Haematology Flashcards
Blood cells
Blood cells develop in the bone marrow. Bone marrow is mostly found in the pelvis, vertebrae, ribs and sternum. Familiarity with the different cell lines helps you understand conditions where things go wrong.
Pluripotent haematopoietic stem cells are undifferentiated cells that can transform into various blood cells. They initially become:
Myeloid stem cells
Lymphoid stem cells
Dendritic cells (via different intermediate stages)
Red blood cells (RBC) develop from reticulocytes, which originate from myeloid stem cells. Reticulocytes are immature red blood cells. Red blood cells survive around four months (120 days).
Platelets are made by megakaryocytes, which develop from the myeloid stem cells. The lifespan of platelets is around ten days. The normal count is 150 – 450 x 109/L. Their role is to clump together (platelet aggregation) and plug gaps where blood clots need to form.
White blood cells
Myeloid stem cells become myeloblasts, which can become:
Monocytes then macrophages
Neutrophils
Eosinophils
Mast cells
Basophils
Lymphocytes come from the lymphoid stem cells and become B cells or T cells.
B lymphocytes (B cells) mature in the bone marrow and differentiate into:
Plasma cells
Memory B cells
T lymphocytes (T cells) mature in the thymus gland and differentiate into:
CD4 cells (T helper cells)
CD8 cells (cytotoxic T cells)
Natural killer cells
Blood film findings
A blood film involves the manual examination of the blood using a microscope, looking for abnormal shapes, sizes and inclusions (contents) of the cells. The key abnormal findings are summarised below.
Anisocytosis refers to a variation in the size of the red blood cells. These can be seen in myelodysplastic syndrome and many types of anaemia (e.g., iron deficiency, pernicious and autoimmune haemolytic anaemia).
Target cells are red blood cells with a central pigmented area surrounded by a pale area, surrounded by a ring of thicker cytoplasm on the outside. They look like a bull’s eye target. These are mostly seen in iron deficiency anaemia and post-splenectomy.
Heinz bodies are individual blobs (inclusions) seen inside red blood cells. These blobs are denatured (damaged) haemoglobin. They are mostly seen in G6PD deficiency and alpha-thalassaemia.
Howell-Jolly bodies are individual blobs of DNA material seen inside red blood cells. The spleen would Normally remove red blood cells with this DNA material inside. They are seen in patients after a splenectomy or with a non-functioning spleen (e.g., caused by sickle cell anaemia). They are also seen in severe anaemia, where the body is regenerating red blood cells very fast.
Reticulocytes are immature red blood cells. They are slightly larger than normal red blood cells (erythrocytes) and still have RNA material in them. The RNA has a reticular (“mesh-like”) appearance inside the cell. It is normal for about 1% of red blood cells to be reticulocytes. This percentage goes up where there is a rapid turnover of red blood cells, such as with haemolytic anaemia, where the bone marrow is actively trying to replace lost cells.
Schistocytes are fragments of red blood cells. They indicate that red blood cells are being physically damaged during their journey through the circulation. Microangiopathic haemolytic anaemia (MAHA) occurs when small blood clots (thrombi) obstruct small blood vessels. These obstructions churn the red blood cells, causing haemolysis (rupture). The key causes of MAHA are haemolytic uraemic syndrome (HUS), disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP). Schistocytes can also be seen in metallic heart valve replacement as the metallic valves damage the red blood cells.
Sideroblasts are immature red blood cells with a nucleus surrounded by iron blobs. Sideroblastic anaemia occurs when the bone marrow cannot incorporate iron into the haemoglobin molecules. This is due to either a genetic defect or myelodysplastic syndrome.
Smudge cells are ruptured white blood cells that occur while preparing the blood film when the cells are aged or fragile. They are particularly associated with chronic lymphocytic leukaemia.
Spherocytes are sphere-shaped red blood cells without the bi-concave disk shape. They can indicate autoimmune haemolytic anaemia or hereditary spherocytosis.
Anaemia
Anaemia is defined as a low concentration of haemoglobin in the blood. This is the consequence of an underlying disease, not a disease itself. An- means without, and -aemia refers to blood.
Haemoglobin is a protein found in red blood cells. Haemoglobin is responsible for picking up oxygen in the lungs and transporting it to the body’s cells. Iron is essential in creating haemoglobin and forms part of it’s structure.
The mean cell volume (MCV) refers to the size of the red blood cells and is highly relevant in anaemic patients. The normal ranges are:
Haemoglobin
Mean Cell Volume (MCV)
Women
120 – 165 grams/litre
80-100 femtolitres
Men
130 -180 grams/litre
80-100 femtolitres
Causes of anaemia
Anaemia is divided into three categories based on the mean cell volume:
Microcytic anaemia (low MCV)
Normocytic anaemia (normal MCV)
Macrocytic anaemia (large MCV)
The mnemonic for remembering the causes of microcytic anaemia is “TAILS”:
T – Thalassaemia
A – Anaemia of chronic disease
I – Iron deficiency anaemia
L – Lead poisoning
S – Sideroblastic anaemia
Anaemia of chronic disease often occurs with chronic kidney disease due to reduced production of erythropoietin by the kidneys, the hormone responsible for stimulating red blood cell production. Treatment is with erythropoietin.
There are 3 As and 2 Hs for normocytic anaemia:
A – Acute blood loss
A – Anaemia of chronic disease
A – Aplastic anaemia
H – Haemolytic anaemia
H – Hypothyroidism
Macrocytic anaemia can be megaloblastic or normoblastic. Megaloblastic anaemia results from impaired DNA synthesis, preventing the cells from dividing normally. Rather than dividing, they grow into large, abnormal cells.
Megaloblastic anaemia is caused by:
B12 deficiency
Folate deficiency
Normoblastic macrocytic anaemia is caused by:
Alcohol
Reticulocytosis (usually from haemolytic anaemia or blood loss)
Hypothyroidism
Liver disease
Drugs, such as azathioprine
Reticulocytosis refers to an increased concentration of reticulocytes (immature red blood cells). This happens when there is a rapid turnover of red blood cells, such as with haemolytic anaemia or blood loss.
Symptoms of anaemia
There are many generic symptoms of anaemia:
Tiredness
Shortness of breath
Headaches
Dizziness
Palpitations
Worsening of other conditions, such as angina, heart failure or peripheral arterial disease
Symptoms specific to iron deficiency anaemia include:
Pica (dietary cravings for abnormal things, such as dirt or soil)
Hair loss
Signs of anaemia
Generic signs of anaemia include:
Pale skin
Conjunctival pallor
Tachycardia
Raised respiratory rate
Signs of specific causes of anaemia include:
Koilonychia refers to spoon-shaped nails and can indicate iron deficiency anaemia
Angular cheilitis can indicate iron deficiency anaemia
Atrophic glossitis is a smooth tongue due to atrophy of the papillae and can indicate iron deficiency anaemia
Brittle hair and nails can indicate iron deficiency anaemia
Jaundice can indicate haemolytic anaemia
Bone deformities can indicate thalassaemia
Oedema, hypertension and excoriations on the skin can indicate chronic kidney disease
Investigating anaemia
Blood tests depend on the suspected cause. Possible blood tests include:
Full blood count for haemoglobin and mean cell volume
Reticulocyte count (indicates red blood cell production)
Blood film for abnormal cells and inclusions
Renal profile for chronic kidney disease
Liver function tests for liver disease and bilirubin (raised in haemolysis)
Ferritin (iron)
B12 and folate
Intrinsic factor antibodies for pernicious anaemia
Thyroid function tests for hypothyroidism
Coeliac disease serology (e.g., anti-tissue transglutaminase antibodies)
Myeloma screening (e.g., serum protein electrophoresis)
Haemoglobin electrophoresis for thalassaemia and sickle cell disease
Direct Coombs test for autoimmune haemolytic anaemia
A colonoscopy and oesophagogastroduodenoscopy (OGD) are indicated for unexplained iron deficiency anaemia to exclude gastrointestinal cancer as a source of bleeding.
A bone marrow biopsy is indicated for unexplained anaemia or possible malignancy (e.g., leukaemia or myeloma).
Iron deficiency anaemia
Iron is an important part of the haemoglobin molecule. Iron deficiency leads to anaemia (a low concentration of haemoglobin). Iron deficiency causes microcytic hypochromic anaemia. Microcytic refers to small red blood cells with a low mean cell volume (MCV). Hypochromic refers to pale cells due to a reduced haemoglobin concentration.
Causes of iron deficiency anaemia
Several scenarios can lead to iron deficiency:
Insufficient dietary iron (e.g., restrictive diets)
Reduced iron absorption (e.g., coeliac disease)
Increased iron requirements (e.g., pregnancy)
Loss of iron through bleeding (e.g., from a peptic ulcer or bowel cancer)
The most common cause in adults is blood loss. There is a clear source of blood loss in menstruating women, particularly in women with heavy periods (menorrhagia). In women not menstruating and men, the most common source of blood loss is the gastrointestinal tract. This bleeding might be from:
Cancer (e.g., stomach or bowel cancer)
Oesophagitis and gastritis
Peptic ulcers
Inflammatory bowel disease
Angiodysplasia (abnormal vessels in the wall)
Dietary insufficiency is the most common cause in children. During growth, iron requirements often exceed the dietary intake. Pica (e.g., eating dirt or soil) is a common exam presentation for iron deficiency anaemia in children.
Iron is mainly absorbed in the duodenum and jejunum. It requires the acid from the stomach to keep the iron in the soluble ferrous (Fe2+) form. When the stomach contents are less acidic, it changes to the insoluble ferric (Fe3+) form. Medications that reduce stomach acid, such as proton pump inhibitors (e.g., omeprazole), can interfere with iron absorption. Inflammation of the duodenum or jejunum (e.g., from coeliac disease or Crohn’s disease) can also reduce iron absorption.
Testing for iron deficiency anaemia
Iron travels around in the blood bound to a carrier protein called transferrin. Total iron-binding capacity (TIBC) is the space for iron to attach to on all the transferrin molecules combined. Total iron-binding capacity is directly related to the amount of transferrin in the blood. Transferrin saturation refers to the proportion of the transferrin molecules bound to iron, expressed as a percentage. The formula for transferrin saturation is:
Transferrin saturation = serum iron / total iron-binding capacity
Ferritin is a protein that stores iron inside cells. Ferritin is an acute-phase protein released with inflammation (e.g., in infection or cancer). Low ferritin is highly suggestive of iron deficiency. Normal ferritin does not exclude iron deficiency. Raised ferritin is difficult to interpret and may be caused by:
Inflammation (e.g., infection or cancer)
Liver disease
Iron supplements
Haemochromatosis
Serum iron varies significantly throughout the day, with higher levels in the morning and after eating iron-containing meals. On its own, serum iron is not a very useful measure.
Total iron-binding capacity is a marker for how much transferrin is in the blood. TIBC and transferrin increase with iron deficiency and decrease with iron overload.
Transferrin saturation indicates the total iron in the body. With less iron in the body, transferrin will be less saturated. With increased iron in the body, transferrin will be more saturated. It can temporarily increase after eating a meal rich in iron or taking iron supplements. Therefore, a fasting sample gives the most accurate results.
Normal Range
Serum Ferritin
41 – 400 ug/L
Serum Iron
12 – 30 μmol/L
Total Iron-Binding Capacity
45 – 80 μmol/L
Transferrin Saturation
15 – 50%
Iron overload results in high values of all of these markers (except TIBC) and may be caused by:
Haemochromatosis
Iron supplements
Acute liver damage (the liver contains lots of iron)
Managing iron deficiency anaemia
New iron deficiency in an adult without a clear underlying cause (e.g., heavy menstruation or pregnancy) should be investigated further, including a colonoscopy and oesophagogastroduodenoscopy (OGD) for malignancy.
There are three options for treating iron deficiency anaemia:
Oral iron (e.g., ferrous sulphate or ferrous fumarate)
Iron infusion (e.g., IV CosmoFer)
Blood transfusion (in severe anaemia)
Oral iron works slowly. A rise in haemoglobin of 20 grams/litre is expected in the first month. Common side effects are constipation and black stools. Prophylactic supplementation may be required in recurrent cases.
Iron infusions provide a rapid boost in iron. There is a small risk of allergic reactions and anaphylaxis. It should be avoided during infections, as there is potential for it to “feed” the bacteria.
Pernicious anaemia
Vitamin B12 deficiency causes macrocytic anaemia. The key causes of a low B12 are:
Pernicious anaemia
Insufficient dietary B12 (particularly a vegan diet, as B12 is mostly found in animal products)
Medications that reduce B12 absorption (e.g., proton pump inhibitors and metformin)
Pernicious anaemia is an autoimmune condition involving antibodies against the parietal cells or intrinsic factor.
Pathophysiology of pernicious anaemia
The parietal cells of the stomach produce a protein called intrinsic factor. Intrinsic factor is essential for the absorption of vitamin B12 in the distal ileum. In pernicious anaemia, autoantibodies target either the parietal cells or intrinsic factor, resulting in a lack of intrinsic factor and a lack of absorption of vitamin B12.
Vitamin B12 deficiency can cause neurological symptoms:
Peripheral neuropathy, with numbness or paraesthesia (pins and needles)
Loss of vibration sense
Loss of proprioception
Visual changes
Mood and cognitive changes
TOM TIP: For your exams, remember to test for vitamin B12 deficiency and pernicious anaemia in patients presenting with peripheral neuropathy, particularly with pins and needles.
Autoantibodies and pernicious anaemia
Autoantibodies used to diagnose pernicious anaemia are:
Intrinsic factor antibodies (the first-line investigation)
Gastric parietal cell antibodies (less helpful)
Managing pernicious anaemia
NICE CKS (April 2023) recommend the below regimes. Check the latest guidelines before treating patients.
Intramuscular hydroxocobalamin is initially given to all patients with B12 deficiency, depending on symptoms:
No neurological symptoms – 3 times weekly for two weeks
Neurological symptoms – alternate days until there is no further improvement in symptoms
Maintenance depends on the cause:
Pernicious anaemia – 2-3 monthly injections for life
Diet-related – oral cyanocobalamin or twice-yearly injections
Where there is B12 and folate deficiency together, it is essential to treat the B12 deficiency first before correcting the folate deficiency. Giving patients folic acid when they have a B12 deficiency can lead to subacute combined degeneration of the cord, with demyelination in the spinal cord and severe neurological problems.
Haemolytic anaemia
Haemolytic anaemia involves the destruction of red blood cells (haemolysis), resulting in a low haemoglobin concentration (anaemia).
Several inherited conditions cause the red blood cells to be more fragile and break down faster than normal, leading to chronic haemolytic anaemia. These include:
Hereditary spherocytosis
Hereditary elliptocytosis
Thalassaemia
Sickle cell anaemia
G6PD deficiency
Several acquired conditions lead to the destruction of red blood cells:
Autoimmune haemolytic anaemia
Alloimmune haemolytic anaemia (e.g., transfusions reactions and haemolytic disease of newborn)
Paroxysmal nocturnal haemoglobinuria
Microangiopathic haemolytic anaemia
Prosthetic valve-related haemolysis
Features of haemolytic anaemia
The features are a result of the destruction of red blood cells:
Anaemia
Splenomegaly (the spleen becomes filled with destroyed red blood cells)
Jaundice (bilirubin is released during the destruction of red blood cells)
Investigating haemolytic anaemia
The key investigation results are:
Full blood count shows a normocytic anaemia
Blood film shows schistocytes (fragments of red blood cells)
Direct Coombs test is positive in autoimmune haemolytic anaemia (not in other types)
Hereditary Spherocytosis
Hereditary spherocytosis is the most common inherited haemolytic anaemia in northern Europeans. It is an autosomal dominant condition. It causes fragile, sphere-shaped red blood cells that easily break down when passing through the spleen.
It presents with anaemia, jaundice, gallstones and splenomegaly. A notable feature is aplastic crisis in the presence of the parvovirus. There is likely to be a positive family history.
Key findings are:
Raised mean corpuscular haemoglobin concentration (MCHC) on a full blood count
Raised reticulocyte count due to rapid turnover of red blood cells
Spherocytes on a blood film
Treatment is with folate supplementation, blood transfusions when required and splenectomy. Gallbladder removal (cholecystectomy) may be required if gallstones are a problem.
Hereditary Elliptocytosis
Hereditary elliptocytosis is similar to hereditary spherocytosis except that the red blood cells are ellipse-shaped. It is also autosomal dominant. The presentation and management are the same as hereditary spherocytosis.
G6PD deficiency
G6PD deficiency is caused by a defect in the gene coding for glucose-6-phosphate dehydrogenase (G6PD), an enzyme responsible for protecting the cells from oxidative damage. It is an X-linked recessive genetic condition (where males are more often affected and females are carriers). It is more common in Mediterranean, Asian and African patients.
The condition results in acute episodes of haemolytic anaemia triggered by infections, drugs or fava beans. Key medication triggers include ciprofloxacin, sulfonylureas (e.g., gliclazide) and sulfasalazine.
G6PD deficiency presents with jaundice (often in the neonatal period), gallstones, anaemia, splenomegaly and Heinz bodies on a blood film. Diagnosis can be made by doing a G6PD enzyme assay.
TOM TIP: The critical piece of knowledge for G6PD deficiency relates to triggers. In your exams, look out for a male patient that turns jaundiced and becomes anaemic after eating fava beans (broad beans), developing an infection or taking antimalarials. The underlying diagnosis might be G6PD deficiency.
Autoimmune Haemolytic Anaemia
Autoimmune haemolytic anaemia (AIHA) occurs when antibodies are created against the patient’s red blood cells. These antibodies lead to red blood cell destruction (haemolysis). There are two types, warm and cold, based on the temperature at which the auto-antibodies destroy red blood cells.
Warm autoimmune haemolytic anaemia is the more common type. Haemolysis occurs at normal or above-normal temperatures. It is usually idiopathic, meaning that it arises without a clear cause.
Cold-reactive autoimmune haemolytic anaemia is also called cold agglutinin disease. At lower temperatures (e.g., less than 10ºC), the antibodies attach to the red blood cells and cause them to clump together, called agglutination. The immune system is activated, and the red blood cells are destroyed. Cold AIHA can be secondary to lymphoma, leukaemia, systemic lupus erythematosus and infections (e.g., mycoplasma, EBV, CMV and HIV).
Management of autoimmune haemolytic anaemia involves:
Blood transfusions
Prednisolone
Rituximab (a monoclonal antibody against B cells)
Splenectomy
Alloimmune Haemolytic Anaemia
Alloimmune haemolytic anaemia occurs due to foreign red blood cells or foreign antibodies. The two scenarios where this happens are transfusion reactions and haemolytic disease of the newborn.
Haemolytic transfusion reactions occur when red blood cells are transfused into the patient. The immune system produces antibodies against antigens on the foreign red blood cells. An immune response leads to the destruction of those foreign red blood cells.
Haemolytic disease of the newborn occurs when maternal antibodies cross the placenta from the mother to the fetus. These maternal antibodies target antigens on the red blood cells of the fetus. These maternal antibodies destroy the neonate’s red blood cells. It occurs when the fetus is rhesus D positive (with rhesus D antigens on their red blood cells), and the mother is rhesus D negative (with no rhesus D antigens on her red blood cells). During a sensitisation event (e.g., antepartum haemorrhage), the mother can get exposed to the fetal red blood cells and start producing anti-D antibodies against the rhesus D antigen. In future, these antibodies can cross to the baby and cause haemolysis. Sensitisation is prevented in rhesus-negative women by using anti-D prophylaxis.
Paroxysmal Nocturnal Haemoglobinuria
Paroxysmal nocturnal haemoglobinuria is caused by a specific genetic mutation in the haematopoietic stem cells in the bone marrow. This mutation occurs during the patient’s lifetime (as opposed to being an inherited genetic condition). It results in a loss of the proteins on the surface of red blood cells that inhibit the complement cascade, allowing activation of the complement cascade on red blood cells and their destruction.
The characteristic presenting symptom is red urine in the morning, which contains haemoglobin and haemosiderin. Other presenting features are anaemia, thrombosis (e.g., DVT, PE and hepatic vein thrombosis) and smooth muscle dystonia (e.g., oesophageal spasm and erectile dysfunction).
Management is with eculizumab or bone marrow transplantation. Eculizumab is a monoclonal antibody that targets complement component 5 (C5). Bone marrow transplantation can be curative.
Microangiopathic Haemolytic Anaemia
Microangiopathic haemolytic anaemia (MAHA) involves the destruction of red blood cells as they travel through the circulation. This is most often caused by abnormal activation of the clotting system, with blood clots (thrombi) partially obstructing the small blood vessels, referred to as thrombotic microangiopathy. These obstructions churn the red blood cells, causing haemolysis (rupture). Picture a mesh inside the small blood vessels shredding the red blood cells.
Microangiopathic haemolytic anaemia is usually secondary to an underlying condition, such as:
Haemolytic uraemic syndrome (HUS)
Disseminated intravascular coagulation (DIC)
Thrombotic thrombocytopenic purpura (TTP)
Systemic lupus erythematosus (SLE)
Cancer
Schistocytes are a key finding on the blood film in patients with microangiopathic haemolytic anaemia.
Prosthetic Valve Haemolysis
Haemolytic anaemia is a key complication of prosthetic heart valves. It occurs in both bioprosthetic and metallic valve replacement, although it varies depending on the type. It is caused by turbulence flow around the valve and the shearing of the red blood cells. The valve churns up the cells, and they break down.
Management involves:
Monitoring
Oral iron and folic acid supplementation
Blood transfusions if severe
Revision surgery may be required in severe cases
Thalassaemia
Thalassaemia is caused by a genetic defect in the protein chains that make up haemoglobin. Normal haemoglobin consists of two alpha-globin and two beta-globin chains.
Defects in alpha-globin chains lead to alpha thalassaemia. Defects in the beta-globin chains lead to beta thalassaemia. Both conditions are autosomal recessive. The overall effect is varying degrees of anaemia, depending on the type and mutation.
In patients with thalassaemia, the red blood cells are more fragile and break down easily, causing haemolytic anaemia. The spleen acts as a sieve, filtering the blood and removing older cells. The spleen collects all the destroyed red blood cells, resulting in splenomegaly.
Features of thalassaemia
The severity of features depends on the type. Universal features include:
Microcytic anaemia (low mean corpuscular volume)
Fatigue
Pallor
Jaundice
Gallstones
Splenomegaly
Poor growth and development
Investigating thalassaemia
Microcytic anaemia (low mean cell volume) is a typical finding on a full blood count. Raised ferritin suggests iron overload.
Haemoglobin electrophoresis is used to diagnose globin abnormalities. DNA testing can be used to look for the genetic abnormality.
All pregnant women in the UK are offered a screening test for thalassaemia at booking.
Iron overload and thalassaemia
Iron overload may occur in thalassaemia due to:
Increased iron absorption in the gastrointestinal tract
Blood transfusions
Iron overload in thalassaemia can cause symptoms and complications of:
Liver cirrhosis
Hypogonadism
Hypothyroidism
Heart failure
Diabetes
Osteoporosis
Serum ferritin levels are monitored. Management involves limiting transfusions and iron chelation.
Alpha-Thalassaemia
Defects in the alpha-globin chains cause alpha-thalassaemia. The genes that code for alpha-globin are found on chromosome 16. The severity of symptoms varies depending on the type and number of genetic defects, ranging from entirely asymptomatic as a carrier, to moderate anaemia (haemoglobin H disease), to intrauterine death due to severe fetal anaemia (alpha thalassemia major).
Management involves:
Monitoring
Blood transfusions
Splenectomy may be performed
Bone marrow transplant can be curative
Beta-Thalassaemia
Defects in beta-globin chains cause beta-thalassaemia. The gene coding for this protein is on chromosome 11. The gene defects can either consist of abnormal copies that retain some function or deletion genes with no function in the beta-globin. Based on this, beta-thalassaemia can be split into three types:
Thalassaemia minor
Thalassaemia intermedia
Thalassaemia major
Thalassaemia Minor
Patients with beta thalassaemia minor (also called thalassaemia trait) are carriers of an abnormally functioning beta-globin gene. They have one abnormal and one normal gene.
Thalassaemia minor causes mild microcytic anaemia and usually only requires monitoring.
Thalassaemia Intermedia
Patients with beta thalassaemia intermedia have two abnormal copies of the beta-globin gene. This can be either:
Two defective genes
One defective gene and one deletion gene
Thalassaemia intermedia causes more significant microcytic anaemia. Patients require monitoring and may need occasional blood transfusions. They may require iron chelation to prevent iron overload.
Thalassaemia Major
Patients with beta thalassaemia major are homozygous for the deletion genes. They have no functioning beta-globin genes. This is the most severe form and usually presents with severe anaemia and failure to thrive in early childhood.
The bone marrow is under so much strain to produce extra red blood cells to compensate for the chronic anaemia that it expands enough to increase the risk of fractures and change the patient’s appearance. Abnormal features relating to bone changes include:
Frontal bossing (prominent forehead)
Enlarged maxilla (prominent cheekbones)
Depressed nasal bridge (flat nose)
Protruding upper teeth
Management involves regular transfusions, iron chelation and splenectomy. A bone marrow transplant can be curative.
Sickle Cell Anaemia
Sickle cell anaemia is a genetic condition that causes sickle (crescent) shaped red blood cells.
The abnormal shape makes the red blood cells more fragile and easily destroyed, leading to haemolytic anaemia. Patients with sickle cell anaemia are prone to various sickle cell crises.
Pathophysiology of sickle cell anaemia
Haemoglobin is the protein in red blood cells that transports oxygen. During fetal development, at around 32-36 weeks gestation, fetal haemoglobin (HbF) production decreases, and adult haemoglobin (HbA) increases. There is a gradual transition from HbF to HbA. At birth, around half the haemoglobin is HbF, and half is HbA. By six months of age, very little HbF is produced, and red blood cells contain almost entirely HbA.
Patients with sickle-cell disease have an abnormal variant called haemoglobin S (HbS). HbS results in sickle-shaped red blood cells.
Sickle cell anaemia is an autosomal recessive condition affecting the gene for beta-globin on chromosome 11. One abnormal copy of the gene results in sickle-cell trait. Patients with sickle-cell trait are usually asymptomatic. They are carriers of the condition. Two abnormal copies result in sickle-cell disease.
Sickle cell disease and malaria
Sickle cell disease is more common in patients from areas traditionally affected by malaria, such as Africa, India, the Middle East and the Caribbean. Having one copy of the gene (sickle cell trait) reduces the severity of malaria. As a result, patients with sickle cell trait are more likely to survive malaria and pass on their genes. Therefore, there is a selective advantage to having the sickle cell gene in areas of malaria, making it more common.
Screening for sickle cell disease
Sickle cell disease is tested for on the newborn blood spot screening test at around five days of age.
Pregnant women at high risk of being carriers of the sickle cell gene are offered testing.
Complications of sickle cell anaemia
Anaemia
Increased risk of infection
Chronic kidney disease
Sickle cell crises
Acute chest syndrome
Stroke
Avascular necrosis in large joints such as the hip
Pulmonary hypertension
Gallstones
Priapism (painful and persistent penile erections)
Sickle cell crisis
Sickle cell crisis refers to a spectrum of acute exacerbations caused by sickle cell disease. These range from mild to life-threatening. They can occur spontaneously or triggered by dehydration, infection, stress or cold weather.
There is no specific treatment for sickle cell crisis. They are managed supportively, with:
Low threshold for admission to hospital
Treating infections that may have triggered the crisis
Keep warm
Good hydration (IV fluids may be required)
Analgesia (NSAIDs should be avoided where there is renal impairment)
Vaso-occlusive crisis
Vaso-occlusive crisis (VOC) is also known as painful crisis and is the most common type of sickle cell crisis. It is caused by the sickle-shaped red blood cells clogging capillaries, causing distal ischaemia.
It typically presents with pain and swelling in the hands or feet but can affect the chest, back, or other body areas. It can be associated with fever.
It can cause priapism in men by trapping blood in the penis, causing a painful and persistent erection. Priapism is a urological emergency, treated by aspirating blood from the penis.
Splenic sequestration crisis
Splenic sequestration crisis is caused by red blood cells blocking blood flow within the spleen. It causes an acutely enlarged and painful spleen. Blood pooling in the spleen can lead to severe anaemia and hypovolaemic shock.
Splenic sequestration crisis is considered an emergency. Management is supportive, with blood transfusions and fluid resuscitation to treat anaemia and shock.
Splenic sequestration crisis can lead to splenic infarction, leading to hyposplenism and susceptibility to infections, particularly by encapsulated bacteria (e.g., Streptococcus pneumoniae and Haemophilus influenzae).
Splenectomy prevents sequestration crises and may be used in recurrent cases.
Aplastic crisis
Aplastic crisis describes a temporary absence of the creation of new red blood cells. It is usually triggered by infection with parvovirus B19.
It leads to significant anaemia (aplastic anaemia). Management is supportive, with blood transfusions if necessary. It usually resolves spontaneously within around a week.
Acute chest syndrome
Acute chest syndrome occurs when the vessels supplying the lungs become clogged with red blood cells. A vaso-occlusive crisis, fat embolism or infection can trigger it.
Acute chest syndrome presents with fever, shortness of breath, chest pain, cough and hypoxia. A chest x-ray will show pulmonary infiltrates.
Acute chest syndrome is a medical emergency with high mortality. It requires prompt supportive management and treatment of the underlying cause:
Analgesia
Good hydration (IV fluids may be required)
Antibiotics or antivirals for infection
Blood transfusions for anaemia
Incentive spirometry using a machine that encourages effective and deep breathing
Respiratory support with oxygen, non-invasive ventilation or mechanical ventilation
General management of sickle cell anaemia
A specialist MDT will manage sickle cell disease. The general principles are:
Avoid triggers for crises, such as dehydration
Up-to-date vaccinations
Antibiotic prophylaxis to protect against infection, typically with penicillin V (phenoxymethylpenicillin)
Hydroxycarbamide (stimulates HbF)
Crizanlizumab
Blood transfusions for severe anaemia
Bone marrow transplant can be curative
Hydroxycarbamide works by stimulating the production of fetal haemoglobin (HbF). Fetal haemoglobin does not lead to the sickling of red blood cells (unlike HbS). It reduces the frequency of vaso-occlusive crises, improves anaemia and may extend lifespan.
Crizanlizumab is a monoclonal antibody that targets P-selectin. P-selectin is an adhesion molecule found on endothelial cells on the inside walls of blood vessels and platelets. It prevents red blood cells from sticking to the blood vessel wall and reduces the frequency of vaso-occlusive crises.
Types of leukaemia
Leukaemia is cancer of a particular line of stem cells in the bone marrow, causing unregulated production of a specific type of blood cell.
Types
The types of leukaemia can be classified depending on how rapidly they progress (chronic is slow and acute is fast) and the cell line that is affected (myeloid or lymphoid) to make four main types:
Acute myeloid leukaemia (rapidly progressing cancer of the myeloid cell line)
Acute lymphoblastic leukaemia (rapidly progressing cancer of the lymphoid cell line)
Chronic myeloid leukaemia (slowly progressing cancer of the myeloid cell line)
Chronic lymphocytic leukaemia (slowly progressing cancer of the lymphoid cell line)
Other rarer types, such as acute promyelocytic leukaemia, are less like to appear in exams.
Most types of leukaemia occur in patients over 60-70. The exception is acute lymphoblastic leukaemia, which most commonly affects children under five years.
TOM TIP: The key differentiating features to remember for exams are:
ALL is the most common leukaemia in children and is associated with Down syndrome
CLL is associated with warm haemolytic anaemia, Richter’s transformation and smudge cells
CML has three phases, including a long chronic phase, and is associated with the Philadelphia chromosome
AML may result in a transformation from a myeloproliferative disorder and is associated with Auer rods
