syndrome (i.e. chest crisis)
Renal infarction
Bone infarction or dactylitis (inflammation of a digit)
Myocardial infarction
Stroke
Venous thromboembolism
Priapism (persistent, painful erection)
What effect do the sickled cells have on the liver and spleen and how does this relate to anemia?
Due to their abnormal shape, red blood cells can get sequestrated (i.e. trapped) within the liver and spleen leading to marked anaemia. If this occurs acutely, if can lead to life-threatening anaemia.
Patients with sickle cell disease are at risk of anaemia for many reasons. Describe some of these reasons
Hyposplenismand/or asplenium/ autosplenectomy can occur due to increased infraction.
- increases the risk of bacterial infections (particularly encapsulated bacteria- Pneumococcal, Meningococcal and Haemophilus.)
- Patients are at increased risk of viral infections (e.g. Parvovirus B19, influenza), which can occasionally cause aplastic crises (i.e. transient arrest of erythropoiesis).
There are 3 main causes of anaemia in patients with sickle cell disease, what are they?
Acute splenic sequestration
- Acute fall on Hb due to pooling of red blood cells in the spleen. Presents with rapidly enlarging spleen, features of anaemia +/- hypovolaemic shock
Transient red cell aplasia
- transient arrest of erythropoiesis, usually induced by infection (e.g. parvovirus B19). Evidence of erythropoiesis recovery is usually seen after 2-14 days through increase in reticulocyte formation.
Hyperhaemolysis in patients with severe infection
- sudden exacerbation of haemolysis. May be associated with acute vaso-occlusive crises, due to excess transfusions and development of alloimmunisation (immune response to foreign antigens) to different red blood cell antigens or coexistence of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Which bacterial and viral infections are those with sickle cell most at risk of developing?
Bacteria - Pneumococcal, Meningococcal and Haemophilus.
Viral - Influenzas, parvovirus
Name the 2 main types of Vaso-occlusive phenomena
Acute painful episodes,
acute chest syndrome
- vaso-occlusive crisis affecting the lungs
Describe the pathophysiology of a Vaso-occlusive crisis
- obstruction of the microcirculation by sickled red blood cells, causing ischaemia
- This causes causes painful episodes which can effect anywhere in the body but especially
Back Chest Abdomen Extremities Dactylitis: inflammation of a digit
Pain can be mild - managed at home
Or sever - managed at hospital
Patient presentation -
Describe how patients suffering from Vaso-occlusive crisis can present and why?
Rapid onset of -
- Bone pain (due to bone marrow infraction)
- Swollen painful joints,
- tachypnoea or other signs of lung involvement,
- neurological signs
- acute abdominal distension and pain (mesenteric sickling and bowel ischaemia),
- loin pain (renal papillary necrosis may cause renal colic or severe haematuria) due to renal impairment
Priapism, hyphaema and retinal occlusion - acute visual loss
Large vessels may also be involved, causing thrombotic strokes, acute sickle chest syndrome and placental infarction.
Describe how patients suffering from Acute chest syndrome can present and why?
Vaso-occlusive crisis affecting the lungs
Defined as new pulmonary infiltrate on the chest X ray plus one or more of
- fever
- cough/wheeze
- sputum production,
- tachypnoea
- dyspnoea
- new-onset hypoxia
Describe how patients suffering from Aplastic crisis can present and why?
Temporary cessation of erythropoiesis, causing severe anaemia
- a drop in haemoglobin over about one week.
- Recovery may be spontaneous but a transfusion is usually required
- patients may present with high-output congestive heart failure.
What are the chronic complications of sickle cell anaemia?
Neurological: cerebrovascular disease with deficits following stroke and seizure disorders.
Blood and bone: chronic anaemia, osteoporosis and avascular necrosis.
Cardiac: cardiomyopathy and heart failure (usually due to heart failure with preserved ejection fraction).
Pulmonary disease: can develop problems with pulmonary hypertension
Kidneys: chronic kidney disease
Hepatobiliary: variety of mechanisms. Often damage to the liver from transfusional iron overload. Increased risk of pigment gallstones due to chronic haemolysis.
Others: chronic pain, delayed puberty, leg ulcers and retinal disease
How is sickle cell disease diagnosed?
- Majority of patients are diagnosed as part of the newborn screening programme within the UK
- Babies at risk of SCD are usually identified from antenatal screening. This screens mothers, and if needed biological fathers, for abnormal haemoglobin variants
Describe the new born screening process
involves a blood spot sample (typically heel prick) that is taken on day 5 of life. The sample is then tested for nine conditions including sickle cell
Which laboratory techniques that can be used to identify the abnormal sickle haemoglobin?
- Haemoglobin electrophoresis: enables identification of the type of haemoglobin.
- High performance liquid chromatography (HPLC): detection of sickle haemoglobin. Results shown as different peaks.
- Capillary electrophoresis: Haemoglobin types are separated using ion migration and electro-osmotic flow
- DNA sequencing: allows direct identification of the beta globin gene sequence.
Describe the investigations conducted to diagnose sickle cell disease
FBC and blood film:
- Hb - 60-80 g/dL with a high reticulocyte count of 10-20%
- blood films may show sickled erythrocytes and features of hyposplenism.
- Sickling of red cells on a blood film with 2% sodium metabisulphite.
- Sickle solubility test: a mixture of HbS in a reducing solution such as sodium dithionite gives a turbid appearance because of precipitation of HbS
- Haemoglobin analysis (eg, by electrophoresis) is always needed to confirm the diagnosis.
- Sickle cell trait differentiated by electrophoresis - Hb A and S identified
- Other investigations such as renal function tests, LFTs and lung function tests. Maybe infection screen, abdominal ultrasound, CT scan of the head (eg, if a subarachnoid haemorrhage is suspected).
What are the indications for urgent referral to hospital in sickle cell disease?
Severe pain not controlled by simple analgesia or low-dose opioids.
Dehydration caused by severe vomiting or diarrhoea.
Severe sepsis: temperature >38.5°C
Symptoms or signs of acute chest syndrome
Marked increase in jaundice.
Haematuria.
Fulminant priapism lasting
more than two hours or worsening of recurrent episodes.
What are the 7 main components in treating people with sickle cell disease?
Patient education
General care
Managing acute complications (e.g. acute painful episodes)
Preventing vaso-occlusive phenomena
Stroke prevention
Managing chronic complications
Curative treatment
What is involved in patient education of those with sickle cell disease?
- nature of SCD
- pain management strategies
- discussion about expected complications
- infection prevention,
- preconception counselling - psychosocial involvement.
How is sickle cell disease generally cared for?
- Regular follow up - 3months in first 2 years, 6 months by age 6, the yearly
Due to chronic haemolysis and hyposplenism
- Folic acid replacement: at risk of bone marrow aplasia due to deficiency from increased red blood cell turnover
- Antibiotic prophylaxis: usually penicillin prophylaxis (e.g. Pen V) or erythromycin in penicillin allergic patients
- Childhood immunisation
- Adult immunisation: pneumococcal vaccine 5-yearly, seasonal influenza vaccine and further vaccinations (e.g. Meningococcal, hepatitis B, Haemophilus) depending on previous vaccinations.
What is the process for stroke prevention in sickle cell disease patients?
- blood transfusions to reduce the HbS percentage
(top-up transfusions for exchange transfusions.) - In children, transcranial doppler ultrasound is performed annually between 2-16 years of age to determine the risk of stroke.
Children and adults who develop strokes can be offered the exchange transfusion programme as part of secondary prevention.
What is the main issue associated with long-term transfusion treatment?
iron overload
. This can lead to secondary haemochromatosis with widespread organ dysfunction from iron deposition.
organs affected include the heart, liver, pancreas and pituitary gland.
Patients may be given iron chelators (e.g. deferoxamine, deferasirox, and deferiprone) to prevent complications.
What is the curative treatment for sickle cell disease?
haematopoietic stem cell transplantation
Which investigations are conducted when a patient presents to the hospital with Acute painful episodes?
Full blood count, reticulocyte count
Group and save
Biochemistry: LDH, U&Es, LFTs, Bone
Septic screen: blood cultures (if fever), chest x-ray, mid-stream urine culture.
Bone x-rays: rarely needed. Usually reserved for suspected acute fractures or osteomyelitis.
How is an Acute painful episode treated?
Initial, rapid assessment - ABCDE
Observations: particular attention to saturations
Check sickle care plan: personalised care plan for patients to manage painful episodes.
Rapid administration of analgesia: usually subcutaneous morphine. Aim within 30 minutes of admission. Paracetamol/ibuprofen can be used as adjuncts.
Regular assessment: regular observations, assessment of pain scores and administration of analgesia essential.
Managing exacerbating factors: ensure well hydrated, treat concurrent infections and provide oxygen as needed (aim sats >94% unless chronic CO2 retention).
How is Acute chest syndrome investigated and diagnosed?
clinical features in the context of new infiltrates on chest x-ray
Bloods: FBC, U&E, Group & save, CRP, LFT
Imaging: chest x-ray (looking for infiltrates)
Infection screen: blood cultures, sputum cultures, viral PCR
Arterial blood gas: ideally on room air to asses the degree of hypoxia
Incentive spirometry. aims to prevent atelectasis. Atelectasis causes ventilation/perfusion mismatch, worsens hypoxia and can precipitate acute chest syndrome.
How is acute chest syndrome treated?
If sever with significant hypoxia = urgent exchange transfusion
the sickle haemoglobin percentage.
All patients -
- hydration (i.e. IV fluids),
- antibiotics if concern regarding infection,
- adequate pain relief,
- physiotherapy (i.e. chest physio)
- VTE prophylaxis if no contraindication
Patients require frequent monitoring and early escalation to intensive care unit (ICU) if deterioration.
Patients with severe hypoxia may require continuous positive airway pressure (CPAP) or invasive ventilation.
If a patient is undergoing active haemolysis, how would this be identified on the blood test?
- High Bilirubin
- high LDH,
- raised reticulocytes
- undetectable haptoglobin
What would the electrophoresis image of a patient with AS, SS and SC look like?
AS - HbA and HbS
SS - HbF and HbS
SC - HbS and HbC
What is Priapism?
Long lasting painful erection
What is a hyphema?
A hyphema is an accumulation of blood in the anterior chamber of the eye
Which factors increase the risk of a patient developing an acute chest crisis?
Surgery/anaesthesia, pregnancy
Infection
chronic lung disease - e.g Asthma
Hypoventilation
Describe the pathophysiology of acute chest syndrome
precipitating factors may present
- Hypoxia, Inflamation and Acidosis occur as with a usual crisis
- Vasoocclusion within the
pulmonary microvasculature occurs - This can be caused by a fat embolism or a pulmonary thrombi
