Haematology
A 24 year old woman presents to the Emergency Department with a one week history of fatigue. She has a past medical history of sickle cell disease. Which of the following is the most common complication of sickle cell disease?
Answer:
Acute painful crisis is the most common complication of sickle cell disease in all age groups. It usually starts with vague pain, often in the back of limb bones, which gradually worsens. There may be local warmth, tenderness, swelling, and fever.Sickle Cell Disease
Haematology
Last Updated: 17th March 2023
Sickle cell disease encompasses a group of inherited conditions which have in common the inheritance of sickle haemoglobin. Sickle cell disease is estimated to affect 1 in every 2000 live births in England, and it is now the most common genetic condition at birth. The highest prevalence of sickle cell disease is among Black African and Black Caribbean people, but cases also occur in families originating from the Middle East, parts of India, the eastern Mediterranean, and South and Central America; the common factor to this distribution is a history of malaria, or migration from a malarial area.
Pathophysiology
People with sickle cell disease have inherited the gene for sickle haemoglobin (Hb S) from one parent and a gene for an abnormal haemoglobin variant from the other parent. If the second abnormal gene is also for Hb S, the person is said to have homozygous sickle cell disease (Hb SS), commonly called sickle cell anaemia. This is the most common and severe type of sickle cell disease. People who inherit a gene for a sickle haemoglobin (Hb S) from one parent and a gene for normal haemoglobin (Hb A) from the other parent have sickle cell traits (previously known as sickle cell carrier), and their genotype is Hb AS. These people rarely have symptoms. However, they have a 50% chance of passing the sickle cell gene to their child. If both parents are carriers, there is a 1 in 4 chance that their child will be born with sickle cell disease.
Sickle haemoglobin has an abnormal beta-globin chain that causes it to polymerise when deoxygenated, which distorts the erythrocyte into a sickle shape. The deformed erythrocytes form clusters which block blood vessels; damage large and small blood vessels; are sequestered in the liver and spleen; and cause anaemia (of varying degrees), intense pain (known as sickle cell crisis), infections, and other complications of sickle cell disease.
Acute complications of sickle cell disease are due to the consequences of the 'sickling' of erythrocytes, which is more likely to happen in certain conditions, such as:
- Intercurrent illness
- Psychological stress
- Cold temperatures
- Pregnancy
- Dehydration
- Reduced oxygen in the blood, for example due to exertion, anaesthesia, and high altitude
Complications
- Acute complications of sickle cell disease include:
- Acute painful crisis
- This is the most common complication of sickle cell disease in all age groups. It usually starts with vague pain, often in the back of limb bones, which gradually worsens. There may be local warmth, tenderness, swelling, and fever.
- Acute abdominal complications
- Abdominal conditions that occur commonly in people with sickle cell disease include acute abdominal sickle crisis (characterised by abdominal pain, distention, rigidity, and diminished bowel sounds); constipation; hepatic infarction, abscess, or sequestration; hepatic or renal vein thrombosis; intra-abdominal abscess; mesenteric or colonic ischaemia; gallstones and splenic infarction.
- Acute anaemia due to rapidly falling haemoglobin
- Acute worsening of anaemia from steady state may be caused by acute splenic sequestration, transient red cell aplasia, or acute hepatic sequestration. Severe haematuria with the passage of clots may rarely cause severe anaemia in adults.
- Acute splenic sequestration usually occurs in children; it is rare in adults. The typical clinical features are development of severe pallor, an acute increase in the size of the spleen, and shock and hypovolaemia (which develop quickly).
- The typical clinical features of transient red cell aplasia are development of severe pallor over several days, fever, headache, myalgia, arthralgia, respiratory symptoms, heart failure, and abdominal pain, typically following parvovirus B19 infection.
- The typical clinical features of acute hepatic sequestration are pain in the right hypochondrium, a tender and enlarged liver, pallor, abdominal distension, and circulatory collapse (infrequent).
- Acute worsening of anaemia from steady state may be caused by acute splenic sequestration, transient red cell aplasia, or acute hepatic sequestration. Severe haematuria with the passage of clots may rarely cause severe anaemia in adults.
- Acute chest syndrome
- This is a common form of acute lung injury that may lead to acute respiratory distress syndrome and death. It is characterised by respiratory symptoms, such as chest pain, tachypnoea, cough, shortness of breath and/or respiratory distress, generally with fever, in the presence of a new infiltrate on chest X-ray. Possible causes include infection, infarction (due to fat emboli that have moved to the lungs from bone infarcts, causing pulmonary infarction), or a combination of both.
- Acute infections
- Life-threatening infections are common in people with sickle cell disease, partly due to splenic dysfunction, which reduces the ability of the immune system to clear circulating antigens. The most common infections are pneumococcal sepsis, gram-negative sepsis, lower respiratory tract infections, urinary tract infections, and osteomyelitis. Lifelong antibiotic prophylaxis is therefore recommended for all people with sickle cell disease.
- Acute osteomyelitis
- This is one of the most common infectious complications in people with sickle cell disease, and it occurs in people of all ages and genotypes. It is most commonly caused by Salmonella species, Gram-negative enteric bacteria, and Staphylococcus aureus. There may be local warmth, swelling, tenderness, and fever (an identical presentation to acute painful crisis). Recurrent bone infarcts may lead to the formation of bone sequestra. These may become secondarily infected, causing osteomyelitis.
- Acute priapism
- This is a persistent painful erection that occurs at least once in 89% of males with sickle cell disease by adulthood. It is caused by obstruction to the venous drainage of the penis due to vaso-occlusion.
- Acute renal impairment
- Vaso-occlusion due to sickle cells blocking small vessels may cause damage to the renal medulla through ischaemia, infarction, and papillary necrosis. This is common because conditions in the renal medulla (a hypoxic, acidotic, hypertonic environment) may promote sickling. The medullary damage results in an inability to concentrate urine, which can lead to dehydration. Cumulative vascular damage due to sickle cells adhering to endothelial cells may damage the glomeruli and cause renal failure. Dehydration, sepsis, or drugs may precipitate acute renal failure, or it may occur during general multi-organ failure.
- Acute neurological complications
- Neurological complications of a sickle cell crisis may present as an acute stroke (due to subarachnoid or intracerebral bleeding or thrombosis) or as hemiparesis, speech problems, seizures, or altered consciousness. An acute stroke due to ischaemia may occur at any age but is common in children, and the incidence increases with age in adults older than 30 years of age. Subarachnoid haemorrhage and intracerebral haemorrhage may occur when there is acute hypertension; these two conditions are associated with recent blood transfusion, bone marrow transplantation, or corticosteroid use.
- Acute painful crisis
- Chronic complications of sickle cell disease include:
- Chronic pain
- Pain may be due to leg ulcers, chronic arthritis, avascular necrosis of femoral or humeral heads, vertebral collapse, or chronic osteomyelitis. Osteopenia may occur due to hyperplasia of the bone marrow, and severe and progressive hip dysfunction may occur (with abnormalities of gait and muscle wasting).
- Chronic anaemia
- Sickle cells have a short lifespan of 16–20 days, compared with 120 days in normal erythrocytes. In sickle cell disease, haemoglobin levels are typically between 6–8 g/dL, with an increased reticulocyte count. In milder forms of sickle cell disease, haemoglobin levels are higher and may be normal. Chronic anaemia is usually well tolerated and as a result may not need treatment. Chronic haemolysis causes bilirubin to be slightly increased, and the products of haemolysis may cause gallstones.
- Chronic sickle lung
- This may develop in children or adults who have had acute chest syndrome, but it may also occur without a history of this, probably because of cumulative low-level pulmonary damage during painful crises. It is characterised by breathlessness, hypoxia, chest pain, and restrictive findings on lung function tests.
- Cognitive impairment
- 17% of children with sickle cell disease have silent cerebral infarcts visible on magnetic resonance imaging (MRI). The silent infarcts are associated with mild cognitive impairment that may be detected by using neurocognitive tests. Cognitive impairment due to silent infarcts may also occur in adults.
- Epilepsy
- This occurs in 10–15% of people with sickle cell disease (10 times the incidence in the general population) and are associated with cerebrovascular disease and silent infarction.
- Eye problems
- Ischaemic changes due to recurrent microvascular occlusion may lead to growth of new vessels. This results in proliferative retinopathy, a serious complication of sickle cell disease, which is most common in people aged 15–30 years and can lead to vitreous haemorrhage and retinal detachment. Loss of vision due to central retinal artery occlusion may also occur.
- Gallstones
- Gallstones are very common and often cause intermittent abdominal pain. They may also cause ascending cholangitis, acute cholecystitis, gallbladder empyema, and acute pancreatitis.
- Impaired nutrition and growth in children
- Impaired growth is often apparent after the age of 6 months and may be due to decreased absorption of nutrients, an increased metabolic rate caused by a marked increase in erythrocyte production, and/or poor appetite caused by recurrent febrile and painful episodes. Puberty may be delayed by 2–3 years in children with sickle cell anaemia. Children on long-term transfusion programmes may have significant iron overload and develop pituitary and/or primary gonadal deficiencies.
- Chronic leg ulcers
- Most leg ulcers are near the ankle, bilateral, and very painful. They are thought to be caused by poor microvascular blood flow and reduced oxygen delivery from sickle cells.
- Penile dysfunction
- Priapism is very common and by adulthood, 89% of men with sickle cell disease will have had at least one episode. Both prolonged episodes and shorter briefer episodes of priapism ('stuttering') may lead to erectile dysfunction in the long term, or permanent deformity of the penis (due to scarring).
- Pulmonary hypertension
- Pulmonary hypertension is common and is associated with increased morbidity and mortality in sickle cell disease. A third of adults with sickle cell disease develop pulmonary hypertension, which may lead to sudden death. SYmptoms may include worsening hypoxia, chest pain and increasing breathlessness.
- Renal complications
- Chronic sickle nephropathy presents as a spectrum from painless haematuria, proteinuria, and progressive loss of function to end-stage renal disease. Renal medullary carcinoma occurs almost exclusively in people with the sickle cell trait, and occasionally in people with sickle cell disease. It is aggressive and has usually metastasized by the time the symptoms (weight loss, fever, haematuria, flank pain, and abdominal pain) have occurred.
- Chronic pain
Diagnosis
Suspect sickle cell disease if a person is in a high-risk group and:
- Is a child aged 9–18 months with painful dactylitis (painful swelling of the bones of the hands and feet). There may be chronic shortening of a digit due to epiphyseal damage.
- Has a sudden severe infection.
- Presents with features of an acute crisis, or with a history of features consistent with an acute crisis.
- Presents with features of a chronic complication of sickle cell disease.
Sickle cell disease is always diagnosed after both an initial and confirmatory test are positive. The choice of test will depend on local guidelines and facilities. Possible tests include full blood count, reticulocyte count, and blood film, together with more specialised laboratory tests to identify haemoglobinopathies.
Suspect an acute sickle cell crisis in a person with sickle cell disease who presents with a sudden onset of pain, infection, anaemia, or other symptoms, such as a stroke or priapism.
- There is often a history of a previous crisis (or rarely, sickle cell disease may be undiagnosed).
- Older children and adults are often able to state whether their pain is typical of sickle cell disease.
Management
Bone marrow transplantation is the only curative treatment, but it is infrequently used owing to lack of suitable bone marrow donors, cost, and risks (10% mortality in children). Prophylactic treatments include: hydroxycarbamide, L-glutamine, crizanlizumab, voxelotor and repeated simple blood transfusion to maintain HbS below 30%.
In young children, the main treatment goal is to improve survival by reducing the threat from infections. This can be achieved through:
- Early diagnosis
- Pneumococcal immunisation
- Antibiotic prophylaxis with penicillin in children under 5 years of age
- Nutritional counselling
- Prompt treatment when infections do occur
In patients who survive early childhood and have chronic disease, the main treatment goals are symptom control and management of disease complications. This can be achieved through:
- Pain management (chronic and acute)
- Pharmacological amelioration of disease severity
- Prophylaxis and prompt treatment of infections
- Prevention and management of acute complications
- Prevention of stroke
- Prevention and treatment of chronic organ damage (kidney, renal, pulmonary)
- Genetic counselling
- Health and nutritional education of patient and/or parents
- Counselling of patient and/or parents to avoid triggers (e.g. dehydration, cold and high altitudes, and strenuous exercise)
Treatment of vaso-occlusive episodes:
The goal of treatment for vaso-occlusive crises is to alleviate pain while minimising adverse effects. Treatment includes:
- Comprehensive pain assessment
- Analgesia (paracetamol, NSAIDs, opioids)
- Oxygen therapy
- Fluid replacement
- Antibiotics if appropriate
- Blood transfusion
Treatment of acute chest syndrome:
The goal of treatment of acute chest syndrome is to prevent progression to acute respiratory failure. Treatment includes:
- Oxygen therapy
- Blood transfusion
- Antibiotics
- Analgesia
- Fluid replacement
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
