Haematology

Question 1

Blood cells

Answer 1

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.

Question 2

White blood cells

Answer 2

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

Question 3

Blood film findings

Answer 3

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.

Question 4

Anaemia

Answer 4

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

Question 5

Causes of anaemia

Answer 5

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.

Question 6

Symptoms of anaemia

Answer 6

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

Question 7

Signs of anaemia

Answer 7

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

Question 8

Investigating anaemia

Answer 8

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).

Question 9

Iron deficiency anaemia

Answer 9

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.

Question 10

Causes of iron deficiency anaemia

Answer 10

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.

Question 11

Testing for iron deficiency anaemia

Answer 11

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)

Question 12

Managing iron deficiency anaemia

Answer 12

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.

Question 13

Pernicious anaemia

Answer 13

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.

Question 14

Pathophysiology of pernicious anaemia

Answer 14

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.

Question 15

Autoantibodies and pernicious anaemia

Answer 15

Autoantibodies used to diagnose pernicious anaemia are:

Intrinsic factor antibodies (the first-line investigation)
Gastric parietal cell antibodies (less helpful)

Question 16

Managing pernicious anaemia

Answer 16

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.

Question 17

Haemolytic anaemia

Answer 17

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

Question 18

Features of haemolytic anaemia

Answer 18

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)

Question 19

Investigating haemolytic anaemia

Answer 19

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)

Question 20

Hereditary Spherocytosis

Answer 20

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.

Question 21

Hereditary Elliptocytosis

Answer 21

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.

Question 22

G6PD deficiency

Answer 22

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.

Question 23

Autoimmune Haemolytic Anaemia

Answer 23

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

Question 24

Alloimmune Haemolytic Anaemia

Answer 24

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.

Question 25

Paroxysmal Nocturnal Haemoglobinuria

Answer 25

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.

Question 26

Microangiopathic Haemolytic Anaemia

Answer 26

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.

Question 27

Prosthetic Valve Haemolysis

Answer 27

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

Question 28

Thalassaemia

Answer 28

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.

Question 29

Features of thalassaemia

Answer 29

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

Question 30

Investigating thalassaemia

Answer 30

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.

Question 31

Iron overload and thalassaemia

Answer 31

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.

Question 32

Alpha-Thalassaemia

Answer 32

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

Question 33

Beta-Thalassaemia

Answer 33

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

Question 34

Thalassaemia Minor

Answer 34

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.

Question 35

Thalassaemia Intermedia

Answer 35

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.

Question 36

Thalassaemia Major

Answer 36

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.

Question 37

Sickle Cell Anaemia

Answer 37

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.

Question 38

Pathophysiology of sickle cell anaemia

Answer 38

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.

Question 39

Sickle cell disease and malaria

Answer 39

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.

Question 40

Screening for sickle cell disease

Answer 40

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.

Question 41

Complications of sickle cell anaemia

Answer 41

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)

Question 42

Sickle cell crisis

Answer 42

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)

Question 43

Vaso-occlusive crisis

Answer 43

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.

Question 44

Splenic sequestration crisis

Answer 44

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.

Question 45

Aplastic crisis

Answer 45

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.

Question 46

Acute chest syndrome

Answer 46

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

Question 47

General management of sickle cell anaemia

Answer 47

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.

Question 48

Types of leukaemia

Answer 48

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

Question 49

Pathophysiology of leukaemia

Answer 49

A genetic mutation in one of the precursor cells in the bone marrow leads to excessive production of a single type of abnormal white blood cell. The excessive production of a single type of cell can suppress the other cell lines, causing the underproduction of different cell types. This can result in pancytopenia, which is a combination of low red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia).

Question 50

Presentation of leukaemia

Answer 50

The presentation of leukaemia is relatively non-specific. An urgent full blood count is required when leukaemia is a differential for a presentation. Potential presenting features include: Fatigue Fever Pallor due to anaemia Petechiae or bruising due to thrombocytopenia Abnormal bleeding Lymphadenopathy Hepatosplenomegaly Failure to thrive (children)

Question 51

Differential diagnosis of petechiae

Answer 51

One key presenting feature of leukaemia is bleeding under the skin due to thrombocytopenia. Bleeding under the skin causes non-blanching lesions. These lesions are called different things based on the size of the lesions: Petechiae are less than 3 and caused by burst capillaries Purpura are 3 – 10mm Ecchymosis is larger than 1cm The top differentials for a non-blanching rash caused by bleeding under the skin are: Leukaemia Meningococcal septicaemia Vasculitis Henoch-Schönlein purpura (HSP) Immune thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura (TTP) Traumatic or mechanical (e.g., severe vomiting) Non-accidental injury Consider non-accidental injury (abuse) as a differential, particularly in children and vulnerable adults.

Question 52

Diagnosing leukaemia

Answer 52

The NICE guidelines on suspected cancer (2021) recommend a full blood count within 48 hours for patients with suspected leukaemia. They recommend children or young people with petechiae or hepatosplenomegaly are sent for immediate specialist assessment. A full blood count is the initial investigation. A blood film is used to look for abnormal cells and inclusions. Lactate dehydrogenase (LDH) is a very non-specific marker of tissue damage. It is often raised in leukaemia but also in other cancers and many non-cancerous conditions, including after heavy exercise. It is not helpful as a screening test but may be used for specialist assessment and monitoring. Bone marrow biopsy is used to analyse the cells in the bone marrow to establish a definitive diagnosis of leukaemia. CT and PET scans may be used to help stage the condition. Lymph node biopsy can be used to assess abnormal lymph nodes. Genetic tests (looking at chromosomes and DNA changes) and immunophenotyping (looking for specific proteins on the surface of the cells) may be performed to help guide treatment and prognosis.

Question 53

Bone marrow biopsy and leukaemia

Answer 53

Bone marrow biopsy is usually taken from the iliac crest. It involves a local anaesthetic and a specialist needle. The options are aspiration or trephine. Bone marrow aspiration involves taking a liquid sample of cells from within the bone marrow. Bone marrow trephine involves taking a solid core sample of the bone marrow and provides a better assessment of the cells and structure.

Question 54

Acute lymphoblastic leukaemia

Answer 54

Acute lymphoblastic leukaemia (ALL) affects one of the lymphocyte precursor cells, causing acute proliferation of a single type of lymphocyte, usually B-lymphocytes. Excessive accumulation of these cells replaces the other cell types in the bone marrow, leading to pancytopenia. ALL most often affects children under five but can also affect older adults. It is more common with Down’s syndrome. It can be associated with the Philadelphia chromosome (but this is more associated with chronic myeloid leukaemia).

Question 55

Chronic lymphocytic leukaemia

Answer 55

Chronic lymphocytic leukaemia is where there is slow proliferation of a single type of well-differentiated lymphocyte, usually B-lymphocytes. It usually affects adults over 60 years of age. It is often asymptomatic but can present with infections, anaemia, bleeding and weight loss. It may cause warm autoimmune haemolytic anaemia. Richter’s transformation refers to the rare transformation of CLL into high-grade B-cell lymphoma. Smear or 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.

Question 56

Chronic myeloid leukaemia

Answer 56

Chronic myeloid leukaemia has three phases: Chronic phase Accelerated phase Blast phase The chronic phase is often asymptomatic, and patients are diagnosed after an incidental finding of a raised white cell count. This phase can last several years before progressing. The accelerated phase occurs when the abnormal blast cells take up a high proportion (10-20%) of the bone marrow and blood cells. In the accelerated phase, patients are more symptomatic and develop anaemia, thrombocytopenia and immunodeficiency. The blast phase follows the accelerated phase and involves an even higher proportion (over 20%) of blast cells in the blood. The blast phase has severe symptoms and pancytopenia and is often fatal. Chronic myeloid leukaemia is particularly associated with the Philadelphia chromosome. This refers to an abnormal chromosome 22 caused by a reciprocal translocation (swap) of genetic material between a section of chromosome 9 and chromosome 22. This translocation creates an abnormal gene sequence called BCR-ABL1, which codes for an abnormal tyrosine kinase enzyme that drives the proliferation of the abnormal cells.

Question 57

Acute myeloid leukaemia

Answer 57

There are many subtypes of acute myeloid leukaemia, with slightly different cytogenetics and presentations. It can present at any age but normally presents from middle age onwards. It can be the result of a transformation from a myeloproliferative disorder, such as polycythaemia ruby vera or myelofibrosis. A blood film and bone marrow biopsy will show a high proportion of blast cells. Auer rods in the cytoplasm of blast cells are a characteristic finding in AML.

Question 58

General management of leukaemia

Answer 58

An oncology and haematology multi-disciplinary team will coordinate treatment. Leukaemia is mainly treated with chemotherapy and targeted therapies, depending on the type and individual features. Examples of targeted therapies include (mainly used in CLL): Tyrosine kinase inhibitors (e.g., ibrutinib) Monoclonal antibodies (e.g., rituximab, which targets B-cells) Other treatments options include: Radiotherapy Bone marrow transplant Surgery

Question 59

Complications of chemotherapy

Answer 59

Chemotherapy comes with a long list of complications and adverse effects: Failure to treat cancer Stunted growth and development in children Infections due to immunosuppression Neurotoxicity Infertility Secondary malignancy Cardiotoxicity (heart damage) Tumour lysis syndrome

Question 60

Tumour lysis syndrome

Answer 60

Tumour lysis syndrome results from chemicals released when cells are destroyed by chemotherapy, resulting in: High uric acid High potassium (hyperkalaemia) High phosphate Low calcium (as a result of high phosphate) Uric acid can form crystals in the interstitial space and tubules of the kidneys, causing acute kidney injury. Hyperkalaemia can cause cardiac arrhythmias. The release of cytokines can cause systemic inflammation. Very good hydration and urine output before chemotherapy is required in patients at risk of tumour lysis syndrome. Allopurinol or rasburicase may be used to suppress the uric acid levels.

Question 61

Lymphoma

Answer 61

Lymphoma is a type of cancer affecting the lymphocytes inside the lymphatic system. Cancerous cells proliferate inside the lymph nodes, causing the lymph nodes to become abnormally large (lymphadenopathy). The many types of lymphoma fall into two categories: Hodgkin’s lymphoma (a specific disease) Non-Hodgkin’s lymphoma (which includes all other types)

Question 62

Hodgkin's lymphoma

Answer 62

Hodgkin’s lymphoma is the most common specific type of lymphoma. It has a bimodal age distribution with peaks around 20-25 and 80 years. Risk factors for Hodgkin’s lymphoma include: HIV Epstein-Barr virus Autoimmune conditions, such as rheumatoid arthritis and sarcoidosis Family history

Question 63

Non-Hodgkin lymphoma

Answer 63

Non-Hodgkin’s lymphoma includes many types. A few notable ones are: Diffuse large B cell lymphoma typically presents as a rapidly growing painless mass in older patients Burkitt lymphoma is particularly associated with Epstein-Barr virus and HIV MALT lymphoma affects the mucosa-associated lymphoid tissue, usually around the stomach Risk factors for non-Hodgkin’s lymphoma include: HIV Epstein-Barr virus Helicobacter pylori (H. pylori) infection is associated with MALT lymphoma Hepatitis B or C infection Exposure to pesticides Exposure to trichloroethylene (a chemical with a variety of industrial uses) Family history

Question 64

Presentation of lymphoma

Answer 64

Lymphadenopathy is the key presenting symptom. The enlarged lymph node or nodes might be in the neck, axilla or inguinal region. They are characteristically non-tender and feel firm or rubbery. Patients with Hodgkin’s lymphoma may experience lymph node pain after drinking alcohol. B symptoms refer to systemic symptoms of lymphoma: Fever Weight loss Night sweats Additional non-specific symptoms can include: Fatigue Itching Cough Shortness of breath Abdominal pain Recurrent infections

Question 65

Investigating lymphoma

Answer 65

Lymph node biopsy is a critical diagnostic investigation. Reed-Sternberg cells are the characteristic finding from a biopsy of Hodgkin’s lymphoma. They are large cancerous B lymphocytes with two nuclei and prominent nucleoli, giving them a cartoonish appearance of an owl face with large eyes. CT, MRI, and PET scans may be used to help diagnose and stage the disease.

Question 66

Lugano classification and lymphoma

Answer 66

The Lugano classification system is used for Hodgkin’s and non-Hodgkin’s lymphoma (replacing the older Ann Arbor system). It emphasises whether the affected nodes are above or below the diaphragm. A simplified version is: Stage 1: Confined to one node or group of nodes Stage 2: In more than one group of nodes but on the same side of the diaphragm (either above or below) Stage 3: Affects lymph nodes both above and below the diaphragm Stage 4: Widespread involvement, including non-lymphatic organs, such as the lungs or liver

Question 67

Managing lymphoma

Answer 67

The critical treatments for Hodgkin’s lymphoma are chemotherapy and radiotherapy. Treatment aims to cure the disease, and this is usually successful. However, there is a risk of relapse and side effects from treatment. Chemotherapy may result in infections, cognitive impairment, secondary cancers (e.g., leukaemia) and infertility. Radiotherapy creates a risk of tissue fibrosis, secondary cancers and infertility. Management of non-Hodgkin’s lymphoma depends on the type and stage. It may involve: Watchful waiting Chemotherapy Monoclonal antibodies (e.g., rituximab, which targets B cells) Radiotherapy Stem cell transplantation

Question 68

Myeloma

Answer 68

Myeloma is a type of cancer affecting the plasma cells in the bone marrow. Plasma cells are B lymphocytes that produce antibodies. Cancer in a specific type of plasma cell results in the production of large quantities of a specific paraprotein (or M protein), which is an abnormal antibody or part of an antibody. Multiple myeloma is where the myeloma affects multiple bone marrow areas in the body. Monoclonal gammopathy of undetermined significance (MGUS) involves the production of a specific paraprotein without other features of myeloma or cancer. Monoclonal refers to identical copies or clones originating from a single cell. MGUS is often an incidental finding in an otherwise healthy person. It has a small risk of progression to myeloma (about 1% per year). Smouldering myeloma involves abnormal plasma cells and paraproteins but no organ damage or symptoms. It has a greater risk of progression to myeloma (about 10% per year).

Question 69

Pathophysiology of myeloma

Answer 69

Plasma cells are B lymphocytes of the immune system that have developed to produce a specific antibody. Antibodies are also called immunoglobulins. They are complex molecules made up of heavy chains and light chains arranged in a Y shape. They help the immune system recognise and fight infections by targeting specific proteins on the pathogen. The five types of antibodies are A, G, M, D and E. Myeloma is cancer of a single type of plasma cell, with a genetic mutation that causes them to rapidly and uncontrollably multiply. They produce a specific paraprotein (or M protein), which is an abnormal antibody (immunoglobulin) or part of an antibody (often the light chain). There is an abnormally high level of this paraprotein (paraproteinaemia). The Bence Jones protein refers to free light chains in the urine.

Question 70

Four features of myeloma

Answer 70

The CRAB mnemonic can be used to remember the four key features of myeloma: C – Calcium (elevated) R – Renal failure A – Anaemia B – Bone lesions and bone pain

Question 71

Anaemia and myeloma

Answer 71

Anaemia is the most common complication of myeloma. The cancerous plasma cells invade the bone marrow (bone marrow infiltration), resulting in suppression of the other blood cell lines, leading to anaemia (low haemoglobin), leukopenia (low white blood cells) and thrombocytopenia (low platelets). Anaemia in myeloma is normocytic (normal size) and normochromic (normal colour).

Question 72

Myeloma bone disease

Answer 72

Myeloma bone disease results from increased osteoclast activity and suppressed osteoblast activity. Osteoclasts absorb bone, and osteoblasts deposit bone. The metabolism of bone becomes imbalanced, with more bone being reabsorbed than constructed. It is caused by cytokines released from abnormal plasma cells and other nearby cells. Common sites of myeloma bone disease are the skull, spine, long bones and ribs. The abnormal bone metabolism is patchy, meaning that the bone becomes very thin in some areas while others remain relatively normal. These patches of thin bone are described as osteolytic lesions. These weak points in the bone lead to pathological fractures. For example, a vertebral body in the spine may collapse (vertebral fracture), or a long bone such as the femur may break under minimal force. Increased osteoclast activity causes calcium reabsorption from the bone into the blood, resulting in hypercalcaemia. Plasmacytomas are individual tumours formed by cancerous plasma cells. They can occur in the bones, replacing normal bone tissue, or in the soft tissues.

Question 73

Renal disease and myeloma

Answer 73

Patients with myeloma often develop renal impairment, which can have various causes: Paraproteins deposited in the kidneys Hypercalcaemia affecting kidney function Dehydration Glomerulonephritis (inflammation around the glomerulus and nephron) Medications used to treat the condition

Question 74

Hyperviscosity syndrome and myeloma

Answer 74

The normal plasma viscosity, or internal friction in blood flow, is between 1.3 and 1.7 times that of water. An oversimplified description is that blood is 1.3 to 1.7 times thicker than water. Plasma viscosity increases when more proteins are in the blood, such as the paraproteins found in myeloma. Hyperviscosity syndrome is considered an emergency. It can cause many issues: Bleeding (e.g., nosebleeds and bleeding gums) Visual symptoms and eye changes (e.g., retinal haemorrhages) Neurological complications (e.g., stroke) Heart failure

Question 75

Risk factors for myeloma

Answer 75

Older age Male Black ethnic origin Family history Obesity

Question 76

Presentation of myeloma

Answer 76

Persistent bone pain (e.g., spinal pain) Pathological fractures Unexplained fatigue Unexplained weight loss Fever of unknown origin Hypercalcaemia Anaemia Renal impairment

Question 77

Investigating myeloma

Answer 77

Laboratory investigations include: FBC (anaemia or leukopenia in myeloma) Calcium (raised in myeloma) ESR (increased in myeloma) Plasma viscosity (increased in myeloma) U&E (for renal impairment) Serum protein electrophoresis (to detect paraproteinaemia) Serum-free light-chain assay (to detect abnormally abundant light chains) Urine protein electrophoresis (to detect the Bence-Jones protein) Bone marrow biopsy is required to confirm the diagnosis and perform cytogenetic testing. Imaging is used to assess for bone lesions. The order of preference is: Whole-body MRI Whole-body low-dose CT Skeletal survey (x-ray images of the entire skeleton) X-ray Findings Typical x-ray changes seen in patients with myeloma include: Well-defined lytic lesions (described as looking “punched-out”) Diffuse osteopenia Abnormal fractures Raindrop skull (sometimes called pepper pot skull) refers to multiple lytic lesions seen in the skull on an x-ray.

Question 78

Managing myeloma

Answer 78

An oncology and haematology multi-disciplinary team will coordinate treatment. Treatment aims to control the disease. It takes a relapsing-remitting course and is never fully cured. Treatment usually involves a combination of chemotherapy, which may include: Bortezomib (a proteasome inhibitor) Thalidomide Dexamethasone High-dose chemotherapy followed by a stem cell transplant is an option for fitter patients and may achieve a more extended period of remission. Stem cell transplantation can be: Autologous (using the person’s own stem cells) Allogeneic (using stem cells from a healthy donor) Management of myeloma bone disease may involve: Bisphosphonates to suppress osteoclast activity Radiotherapy for bone lesions can improve bone pain Orthopaedic surgery to stabilise bones (e.g., by inserting a prophylactic intramedullary rod) or treat fractures Cement augmentation (injecting cement into vertebral fractures or lesions) to improve spine stability and pain

Question 79

Complications of myeloma

Answer 79

There are many complications of myeloma and its treatment, including: Infection Bone pain Fractures Renal failure Anaemia Hypercalcaemia Peripheral neuropathy Spinal cord compression Hyperviscosity syndrome Venous thromboembolism

Question 80

Myeloproliferative disorders

Answer 80

Myeloproliferative disorders involve the uncontrolled proliferation of a single type of stem cell. They are considered a form of cancer occurring in the bone marrow, although they tend to develop and progress slowly. They have the potential to transform into acute myeloid leukaemia. The myeloproliferative disorders to remember are: Primary myelofibrosis Polycythaemia vera Essential thrombocythaemia Disease Proliferating Cell Line Blood Finding Primary Myelofibrosis Haematopoietic stem cells Low haemoglobin High or low white cell count High or low platelet count Polycythaemia Vera Erythroid cells High haemoglobin Essential Thrombocythaemia Megakaryocyte High platelet count These conditions are associated with mutations in certain genes: JAK2 MPL CALR TOM TIP: The mutation to remember is JAK2. Treatment might involve JAK2 inhibitors, such as ruxolitinib.

Question 81

Myelofibrosis

Answer 81

Myelofibrosis can result from primary myelofibrosis, polycythaemia vera or essential thrombocythaemia. Myelofibrosis is where the proliferation of a single cell line leads to bone marrow fibrosis, where bone marrow is replaced by scar tissue. This is in response to cytokines released from the proliferating cells. One particular cytokine is fibroblast growth factor. Fibrosis affects the production of blood cells and can lead to low haemoglobin (anaemia), low white blood cells (leukopenia) and low platelets (thrombocytopenia). When the bone marrow is replaced with scar tissue, the production of blood cells (haematopoiesis) starts to happen in other areas, known as extramedullary haematopoiesis. Production of blood cells in the liver and spleen causes hepatomegaly, splenomegaly, and portal hypertension. When it occurs around the spine, it can cause spinal cord compression. A blood film in myelofibrosis can show: Teardrop-shaped red blood cells Anisocytosis (varying sizes of red blood cells) Blasts (immature red and white cells)

Question 82

Presentation of myeloproliferative disorders

Answer 82

Initially, myeloproliferative disorders may be asymptomatic. They can present with non-specific symptoms: Fatigue Weight loss Night sweats Fever There may be signs and symptoms of underlying complications: Anaemia (tiredness, shortness of breath and dizziness) Splenomegaly (abdominal pain) Portal hypertension (ascites, varices and abdominal pain) Low platelets (bleeding and petechiae) Raised haemoglobin (itching, headaches and a red face) Low white blood cells (infections) Gout is a complication of polycythaemia Thrombosis is a common complication of polycythaemia and thrombocythaemia, leading to myocardial infarction, stroke or venous thromboembolism (e.g., DVT and PE). Clinical signs of polycythaemia include: Ruddy complexion (red face) Conjunctival plethora (the opposite of conjunctival pallor) Splenomegaly Hypertension

Question 83

Diagnosing myeloproliferative disorders

Answer 83

Bone marrow biopsy is required to confirm the diagnosis. Bone marrow aspiration may be “dry” with myelofibrosis, as the bone marrow has turned to scar tissue. Testing for the JAK2, MPL and CALR genes can help with diagnosis and management.

Question 84

Managing primary myelofibrosis

Answer 84

Management of primary myelofibrosis may involve: No active treatment for mild disease with minimal symptoms Supportive management of complications, such as anaemia, splenomegaly and portal hypertension Chemotherapy (e.g., hydroxycarbamide) to help control the disease Targeted therapies, such as JAK2 inhibitors (ruxolitinib) Allogeneic stem cell transplantation (risky but potentially curative)

Question 85

Managing polycythaemia vera

Answer 85

Management of polycythaemia vera may involve: Venesection to keep the haemoglobin in the normal range Aspirin to reduce the risk of thrombus formation Chemotherapy (typically hydroxycarbamide) to help control the disease

Question 86

Managing essential thrombocythaemia

Answer 86

Management of essential thrombocythaemia may involve: Aspirin to reduce the risk of thrombus formation Chemotherapy (typically hydroxycarbamide) to help control the disease Anagrelide is a specialist platelet-lowering agent

Question 87

Myelodysplastic syndrome

Answer 87

Myelodysplastic syndrome is a form of cancer caused by a mutation in the myeloid cells in the bone marrow, resulting in inadequate production of blood cells (described as ineffective haematopoiesis). There are various types of myelodysplastic syndrome. It has the potential to transform into acute myeloid leukaemia. Myelodysplastic syndrome causes low levels of blood components that originate from the myeloid cell line: Anaemia (low haemoglobin) Neutropenia (low neutrophil count) Thrombocytopenia (low platelets) Pancytopenia is a combination of low red blood cells, white blood cells and platelets. Risk factors are older age and previous chemotherapy or radiotherapy.

Question 88

Presentation of myelodysplastic syndrome

Answer 88

Patients may be asymptomatic. It may be diagnosed after incidental findings on a full blood count. They may present with symptoms of: Anaemia (fatigue, pallor or shortness of breath) Neutropenia (frequent or severe infections) Thrombocytopenia (bleeding and purpura)

Question 89

Diagnosing myelodysplastic syndrome

Answer 89

Full blood count will be abnormal. There may be blasts on the blood film. Bone marrow biopsy is required to confirm the diagnosis.

Question 90

Managing myelodysplastic syndrome

Answer 90

Depending on the symptoms, risk of progression and overall prognosis, the treatment options are: Watchful waiting Supportive treatment (e.g., blood or platelet transfusions) Erythropoietin (stimulates red blood cell production) Granulocyte colony-stimulating factor (stimulates neutrophil production) Chemotherapy and targeted therapies (e.g., lenalidomide) Allogenic stem cell transplantation (risky but potentially curative)

Question 91

Thrombocytopenia

Answer 91

Thrombocytopenia describes a low platelet count. The normal platelet count is 150-450 x 109/L. There is a long list of causes of a low platelet count. They can be split into problems with production or destruction. Reduced platelet production can occur with: Certain viral infections (e.g., Epstein-Barr virus, cytomegalovirus and HIV) B12 deficiency Folic acid deficiency Liver failure, causing reduced thrombopoietin production by the liver Leukaemia Myelodysplastic syndrome Chemotherapy Increased platelet destruction can occur with: Medications (e.g., sodium valproate and methotrexate) Alcohol Immune thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura (TTP) Heparin-induced thrombocytopenia (HIT) Haemolytic uraemic syndrome (HUS)

Question 92

Presentation of thrombocytopenia

Answer 92

Mild thrombocytopenia may be asymptomatic and found incidentally on a full blood count. Platelet counts below 50 x 109/L will result in easy bruising and prolonged bleeding times. It may present with: Nosebleeds Bleeding gums Heavy periods Easy bruising Haematuria (blood in the urine) Rectal bleeding Platelet counts below 10 x 109/L are at high risk for spontaneous bleeding. Particularly concerning are: Intracranial haemorrhage Gastrointestinal bleeding

Question 93

Differential diagnosis of abnormal bleeding

Answer 93

The clotting system creates blood clots to stop bleeding. There are several ways this system can malfunction. The top differentials of abnormal or prolonged bleeding to remember are: Thrombocytopenia Von Willebrand disease Haemophilia A and haemophilia B Disseminated intravascular coagulation (usually secondary to sepsis)

Question 94

Immune Thrombocytopenic Purpura

Answer 94

Immune thrombocytopenic purpura (ITP) can also be called autoimmune thrombocytopenic purpura, idiopathic thrombocytopenic purpura and primary thrombocytopenic purpura. They all refer to the same condition. ITP is a condition where antibodies are created against platelets. An immune response against platelets leads to their destruction and a low platelet count (thrombocytopenia). It characteristically presents with purpura, which are non-blanching lesions caused by bleeding under the skin. Care involves monitoring the platelet count, controlling blood pressure, and suppressing menstrual periods.

Question 95

Managing immune thrombocytopenic purpura

Answer 95

Management options include: Prednisolone (steroids) IV immunoglobulins Thrombopoietin receptor agonists (e.g., avatrombopag) Rituximab (a monoclonal antibody that targets B cells) Splenectomy TOM TIP: B cells produce antibodies. Rituximab is worth remembering as a monoclonal antibody that targets the CD20 proteins on the surface of B cells. By attacking B cells and reducing their numbers, it reduces the production of the antibodies that are responsible for autoimmune disease. It treats many autoimmune conditions, from rheumatoid arthritis to ITP.

Question 96

Thrombotic Thrombocytopenic Purpura

Answer 96

Thrombotic thrombocytopenic purpura (TTP) is a condition where tiny thrombi develop throughout the small vessels, using up platelets. As the problem is in the small vessels, it is described as a microangiopathy. It causes: Thrombocytopenia Purpura Tissue ischaemia and end-organ damage Thrombi develop due to a problem with a specific protein called ADAMTS13. This protein normally: Inactivates von Willebrand factor Reduces platelet adhesion to vessel walls Reduces clot formation Deficiency in the ADAMTS13 protein can be due to: An inherited genetic mutation (hereditary) Autoimmune disease, where antibodies are created against the protein (acquired) Treatment is guided by a haematologist and may involve plasma exchange, steroids and rituximab.

Question 97

Heparin-Induced Thrombocytopenia

Answer 97

Heparin-induced thrombocytopenia (HIT) involves the development of antibodies against platelets in response to heparin (usually unfractionated heparin, but it can occur with low-molecular-weight heparin). Heparin-induced antibodies target a protein on platelets called platelet factor 4 (PF4). The condition typically presents around 5-10 days after starting treatment with heparin. HIT antibodies bind to platelets and activate the clotting system, causing a hypercoagulable state and thrombosis (e.g., deep vein thrombosis). They also break down platelets and cause thrombocytopenia. Therefore, there is a counterintuitive situation where a patient is on heparin, has a low platelet count, and develops abnormal blood clots. Diagnosis is by testing for HIT antibodies on a blood sample. Management involves stopping heparin and using an alternative anticoagulant guided by a specialist (e.g., fondaparinux or argatroban).

Question 98

Von Willebrand disease

Answer 98

Von Willebrand disease (VWD) is the most common inherited cause of abnormal and prolonged bleeding. There are many underlying genetic causes, most of which are autosomal dominant. There is also a rarer acquired version, usually secondary to an underlying disease (e.g., leukaemia). In von Willebrand disease, there is a deficiency, absence or malfunctioning of a glycoprotein called von Willebrand factor (VWF). Von Willebrand factor is important in platelet adhesion and aggregation in damaged vessels. There are three types of von Willebrand disease: Type 1 involves a partial deficiency of VWF and is the most common and mildest type Type 2 involves the reduced function of VWF Type 3 involves a complete deficiency of VWF and is the most rare and severe type

Question 99

Presentation of Von Willebrand disease

Answer 99

Patients present with a history of unusually easy, prolonged or heavy bleeding: Bleeding gums with brushing Nosebleeds (epistaxis) Easy bruising Heavy menstrual bleeding (menorrhagia) Heavy bleeding during and after surgical operations A family history of heavy bleeding (e.g., menorrhagia) or von Willebrand disease is relevant.

Question 100

Diagnosing Von Willebrand disease

Answer 100

Diagnosis is based on a history of abnormal bleeding, family history, bleeding assessment tools and laboratory investigations. Due to the various underlying causes and types, there is no single von Willebrand disease test.

Question 101

Managing Von Willebrand disease

Answer 101

Von Willebrand disease does not generally require daily treatment. Management is needed in response to significant bleeding or trauma (to stop bleeding) or in preparation for operations (to prevent bleeding). Options include: Desmopressin (stimulates the release of vWF from endothelial cells) Tranexamic acid Von Willebrand factor infusion Factor VIII plus von Willebrand factor infusion Options for heavy menstrual periods include: Tranexamic acid Mefenamic acid Mirena coil Combined oral contraceptive pill Norethisterone A hysterectomy (surgical removal of the uterus) may be required in severe cases of heavy menstrual bleeding.

Question 102

Haemophilia

Answer 102

Haemophilia A and B are severe inherited bleeding disorders. Haemophilia A is caused by a deficiency of factor VIII. Haemophilia B (also known as Christmas disease) is caused by a deficiency in factor IX.

Question 103

X-linked recessive haemophilia

Answer 103

Both haemophilia A and B are X-linked recessive diseases. All X chromosomes need to have the abnormal gene to have haemophilia. Males only have one X chromosome and require only one abnormal copy to have the disease. Females have two X chromosomes, so when one copy is affected, they are asymptomatic carriers of the gene. Therefore, haemophilia A and B primarily affect males. For a female to be affected, they would require an affected father and a mother who is either a carrier or affected.

Question 104

Features of haemophilia

Answer 104

Both haemophilia A and B are severe bleeding disorders. Patients can bleed excessively in response to minor trauma and are at risk of spontaneous bleeding without any trauma. Most cases present in neonates or early childhood. It can present with intracranial haemorrhage, haematomas and cord bleeding in neonates. Spontaneous bleeding into joints (haemarthrosis) such as the ankle, knee or elbow can lead to joint damage and deformity. Bleeding into the muscles can cause compartment syndrome. Other areas of bleeding include: Oral mucosa Nosebleeds (epistaxis) Gastrointestinal tract Urinary tract, causing haematuria Intracranial haemorrhage Surgical wounds

Question 105

Diagnosing haemophilia

Answer 105

Diagnosis is based on bleeding scores, coagulation factor assays and genetic testing.

Question 106

Managing haemophilia

Answer 106

The affected clotting factors (VIII or IX) can be given by intravenous infusion, either regularly or in response to bleeding. A complication of this treatment is the formation of antibodies (called inhibitors) against the treatment, resulting in it becoming ineffective.

Question 107

Venous thromboembolism

Answer 107

Venous thromboembolism (VTE) is a common and potentially fatal condition. It involves a blood clot (thrombus) developing in the circulation, usually secondary to blood stagnation or hypercoagulable states. When a thrombus develops in a deep vein, it is called a deep vein thrombosis (DVT). Once a thrombus has developed, it can travel (embolise) from the deep veins, through the right side of the heart and into the lungs, where it becomes lodged in the pulmonary arteries. This blocks blood flow to areas of the lungs and is called a pulmonary embolism (PE). If the patient has a septal defect in their heart (e.g., an atrial septal defect), the thrombus can pass through to the left side of the heart and into the systemic circulation. If it travels to the brain, it can cause a large stroke.

Question 108

Risk factors for thromboembolism

Answer 108

Immobility Recent surgery Long haul travel Pregnancy Hormone therapy with oestrogen Malignancy Polycythaemia Systemic lupus erythematosus Thrombophilia TOM TIP: In your exams, when a patient presents with possible features of a DVT or PE, ask about risk factors such as periods of immobility, surgery and long-haul flights to score extra points.

Question 109

Thrombophilias

Answer 109

Thrombophilias are conditions that predispose patients to develop blood clots. There are a large number of these: Antiphospholipid syndrome Factor V Leiden Antithrombin deficiency Protein C or S deficiency Hyperhomocysteinaemia Prothombin gene variant Activated protein C resistance TOM TIP: The cause of recurrent venous thromboembolism to remember is antiphospholipid syndrome, which is associated with recurrent miscarriage and diagnosed with a blood test for antiphospholipid antibodies.

Question 110

VTE prophylaxis

Answer 110

Every patient admitted to hospital is assessed for their risk of venous thromboembolism (VTE). Patients at increased risk receive prophylaxis unless contraindicated. Prophylaxis usually involves low molecular weight heparin (LMWH), such as enoxaparin. Contraindications include active bleeding or existing anticoagulation with warfarin or a DOAC. Anti-embolic compression stockings are also used. Peripheral arterial disease is the main contraindication for compression stockings.

Question 111

DVT presentation

Answer 111

DVTs are almost always unilateral. Bilateral DVT is rare and bilateral symptoms are more likely due to an alternative diagnosis, such as chronic venous insufficiency or heart failure. DVTs can present with: Calf or leg swelling Dilated superficial veins Tenderness to the calf (particularly over the site of the deep veins) Oedema Colour changes to the leg The calf circumference is measured 10cm below the tibial tuberosity. More than a 3cm difference is significant. Consider a pulmonary embolism (e.g., shortness of breath and chest pain) in patients with features of a DVT.

Question 112

Wells score

Answer 112

The Wells score predicts the risk of a patient presenting with symptoms having a DVT or PE. It includes risk factors (e.g., recent surgery) and clinical findings (e.g., unilateral calf swelling over 3cm greater than the other leg).

Question 113

Diagnosing DVT

Answer 113

The Wells score is used when considering deep vein thrombosis. The outcome decides the next step: Likely: perform a leg vein ultrasound Unlikely: perform a d-dimer, and if positive, perform a leg vein ultrasound D-dimer is a sensitive (95%) but not a specific blood test for VTE. It helps exclude VTE where there is a low suspicion. It is almost always raised if there is a DVT or PE. However, other conditions can cause a raised d-dimer: Pneumonia Malignancy Heart failure Surgery Pregnancy Ultrasound of the leg is required to diagnose deep vein thrombosis. NICE recommends repeating negative ultrasound scans after 6-8 days if the patient has a positive D-dimer and the Wells score suggests a DVT is likely. CT pulmonary angiogram (CTPA) is the usual first-line imaging investigation for a pulmonary embolism.

Question 114

Initial management of venous thromboembolism

Answer 114

In most patients, NICE (2020) recommend treatment-dose apixaban or rivaroxaban as the initial anticoagulant. Low molecular weight heparin (LMWH) is the main alternative. This should be started immediately in patients where a DVT or PE is suspected and there is a delay in getting a scan to confirm the diagnosis. The NICE guidelines (2020) recommend considering catheter-directed thrombolysis in patients with a symptomatic iliofemoral DVT and symptoms lasting less than 14 days. A catheter is inserted under x-ray guidance through the venous system to apply thrombolysis directly into the clot.

Question 115

Long term anticoagulation and venous thromboembolism

Answer 115

The options for long-term anticoagulation in VTE are a DOAC, warfarin or LMWH. Direct-acting oral anticoagulants (DOACs) are oral anticoagulants that do not require monitoring. Options are apixaban, rivaroxaban, edoxaban and dabigatran. They are suitable for most patients. Exceptions include severe renal impairment (creatinine clearance less than 15 ml/min), antiphospholipid syndrome and pregnancy. Warfarin is a vitamin K antagonist. The target INR for warfarin is between 2 and 3 when treating DVTs and PEs. It is the first line in patients with antiphospholipid syndrome (who require initial concurrent treatment with LMWH). Low molecular weight heparin (LMWH) is the first-line anticoagulant in pregnancy. Anticoagulation is continued for: 3 months with a reversible cause (then review) 3-6 months in active cancer (then review) Long-term for unprovoked VTE, recurrent VTE or an irreversible underlying cause (e.g., thrombophilia)

Question 116

Inferior vena cava filter

Answer 116

Inferior vena cava filters are devices inserted into the inferior vena cava, designed to filter the blood and catch any blood clots travelling from the venous system towards the heart and lungs. They act as a sieve, allowing blood to flow through whilst stopping larger blood clots. They are used in those unsuitable for anticoagulation or where a PE has occurred whilst already on anticoagulation.

Question 117

Investigating unprovoked DVT

Answer 117

When patients have their first VTE without a clear cause, NICE (2020) recommend reviewing the medical history, baseline blood results and physical examination for evidence of cancer. In patients with an unprovoked DVT or PE that are not going to continue anticoagulation beyond 3-6 months, NICE recommend considering testing for: Antiphospholipid syndrome (check antiphospholipid antibodies) Hereditary thrombophilias (only if they have a first-degree relative also affected by a DVT or PE)

Question 118

Budd-Chiari Syndrome

Answer 118

Budd-Chiari syndrome involves obstruction to the outflow of blood from the liver caused by thrombosis in the hepatic veins or inferior vena cava. It is associated with hypercoagulable states (e.g., myeloproliferative disorders). It presents with a classic triad of: Abdominal pain Hepatomegaly Ascites Doppler ultrasonography is the usual imaging investigation for establishing the diagnosis. Treatment options include: Anticoagulation (e.g., low molecular weight heparin and warfarin) Endovascular procedures (e.g., thrombolysis or angioplasty) Transjugular intrahepatic portosystemic shunt (TIPS) Liver transplant

Question 119

This is easy to memorise: PT - measures the speed of clotting via the coagulation factors involved in the extrinsic and common pathways APTT - measures the speed of clotting via the coagulation factors involved in the intrinsic and common pathways The factors in each pathway are: Intrinsic: 8, 9, 11, 12 Extrinsic: 3, 7 Common: 1,2,5,10

Question 120

If vitamin B12 deficiency coexists with folate deficiency, vitamin B12 should be replaced before folate to prevent subacute combined degeneration of the spinal cord (remember B comes before F in the alphabet).

Question 121

Encapsulated organisms such as streptococcus pneumoniae are normally destroyed in the spleen. After a splenectomy, patients are at a higher risk of infection from these pathogens so should be offered vaccinations and antibiotic prophylaxis to reduce their risk of serious infections. Overwhelming post-splenectomy infection is a life-threatening condition which is often caused by encapsulated bacteria and fungi. An easy way to remember some of the key encapsulated organisms which can affect these patients is ‘Some Killers Have Pretty Nice Capsules’ – Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Neisseria meningitidis, and Cryptococcus neoformans.