11/14/24, 10\:44 AM Sickle Cell Anaemia

Sickle Cell Anaemia

Table of contents
Key points ⚡
Succinct notes to superpower your revision
Sickle cell disease (SCD)\: group of disorders with deformed red blood cells (sickled shape).
Sickle cell anaemia (SCA)\: most common and severe form of SCD, caused by two abnormal sickle cell genes.
Genetics\: autosomal recessive inheritance; mutation in beta-globin gene (glutamic acid to valine) resulting in sickled
haemoglobin (HbS).
Pathophysiology\: HbSS polymerises under stress (hypoxia, dehydration, infection, cold, acidosis), deforming red cells into a
sickled shape.
Clinical features\: acute/chronic pain (vaso-occlusion), anaemia (pallor, weakness), growth restriction, delayed puberty,
splenomegaly, recurrent infections, jaundice.
Vaso-occlusive crises\: pain due to microcirculation obstruction; a
and penis.
Acute chest syndrome\: pulmonary in
Aplastic crisis\: temporary cessation of erythropoiesis, often due to parvovirus B19; may require transfusion.
Sequestration crisis\: sudden splenic enlargement, acute drop in haemoglobin, may lead to hypovolemic shock.
Investigations\: FBC (low Hb, high reticulocytes), blood
haemoglobin electrophoresis (for diagnosis).
Management\: prevention (avoid triggers, antibiotics, vaccinations, folic acid); acute crises (pain management, infection
screening, transfusion); hydroxycarbamide (increases HbF), bone marrow transplant (curative), gene therapy (experimental).
Complications\: chronic pain, cardiac failure, pulmonary disease, gallstones, retinopathy, transfusion-related issues, leg
ulcers, avascular necrosis, chronic kidney disease.
Prognosis\: median life expectancy 40-60 years in high-income countries; common causes of death include infections in
children and cerebrovascular events, acute chest syndrome, pulmonary hypertension, sepsis in adults.
Article 🔍
A comprehensive topic overview

Introduction

Sickle cell disease (SCD) is the name given to a group of disorders associated with the deformation of red blood cells into
a sickled shape.
1
Sickle cell anaemia (SCA) is the name given to the most common and serious form of SCD. SCA is caused by the
inheritance of two abnormal sickle cell genes.
In the UK, approximately 300 babies are born with SCD every year and 14,000 people are currently living with SCD. SCD is
most commonly seen in patients of African and Caribbean ancestry.
2-4

Aetiology

Genetics

https\://app.geekymedics.com/notebook/2640/ 1/811/14/24, 10\:44 AM Sickle Cell Anaemia
The most common type of haemoglobin present in the foetus and neonate is haemoglobin F (HbF). This is composed of
two alpha chains and two gamma chains. By the time an infant reaches the age of 6 months, HbF production decreases
such that it accounts for less than 1% of the total haemoglobin in circulation.
1
The most common haemoglobin type present in people older than 6 months of age is haemoglobin A (HbA). This is
composed of two alpha chains and two beta chains and accounts for 97% of all haemoglobin in adults.
5
In SCD, a single point mutation in the beta-globin gene is inherited in an autosomal recessive fashion (Figure 1). This results
in an amino acid replacement at position 6 in the beta-globin chain from glutamic acid to valine. 6
This results in sickled
haemoglobin (HbS).
In SCA, a mutation is present in both inherited beta-globin genes, resulting in haemoglobin SS (HbSS).
Patients who carry one abnormal sickle cell gene AND one normal haemoglobin gene are said to have sickle cell trait
(HbAS). These patients do not have SCD and are said to be "carriers.
" Their red blood cells do not sickle and therefore
patients tend to live normal lives.
1
Figure 1. The inheritance pattern of SCD (adapted from the
Sickle Cell Society)

Pathophysiology

Under physiological stress, sickled haemoglobin (HbSS) polymerises and causes erythrocytes to deform into a sickled
shape (Figure 2). Physiological stressors include\:
*
Hypoxia
Dehydration
Infection
Cold temperatures
Acidosis (e.g. lactic acidosis following exertion)
6,7
*The above stressors do not usually induce sickling in patients with sickle cell trait (HbAS).
Figure 2. Sickled red blood cells in SCA
8

Clinical features

Clinical features of SCA begin between three and six months of age as this is when HbF levels fall and the proportion of
HbSS in the blood rises.

History

Typical signs and symptoms of SCA may include\:
https\://app.geekymedics.com/notebook/2640/ 2/811/14/24, 10\:44 AM Sickle Cell Anaemia
Acute or chronic pain\: due to vaso-occlusion
Features of anaemia such as pallor, weakness and lethargy\: due to chronic haemolysis, transient red cell aplasia or
splenic sequestration
Growth restriction
Delayed puberty
Splenomegaly\: due to increased haemolysis in the spleen. Notably recurrent splenic infarcts usually cause asplenism by
two years of age.
Recurrent infections\: as there is an increased risk of infection from encapsulated bacteria including p n e u m o c o c c u s ,
H a e m o p h i l u s i n
Jaundice\: due to increased haemolysis
Over time, patients may adapt to the chronic anaemia but their disease is usually complicated by interspersed episodes of
acute sickle cell crises.
7
Vaso-occlusive crises
Vaso-occlusive crises are the most common reason for hospital admission among SCA patients (Figure 3). 7
Sickled red
blood cells can obstruct the microcirculation anywhere in the body leading to pain and ischemia +/- infarction. Pain may
be severe and should be managed aggressively.
Vaso-occlusion, pain and ischemia commonly a
Bones\: leading to bone pain and avascular necrosis.
Joints\: leading to painful swollen joints and dactylitis. More common in children.
Lungs\: leading to chest pain, shortness of breath and tachypnoea. Up to 30% mortality in adult patients.
Brain\: leading to headaches and strokes.
Bowel and mesentery\: leading to abdominal pain and features of bowel ischemia.
Kidneys\: leading to loin pain, renal papillary necrosis and haematuria.
Eyes\: leading to retinal occlusion or a hyphaema.
Penis\: leading to priapism.
Figure 3. Vaso-occlusive crises of SCA
7
Acute chest syndrome
This is the second most frequent reason for hospitalisation and is a leading cause of death in patients with SCA. 7
chest syndrome presents as new pulmonary in
manifestations\:
6
Acute
Fever
Cough
Tachypnoea
Dyspnoea
Sputum production
New-onset hypoxia
The initial injury is multifactorial and may include infection, pulmonary infarction, pulmonary embolism or pulmonary fat
embolism (as a complication from bone marrow infarction).
7,9
Aplastic crisis
This is the temporary cessation of erythropoiesis, causing severe anaemia. Aplastic crises are usually precipitated by
infection with parvovirus B19. Patients may present with high-output congestive heart failure secondary to anaemia.
A transfusion is usually required but recovery may also occur spontaneously.
https\://app.geekymedics.com/notebook/2640/ 3/811/14/24, 10\:44 AM Sickle Cell Anaemia
Sequestration crisis
This is de
in haemoglobin and a markedly raised reticulocyte count\:
Sequestration may lead to circulatory collapse and hypovolemic shock
Recurrent splenic sequestration is an indication for splenectomy
Occurs mainly in babies and young children.

Clinical examination

A head-to-toe examination guided by symptoms at presentation should be performed in all patients presenting with acute
symptoms. This may include a neurological examination, a cardiovascular examination, a respiratory examination, an
abdominal examination and/or a musculoskeletal examination looking for disease-speci
On examination, typical clinical
Conjunctival pallor +/- pallor\: due to anaemia
Dactylitis\: due to vaso-occlusion in
Jaundice\: due to chronic haemolysis
Splenomegaly\: due to chronic haemolysis

Di

Possible di
Thalassemia\: a group of haemoglobinopathies characterised by the reduced production or absence of haemoglobin
peptide chains, rather than the production of abnormal haemoglobin peptide chains as seen in sickle cell. It is
di
1,7
Other causes of haemolysis\: autoimmune haemolytic anaemia, hereditary spherocytosis, G6PD de

Investigations

Laboratory investigations

Relevant laboratory investigations in the context of SCD/SCA, include\:
FBC\: Hb 60-80g/L, with a high reticulocyte count of 10-20% is often normal for the patient
Blood
3)
6,10
Sickle solubility test\: when blood with HbS is mixed with sodium dithionite a precipitate is formed and the solution
becomes turbid. When blood with normal haemoglobin is mixed with sodium dithionite the solution remains clear.
Haemoglobin electrophoresis (this is required for diagnosis)

Investigations for SCD complications

Further tests may be required based on suspected complications\:
Infection screen
Chest X-ray
Abdominal ultrasound
CT abdomen
CT head
CT pulmonary angiogram
https\://app.geekymedics.com/notebook/2640/ 4/811/14/24, 10\:44 AM Sickle Cell Anaemia
Figure 3. Blood
11

Screening for SCD/SCA

In the UK, screening for SCD is o
Neonatal heel prick blood spots are collected 3 to 10 days after birth for haemoglobin analysis.

Diagnosis

Haemoglobin electrophoresis is necessary for a diagnosis of SCD/SCA to be made. The following are typically found in
the context of SCD/SCA\:
Sickle cell anaemia\: there is no HbA, 80-95% HbSS and 1-20% HbF
Sickle cell trait\: both HbA and HbS are present on electrophoresis

Management

Management of a patient with SCA generally involves preventative measures and speci
depending on the acute complication.

Preventative management

Prevention of crises by avoiding potential triggers including\:
Cold temperatures
Dehydration
Exhaustion\: may lead to lactic acidosis
Alcohol\: may cause dehydration
Smoking\: may cause the acute sickle chest syndrome
Prevention of infection with antibiotics, including\:
Oral penicillin prophylaxis is recommended until at least age
Vaccinations\: regular childhood vaccinations plus vaccinations against m e n i n g o c o c c u s , p n e u m o c o c c u s , hepatitis B and
i n
Prevention of severe anaemia\:
Folic acid supplementation is given(increased red cell synthesis due to chronic haemolysis leads to increased folate
requirements).

Regular medical management

Blood transfusion
‘Top-up’ transfusions may be required if the patient is severely anaemic or if the proportion of HbSS in the blood needs to
be reduced when an acute complication is present.
Exchange transfusions are preferred when the proportion of HbSS needs to be reduced quickly when acute complications
are life-threatening and there is concern about hyperviscosity associated with ‘top-up' transfusion.
https\://app.geekymedics.com/notebook/2640/ 5/811/14/24, 10\:44 AM Sickle Cell Anaemia
Iron overload is a complication of regular transfusion so patients are often considered for iron chelation therapy at a young
age.
Hydroxycarbamide
the blood.
Hydroxycarbamide is a once-daily medication which increases HbF production and thus reduces the proportion of HbS in
It is o
without contraception.
12
Bone marrow transplant
An allogeneic bone marrow transplant is potentially curative.
Bone marrow transplant is only o
matched donor. This is a major obstacle for many patients as HLA types are more likely to be shared within ethnic groups,
and people from Black and minority ethnic groups only make up a small proportion of the bone marrow donor registries.
Its use is limited by its high mortality rate (5-7%), long term complications and the limited availability of suitable donors.
13
Gene therapy
Gene therapy is a novel therapeutic option showing huge promise in ongoing clinical trials.
14

Management of acute complications

Painful vaso-occlusive crisis
Most cases of painful vaso-occlusive crisis are managed in the community with simple analgesia (paracetamol +/-NSAIDs),
warmth, rehydration and rest.
Patients should be admitted if strong opioids are required and the patient should be screened for a trigger (e.g. infection).
Inadequate management of painful crises (especially those a
to the subsequent reduced respiratory e
respiratory tract infections which leads to reduced pulmonary ventilation in the a
lead to further sickling. This vicious circle increases the risk of acute chest crisis which can cause critical illness and death.
Racial bias against patients with sickle cell anaemia is a recognised problem that needs addressing by all members of the
MDT. It is not uncommon for patients with sickle cell to face resistance from sta
particularly opioid analgesia. Analgesia should be titrated to all patient needs, regardless of race, in order to minimise the
morbidity and mortality associated with sickle cell crises and thus tackle the health inequities faced by Black patients.
15
Many patients will have a treatment plan in place to guide clinicians in the acute setting.
Stroke
Transcranial doppler ultrasonography is recommended in children to identify those at higher risk of stroke, and regular
transfusions are o
Acute chest syndrome
Acute chest syndrome is managed with oxygen\: consider continuous positive airway pressure, intravenous antibiotics,
transfusion or exchange transfusion and ventilation if necessary.

Complications

Long-term complications of SCD/SCA include\:
Chronic pain
Cardiac failure
Chronic pulmonary disease, cor pulmonale and pulmonary hypertension
Gallstones\: the increased rate of haemolysis increases the risk of gallstones and acute cholecystitis
1
Retinopathy, retinal infarcts, retinal haemorrhage and retinal detachment
Transfusion-associated complications\: iron overload, exposure to transfusion-related infection, alloimunisation
Chronic leg ulcers
Avascular necrosis\: commonly a
https\://app.geekymedics.com/notebook/2640/ 6/811/14/24, 10\:44 AM Sickle Cell Anaemia
Chronic kidney disease\: may cause worsening anaemia requiring high doses of erythropoietin

Prognosis

Median life expectancy is 40-60 years in high-income countries but much lower in low-income areas.
6
The most common cause of death in children under 2 years of age is an infection, with or without splenic sequestration
episodes.
7
The most common causes of death in adults are cerebrovascular events, acute chest syndrome, pulmonary
hypertension and sepsis.

Feedback

Please click here to
allows authors to improve their articles, leading to even better content on Geeky Medics!

References

Piel FB et al. S i c k l e C e l l D i s e a s e . Published in 2017. Available from\: [LINK]
Inusa BPD et al. S i c k l e C e l l D i s e a s e - G e n e t i c s , Available from\: [LINK]
P a t h o p h y s i o l o g y , C l i n i c a l P r e s e n t a t i o n a n d T r e a t m e n t . Published in 2019.
Dormandy E et al. H o w m a n y p e o p l e h a v e s i c k l e c e l l d i s e a s e i n t h e U K ? Published in 2018. Available from\: [LINK]
World Health Organisation. G l o b a l e p i d e m i o l o g y o f h a e m o g l o b i n d i s o r d e r s a n d d e r i v e d s e r v i c e i n d i c a t o r s . Published 2008. Available from\: [LINK]
in
Weatherall D et al. I n h e r i t e d D i s o r d e r s o f H e m o g l o b i n . Published in 2006. Available from\: [LINK]
Patient UK. S i c k l e C e l l D i s e a s e , S i c k l e C e l l A n a e m i a . Published in 2020. Available from\: [LINK]
Kato GJ et al. S i c k l e c e l l d i s e a s e . Published in 2018. Available from\: [LINK]
Bruce Blaus. Sickled R e d B l o o d C e l l s . Licence\: [CC BY-SA 4.0]. Available from\: [LINK]
Hutchinson RM et al. F a t e m b o l i s m i n s i c k l e c e l l d i s e a s e . Published in 1973. Available from\: [LINK]
Mohamed Berjaoui M. Z et F u n c t i o n a l h y p o s p l e n i s m d i a g n o s e d b y b l o o d CC BY 2.0]. Available from\: [LINK]
Published in 2014. Available from\: [LINK]
B l o o d F i l m o f P a t i e n t w i t h S i c k l e C e l l .
Agrawal RK et al. H y d r o x y u r e a i n S i c k l e C e l l D i s e a s e \: D r u g R e v i e w . Published in 2014. Available from\: [LINK]
al. Kassim AA et Available from\: [LINK]
H e m a t o p o i e t i c s t e m c e l l t r a n s p l a n t a t i o n f o r s i c k l e c e l l d i s e a s e \: T h e c h a n gi n g l a n d s c a p e . Published in 2017.
The Lancet Haematology. G e n e t h e r a p y f o r s i c k l e c e l l d i s e a s e . Published in 2016. Available from\: [LINK]
Bulgin D et al. S t i g m a o f S i c k l e C e l l D i s e a s e \: A S y s t e m a t i c R e v i e w . Published in 2018. Available from\: [LINK]

Reviewer

Dr Alex Langridge
Speciality Haematology Trainee (ST7)
Founder of Buku Medicine, a free app answering the commonest questions put to haematology, renal and endocrine
specialties.
https\://app.geekymedics.com/notebook/2640/ 7/811/14/24, 10\:44 AM Sickle Cell Anaemia

Related notes

Acute Myeloid Leukaemia
Anaemia Overview
Chronic Myeloid Leukaemia
Disseminated Intravascular Coagulation (DIC)
Haemolytic anaemia

Test yourself

Contents

Source\: geekymedics.com
https\://app.geekymedics.com/notebook/2640/ 8/8