Haematology Flashcards

Question

What are the mean cell volume for macrocytic anaemia

Answer 1

Caused by problems in producing RBCs Megaloblastic causes: - A result of impaired DNA synthesis preventing the cell from dividing normally, caused by - B12 deficiency - Folate deficiency Non-megaloblastic causes: - Alcohol - Reticulocytosis (usually from haemolytic anaemia or blood loss) - Hypothyroidism - Liver disease - Drugs such as azathioprine

Answer 2

- Found in animal protein so vegans who don't take supplements may be deficient - May also be an issue with malabsorption - Normally, meat or dairy are broken down in the stomach and the B12 is released. Intrinsic factor, made by parietal cells binds to the B12. Then, the B12-intrinsic factor complex moves through the intestines to the terminal ileum, where the complex is absorbed - In pernicious anaemia: IgA antibodies attack intrinsic factor or the parietal cells - In Crohn's disease: the terminal ileum is damaged which affects absorption - In patient's with a gastric bypass, food moves through too quickly for effective absorption of B12 - B12 is used throughout the body, so people with B12 deficiency develop a variety of neurologic symptoms.

Answer 3

- Oral B12 supplements - If issues with malabsorption, extremely high doses or IV B12 could be given

Answer 4

- We have up to six weeks supply of folate in the body, but this can get used up even quicker during pregnancy. - Individuals on a restricted diet may also have folate deficiency

Answer 5

Folate supplements

Answer 6

- Generic signs: - Pale skin - Conjunctival pallor - Tachycardia - Bounding pulse - Raised respiratory rate - Postural hypotension - Shock - Symptoms - Tiredness - Shortness of breath - Headaches - Dizziness - Palpitations - Confusion - Syncope - Worsening of other conditions such as angina, heart failure or peripheral vascular disease - Pica (abnormal cravings) and hair loss may signify iron deficiency anaemia

Answer 7

- Koilonychia: spoon shaped nails and can indicate iron deficiency - Angular chelitis (red, swollen patches in the corners of your mouth) can indicate iron deficiency - Atrophic glossitis: smooth tongue due to atrophy of the papillae and can indicate iron deficiency - Brittle hair and nails: can indicate iron deficiency - Jaundice: occurs in haemolytic anaemia - Bone deformities: occur in thalassaemia - Oedema, hypertension and excoriations on the skin: can indicate chronic kidney disease

Answer 8

- Full blood count for haemoglobin and MCV - Blood film - Reticulocyte count - Ferritin (an iron store) - B12 and folate - Bilirubin (raised in haemolysis) - Direct Coombs test (autoimmune haemolytic anaemia) - Haemoglobin electrophoresis (haemoglobinopathies)

Answer 9

- Oesophago-gastroduodenoscopy (OGD) and colonoscopy: to investigate for a gastrointestinal cause of unexplained iron deficiency anaemia. This is done on an urgent cancer referral for suspected gastrointestinal cancer. - Bone marrow biopsy: may be required if the cause is unclear

Answer 10

To detect antibodies that are stuck to the surface of RBCs

Answer 11

Management depends on establishing the underlying cause and directing treatment accordingly. Iron deficiency can be treated with iron supplementation. Severe anaemia may require blood transfusions.

Answer 12

- Haemoglobin is made of four haem molecules which contain iron. This iron molecule is what binds to oxygen, so each haemoglobin molecule can bind four molecules of oxygen. - In addition, iron is also an important part of proteins like myoglobin, which delivers and stores oxygen in muscles; and mitochondrial enzymes like cytochrome oxidase, which help generate ATP.

Answer 13

- Each day, around 1-2 mg of iron is absorbed and 1-2 mg is lost from the body. The total iron content within our body is approximately 3-4 grams, which is distributed among different structures: - Hb: 2-3 grams - Plasma iron (e.g. bound to transferrin): 3-7 mg - Iron-containing proteins (e.g. myoglobin): 300-400 mg - Stored iron (e.g. ferritin, haemosiderin): 1 gram

Answer 14

Absorption of iron from enterocytes in the gastrointestinal tract is highly regulated to match the loss of iron from the body each day. When the rate of iron absorption cannot keep up with the rate of iron loss, it will lead to depletion of iron stores within the body and eventually IDA.

Answer 15

- Our diet contains two forms of iron. - The first is heme iron, or iron bound to haemoglobin or myoglobin. This is in the ferrous, or Fe2+, state. - The other form is non-heme iron, which is free iron molecules in the ferric, or Fe3+, state. - When food is broken down in the stomach, iron is released. - Heme iron is absorbed directly into the duodenal cells, where it is broken down to release Fe2+ molecules. - Non-heme iron, however, needs to be reduced to heme iron first. The stomach’s hydrochloric acid activates a group of enzymes in the duodenal cells, collectively called ferri-reductase. - Fe2+ molecules then bind to a protein in the duodenal cells called ferritin, which temporarily stores the iron. - When iron is needed in the body, some Fe2+ molecules are released from ferritin and transported into the blood, where the enzyme hephaestin converts them back to the Fe3+ state. - Fe3+ molecules then bind to an iron transport protein called transferrin that carries iron to various target tissues and releases them there. - Fe3+ enters these various tissue cells, where there’s some more ferritin that can store them for future use.

Answer 16

Anaemia (low levels of Hb in the blood) caused by iron deficiency

Answer 17

Most common cause of anaemia worldwide

Answer 18

- Vegetarian/ vegan diet - H.pylori infection - Pregnancy - Young children and adolescents - Inflammatory bowel disease - Coeliac disease - Certain drugs e.g. PPIs

Answer 19

- Dietary insufficiency - Loss of iron e.g. in heavy menstruation, gastric ulcers, and colon cancer - Inadequate iron absorption e.g. after gastric surgery resulting in less HCl production, Crohn’s disease, coeliac disease - Increased requirements e.g. during pregnancy, growing children and adolescents Other causes include H.pylori infection, which causes gastric ulcers and gastrointestinal bleeding. H.pylori also traps dietary iron for itself, preventing it from reaching the duodenum.

Answer 20

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 there is less acid in the stomach, it changes to the insoluble ferric (Fe3+) form. Therefore, medications that reduce the stomach acid, such as proton pump inhibitors (lansoprazole and omeprazole) can interfere with iron absorption.

Answer 21

Regardless of the cause, iron deficiency leads to impaired haemoglobin production. Since there’s not enough haemoglobin for a normal sized RBC, the bone marrow starts pumping out microcytic RBCs. These cells containing less haemoglobin are called hypochromic, since they appear pale. These microcytic RBCs can’t carry enough oxygen to the tissues - hypoxia. Hypoxia signals the bone marrow to increase RBC production. The bone marrow goes into overdrive and pumps out incompletely formed RBCs. In addition to anaemia, iron deficiency also results in defective production of mitochondrial enzymes that generate necessary ATP for growth and development and this affects fast growing tissues, like hair and nails the most. Sometimes iron deficiency anaemia may occur in the context of Plummer-Vinson syndrome, resulting in features such as glossitis and oesophageal webs.

Answer 22

- Signs - Pallor - Conjunctival pallor - Glossitis - Koilonychia (spoon-shaped nails) - Angular stomatitis - Symptoms - Fatigue - Dyspnoea - Dizziness - Headache - Nausea - Bowel disturbance - Hairloss - Pica (abnormal cravings) - Possible exacerbation of cardiovascular co-morbidities causing angina, palpitations, and intermittent claudication.

Answer 23

- FBC: low Hb, low MCV, low MCHC - Iron studies: - Serum iron - Serum ferritin: low in anaemia - Total iron binding capacity: can be used as a marker for how much transferrin is in the blood. Increased in anaemia - Transferrin saturation: gives a good indication of the total iron in the body. Decreased in anaemia

Answer 24

Serum ferritin - 12-200ug/L Serum iron - 14-31 micromol/L Total iron binding capacity - 54-75 micromol/L

Answer 25

- Oesophago-gastroduodenoscopy (OGD) and a colonoscopy to look for cancer of the gastrointestinal tract: for new iron deficiency in an adult without a clear underlying cause - Bone marrow biopsy: may be required if the cause is unclear

Answer 26

- Treat the underlying cause - Oral iron supplements: ferrous sulphate or ferrous fumarate - Side effects: constipation and black coloured stools, diarrhoea, nausea and dyspepsia/epigastric discomfort. - Iron infusion e.g. cosmofer - Blood transfusions may be needed in severe cases

Answer 27

Anaemia of chronic disease (ACD) is a complex and multi-factorial condition due to a chronic inflammatory process from underlying infection, malignancy or systemic disease. ACD is classically described as a normocytic, normochromic anaemia, but can also be microcytic anaemia.

Answer 28

ACD is the second most common cause of anaemia worldwide, and commonly seen among hospitalised patients.

Answer 29

- ACD may be associated with many chronic disease states like infections, malignancy, diabetes, or autoimmune disorders. - The continuous inflammation generated by chronic disease impairs iron metabolism and, in turn, RBC production. - In general, the disease mechanism is a two fold process; decreased RBC lifespan and decreased RBC production. - Shortened RBC lifespan is a result of direct cellular destruction via toxins from cancer cells, viruses, or bacterial infections. - Decreased RBC production involves several mechanisms: - In chronic disease states, cytokines mediate this pathologic process in the kidney, immune system, and the GI tract. Two cytokines called TNF-a and IFN-y inhibit the production of erythropoietin in the kidney, which subsequently prevents RBC production in the bone marrow. Additionally, - TNF-a promotes RBC degradation in macrophages via phagocytosis - IF-Y increases the expression of a protein channel called divalent metal transporter one on the surface of macrophages. This channel serves as a pathway for iron to enter the macrophage at increased rates, so less iron is available for the production of haemoglobin. - IL-10 mediates the expression of increased ferritin receptors on the surface of macrophages, which then sequesters even more iron. - IL-6 also works in the liver by increasing production of a molecule called hepcidin, which blocks further uptake of iron from the small intestine.

Answer 30

- Fatigue - Pallor - Shortness of breath - Headache - Dizziness - May worsen palpitations, angina and intermittent claudication

Answer 31

- FBC: normocytic normochromic anaemia (approx. 75%) OR microcytic anaemia - CRP - Blood film - Haematinics: check for iron, B12 and folate deficiencies - Iron studies: - Serum ferritin: normal or raised - Serum iron: tends to be low - Total iron binding capacity: tends to be low

Answer 32

Marrow biopsy: iron stores are normal or increased

Answer 33

- Treatment of underlying cause e.g. - Antibiotics for infection - Surgical resection of tumour - Treatment of diabetes - EPO injections - Parenteral iron - Transfusions

Answer 34

Hereditary spherocytosis (HS) is an inherited haemolytic anaemia and is autosomal dominant in the majority of cases (75%), but can also be autosomal recessive.

Answer 35

- HS is the most common genetic haemolytic disease. - It is more common in Northern Europe and North America but can affect people of any race. - It is diagnosed in 1 in 2000 people, whilst a large proportion of these individuals are asymptomatic

Answer 36

- Family history - Northern European descent

Answer 37

- HS occurs due to a defect in red cell membrane proteins, such as ankyrin and spectrin. - This causes red blood cells (RBCs) to lose their biconcave shape and appear spherical. - Subsequently, there is accelerated degradation of RBCs in the spleen (extravascular haemolysis), resulting in a normocytic anaemia. - Splenomegaly occurs because the spleen has to work harder (hypersplenism) to clear out the abnormal RBCs and their products. - As haemolysis occurs, haemoglobin is broken down to bilirubin by macrophages, which increases the risk of gallstones and cholecystitis. - Patients can have episodes of haemolytic crisis, often triggered by infections, where the haemolysis, anaemia and jaundice is more significant. - Patients with hereditary spherocytosis can develop aplastic crisis. During aplastic crisis there is increased anaemia, haemolysis and jaundice, without the normal response from the bone marrow of creating new red blood cells. This is often triggered by infection with parvovirus.

Answer 38

- Signs - Splenomegaly - Pallor - Jaundice - Tachycardia - Flow murmur - Symptoms - Fatigue - Dizziness - Palpitations - RUQ pain: due to gallstones - Neonatal jaundice: in 50% of patients - Failure to thrive

Answer 39

No further tests are needed for diagnosis, if: - Family history of HS and - Typical clinical features and - Positive laboratory investigations (spherocytes, raised MCHC, increase in reticulocytes)

Answer 40

- FBC: normocytic anaemia with an increased reticulocyte count and raised MCHC - MCHC is increased as spherical RBCs lead to water diffusing out of the cell - Blood film: spherocytosis - LFTs: increased (unconjugated) bilirubin due to haemolysis - Coombs test: negative in hereditary spherocytosis. This is an important test to perform as spherocytes are also seen in autoimmune hemolytic anaemia (Coombs positive) and will, therefore, allow for differentiation between the two conditions

Answer 41

- Phototherapy or exchange transfusion: conducted in neonatal jaundice to reduce bilirubin levels - Blood transfusion: patients should be managed with transfusions for symptomatic anaemia until splenectomy is possible or deemed appropriate - Folic acid: all patients require daily folic acid supplementation until splenectomy - Splenectomy: removing the spleen reduces haemolysis - Splenectomy is delayed until patients are > 6 years old to reduce the risk of post-splenectomy sepsis - Patients must be vaccinated against encapsulated bacteria and be prescribed lifelong phenoxymethylpenicillin

Answer 42

- Gallstones: the high level of bilirubin due to haemolysis increases the risk of gallstones - Aplastic crisis: parvovirus B12 infection attacks erythroid precursors in the marrow, resulting in anaemia with reduced reticulocyte count. Any patient with a haemolytic condition is at risk due to reduced RBC life span - Bone marrow expansion: in conditions where there is a chronic, increased need for RBC production, such as haemolytic anaemias, bone marrow can expand. This particularly affects the face and skull - Post-splenectomy sepsis: prevented by lifelong penicillin and vaccination against S. pneumoniae, H. influenzae, influenza, and meningitis A&C. Vaccination is offered two weeks prior to the procedure

Answer 43

Most patients with HS are asymptomatic with a near-normal Hb post-splenectomy, as this increases RBC lifespan

Answer 44

- Normally, as a part of the metabolic process, our body produces free radicals like hydrogen peroxide, or H2O2. - Free radicals can damage the cells in many ways including destroying the DNA, proteins, and the cell membrane. - Glutathione acts as an antioxidant and goes around and neutralises these free radicals. - In order to function, glutathione needs to be in the reduced state where they can donate an electron to the H2O2 and convert them into harmless water and oxygen. - However this causes the glutathione to become oxidised, so before it can be reused, glutathione reductase will use an NADPH as an electron donor to reduce the oxidised glutathione back into its working state. - After giving up its electron, the NADPH will become NADP+. - To replenish the supply of NADPH, the glucose-6-phosphate dehydrogenase enzyme, or G6PD, reduces NADP+ back to NADPH by oxidising a glucose-6-phosphate. - Glucose-6-phosphate is a metabolite of glucose so we usually have a ready supply of this molecule as long as we are not in a starving state.

Answer 45

G6PD deficiency is a condition where there is a defect in the G6PD enzyme normally found in all cells in the body.

Answer 46

- It is inherited in an X linked recessive pattern, meaning it usually affects males. - It is more common in Mediterranean, Middle Eastern and African patients. - 6DPD deficiency can be protective against malaria

Answer 47

- Fava beans - Soy products - Red wine - Infections (viral hepatitis or pneumonia) - Metabolic acidosis - Medications: - Primaquine (an antimalarial) - Ciprofloxacin - Nitrofurantoin - Trimethoprim - Sulfonylureas (e.g gliclazide) - Sulfasalazine and other sulphonamide drugs

Answer 48

G6PD deficiency is caused by mutations on the G6PD gene which is found on the X chromosome and thus it’s an X-linked recessive genetic condition and it almost exclusively manifests as a disease in men. The G6PD mutations cause defective G6PD enzymes to be produced that have a shorter half-life. There are two common types of G6PD deficiency: a Mediterranean and an African variant. Low levels of G6PD causes low levels of NADPH, leading to low levels of reduced glutathione. G6PD is the only way for red blood cells to get NADPH so they are especially susceptible to damage caused by free radicals. When these build up, it causes the cell membrane to become unstable, causing haemolysis. Free radicals can also directly damage haemoglobin molecules which are the oxygen carrying protein in red blood cells. These damaged proteins precipitates inside the cells and are called Heinz bodies. The spleen macrophages notice these Heinz bodies and try to remove them by taking a chunk out of the cells, leaving these red blood cells partially devoured. These are known as bite cells. When haemolysis occurs, this leads to conversion to bilirubin, which can result in jaundice and further complications e.g. gallstones. Some of the bilirubin is converted to urobilin, which builds up to give the urine a dark tea-like colour. This could cause damage to the kidneys.

Answer 49

Periods of increased stress, with a higher production of ROS, can lead to acute haemolytic anaemia. e.g. infections (viral hepatitis or pneumonia), metabolic acidosis, fava beans, soy products, red wine, certain medications

Answer 50

- Signs - Jaundice - Pallor - Splenomegaly - Dark tea-like coloured urine - Symptoms - Shortness of breath - Fatigue - Dizziness - Headaches - Palpitations

Answer 51

- FBC: low levels of RBC, high reticulocytes - Blood film: heinz bodies and bite cells - LDH: elevated - Bilirubin: elevated - Haptoglobin: low - Coomb's test: negative (used to detect immune mediated anaemias) - Diagnosis can be made by doing a G6PD enzyme assay

Answer 52

- Avoid trigger of haemolysis e.g. fava beans and certain medications - In certain cases, transfusions may be needed

Answer 53

- Gallstones: due to jaundice - Kidney damage

Answer 54

Aplastic anaemia is a stem cell disorder characterised by pancytopenia. This means there is anaemia, leukopenia, and thrombocytopenia. It is usually an acquired condition but may be inherited

Answer 55

- Idiopathic (most common) - Radiation and toxins - Drugs e.g. certain chemotherapeutic agents, anti-seizure medication, anti-inflammatory medications, anti-thyroid medications and certain antibiotics - Infections e.g. HIV, EBV - Clonal or genetic disorders e.g. Fanconi's anaemia

Answer 56

- The most common cause of aplastic anaemia is autoimmune destruction of haematopoietic stem cells. - Research shows that there are alterations in the immunologic appearance of haematopoietic stem cells because of genetic disorders, or after exposure to environmental agents, like radiation or toxins. - This means that the hematopoietic stem cells start expressing non-self antigens and the immune system subsequently targets them for destruction.

Answer 57

- Signs - Pallor - Symptoms - Fatigue - Palpitations - Dizziness - Headaches - Chest pain and shortness of breath: as heart works harder to compensate for low RBC count - Increased bleeding and petechiae: due to thrombocytopenia - Recurrent infections: due to leukopenia

Answer 58

- FBC: anaemia, leukopenia, thrombocytopenia, low reticulocyte count - Erythropoietin: may be raised to try and compensate for low RBC - Bleeding time: increased - Bone marrow biopsy: shows low counts of haematopoietic stem cells

Answer 59

- Removal/ treatment of causes e.g. drugs or infections - Transfusions - Stem cell transplant - Immunosuppressive treatment

Answer 60

Haemoglobin is made up of four globin chains, each bound to a heme group. There are four major globin chain types - alpha (α), beta (β), gamma (γ), and delta (δ). These four globin chains combine in different ways to give rise to different kinds of haemoglobin. Blood consists of HbA, HbA2 and HbF. HbS is when Hb contains 2 alpha chains and 2 mutated beta chains.

Answer 61

Sickle cell anaemia is an autosomal recessive mutation in the beta chain of haemoglobin, resulting in sickling of red blood cells (RBCs) and haemolysis.

Answer 62

The prevalence of sickle cell trait in sub-Saharan Africa is the highest in the world. This may be because it is protective against malaria.

Answer 63

- African: 8% of black people carry the sickle cell gene - Family history: autosomal recessive pattern - Triggers of sickling: dehydration, acidosis, infection, and hypoxia - GENETIC

Answer 64

Neonates with sickle cell disease are often asymptomatic for the first 4-6 months of life due to high levels of HbF (foetal haemoglobin), which is protective against sickling due to its high oxygen affinity. Over time, as HbF falls and HbS predominates, patients eventually become symptomatic.

Answer 65

Under physiological stress, sickled haemoglobin (HbSS) polymerises and caused erythrocytes to deform into a sickled shape. Stressors are: hypoxia, acidosis, infection, cold temperatures, dehydration. Deformed RBCs may cause vaso-occlusion or slow the blood flow. Repeated sickling of RBCs damages the cell membrane and promotes premature haemolysis, causing anaemia. Bone marrow and liver compensate for haemolysis by produces more RBCs, causing bone deformities and hepatomegaly

Answer 66

- Pain - Related to anaemia: fatigue, dizziness, palpitations - Related to haemolysis: jaundice, and gallstones

Answer 67

- RBCs sickle in the spleen, causing pooling of blood and a rapid drop in Hb and platelets - Abdominal pain secondary to massive splenomegaly, possibly with hypovolaemic shock - Autosplenectomy: repeated episodes lead to splenic infarction, fibrosis, and atrophy.

Answer 68

- Infection with parvovirus B19 causes bone marrow suppression - Sudden onset pallor, fatigue, and anaemia - Differentiated from sequestration as it usually causes anaemia with reduced reticulocyte count and no splenomegaly

Answer 69

Increased rate of intravascular and extravascular haemolysis; rare

Answer 70

Painful, vaso-occlusive episodes occur as RBCs sickle in various organs - Bone - Dactylitis: inflammation of digits - Avascular necrosis: death of bone tissue due to a lack of blood supply - Osteomyelitis: most commonly due to salmonella - Lungs - Acute chest syndrome: severe and potentially life-threatening - Dyspnoea - Chest pain - Hypoxia - Pulmonary infiltrates on chest X-ray - Spleen - Autosplenectomy - Patients are at risk of infection from encapsulated bacteria - CNS - Stroke - Kidney - Renal papillary necrosis - Genitalia - Priapism: painful prolonged erection

Answer 71

- Newborn screening with Guthrie heel prick: sickle cell anaemia is one of a number of conditions screened for in all neonates in the UK at 5 days of age - FBC: normocytic anaemia with reticulocytosis - Blood film: sickled RBCs, target cells, Howell-Jolly bodies (RBC nuclear remnants seen later in the disease due to hyposplenism) - Hb electrophoresis and solubility: diagnostic investigation, demonstrating increased HbS (2 alpha chains and 2 abnormal beta chains) and reduced/absent HbA (α2 β2)

Answer 72

- Bedside - Urinary Legionella/Pneumococcal antigen: in chest crisis - Sputum culture and sputum/nasopharyngeal aspirate: in chest crisis - Bloods - ABG: if SpO2 < 94% - FBC: normocytic anaemia, generally reticulocytosis; aplastic crisis causes reduced reticulocytes - U&Es and LFTs - G&S and crossmatch: in case of transfusion - Blood cultures: in all febrile patients with chest crisis - Serology (atypical respiratory organisms): in chest crisis - Imaging - CXR pulmonary infiltrates in chest crisis - Bone X-ray: if suspecting osteomyelitis or dactylitis

Answer 73

Acute management depends on which type of complication has occurred. - Analgesia: patients often require opiates or patient-controlled analgesia - Hydration: dehydration precipitates sickling so it is important that patients are well hydrated - Oxygen: used if hypoxic or there is evidence of chest crisis - Antibiotics: used in chest crisis or if evidence of infection, e.g. osteomyelitis - Blood transfusion: in a severe crisis, a blood transfusion reduces the proportion of HbS and is often required in a chest crisis - Exchange transfusion: involves removal of HbS in exchange for normal Hb in a life-threatening crisis, for example, a severe chest crisis or stroke - Penile aspiration: in priapism

Answer 74

Chronic management is largely supportive and aimed at preventing infections and sickle crises, as well as managing anaemia. - Pain management: regularly prescribed medications to manage chronic pain - Hydroxycarbamide: increases the level of HbF, which is protective against sickling and reduces the frequency of crises and blood transfusions - Lifelong phenoxymethylpenicillin: patients are at risk of infection from encapsulated bacteria due to hyposplenism from autosplenectomy. Lifelong penicillin V prophylaxis for patients with sickle cell disease, starting from 3 months old, is required - Regular vaccinations: pneumococcal polysaccharide vaccine every 5 years and yearly influenza - Blood transfusion - Iron chelation: to prevent iron overload from blood transfusions - Folic acid supplementation: offered to all patients as it raises haemoglobin levels - Bone marrow transplant: could be curative

Answer 75

- Sickle cell crises - Anaemia - Increased risk of infection

Answer 76

Prognosis is variable. The median age at death is 40-50 for patients with sickle cell disease, with a third of patients dying during an acute crisis

Answer 77

- Vitamin B12, also known as cobalamin, is a complex organometallic compound found in animal and dairy products like meat, eggs or milk - Dairy and animal products are broken down in the stomach by pepsin, to release B12 - Intrinsic factor, made by parietal cells, can bind to B12, and the B12-intrinsic factor complex passes into the intestines - When the complex reaches the terminal ileum, the enterocytes recognise intrinsic factor and absorb the whole complex - Inside the enterocytes, intrinsic factor gets removed and a protein called transcobalamin-II binds the free B12 and transports it into the blood and from there, to various target tissues - Some of the transcobalamin-B12 complex gets to the liver, where B12 can be stored for several years

Answer 78

Anaemia (low levels of Hb in the blood) caused by B12 deficiency. This is a macrocytic megaloblastic anaemia.

Answer 79

- Vitamin B12 is predominantly found in meat and dairy products (due to bacterial synthesis) and is not present in plants. Thus, dietary deficiency is uncommon and typically seen in strict vegans. - Vitamin B12 deficiency increases with age. - Unlike folate, vitamin B12 stores last for years before deficiency develops. - B12 deficiency most commonly due to pernicious anaemia - Pernicious anaemia: relatively common amongst Northern Europeans, with a high prevalence in those aged 60-70 years old - F>M

Answer 80

- Vitamin B12 (cobalamin) is found in meats and diary products. It is an essential vitamin for DNA synthesis in cells undergoing rapid proliferation. - Deficiency of Vitamin B12 affects rapidly dividing cells, such as those in the bone marrow. This can lead to pancytopenia. As compensation for anaemia, the bone marrow produces abnormal precursors of RBCs - macrocytic, megaloblastic RBCs - Other cells that are affected include rapidly dividing mucosal epithelium cells of the tongue, causing glossitis. - Vitamin B12 also plays a role in keeping levels of methylmalonic acid low. This is a harmful substance that can cause neurological damage. - Neurological features: - Peripheral neuropathy - Subacute degeneration of the cord - Focal demyelination

Answer 81

- Causes of vitamin B12 deficiency include: - Inadequate intake (e.g. strict vegetarians, vegans) - Inadequate secretion of intrinsic factor (e.g. pernicious anaemia, gastrectomy) - Malabsorption (e.g. Crohn’s, tropical sprue, patients who have had gastric bypass) - Inadequate release of B12 from food (e.g. gastritis, alcohol abuse) Pernicious anaemia (PA) refers to vitamin B12 deficiency as a result of autoimmune destruction of the gastric epithelium. This may be due to anti-parietal cell antibodies or anti-IF antibodies. Patients with PA typically develop chronic gastric inflammation, which may lead to gastric atrophy. Over time, the basal secretion of IF is severely decreased leading to the development of vitamin B12 deficiency.

Answer 82

- Signs - Pallor - Signs of neurological deficit e.g. confusion, ataxia etc - Symptoms - Shortness of breath - Fatigue - Palpitations - Headaches - Glossitis - CNS involvement - Personality change - Depression - Memory loss - Visual disturbances - Numbness, weakness and paraesthesia affecting the lower extremities - Ataxia - Loss of vibration sense or proprioception - Autonomic dysfunction (e.g. bladder/bowel dysfunction)

Answer 83

- Full blood count (FBC): raised MCV - Blood film: megaloblastic anaemia +/- hypersegmented neutrophils - Haematinics: look for iron, B12, folate deficiency - Lactate dehydrogenase (LDH): may be elevated - Liver function tests (LFTs)

Answer 84

- Bone marrow aspirate: megaloblastic erythropoiesis, marked erythroid hyperplasia with ineffective erythropoiesis with the development of giant metamyelocytes - Investigations to identify the underlying cause e.g. - Schilling's test: to test for pernicious anaemia; radiolabelled B12 given and absorption measured. Later repeated with IF administration to see if B12 absorption increases - Serological assessment e.g. autoantibodies seen in pernicious anaemia - Gastroscopy

Answer 85

- Treatment of the underlying cause - B12 supplementation e.g. oral cyanocobalamin; intramuscular hydroxocobalamin

Answer 86

Anaemia (low levels of Hb in the blood) caused by folate (vitamin B9) deficiency. This is a type of macrocytic megaloblastic anaemia.

Answer 87

- In general, megaloblastic anaemia and folate deficiency are seen most commonly in countries where malnutrition is problematic. - High-risk patient groups include: children, pregnant women and the elderly.

Answer 88

- Elderly - Poverty - Alcoholic - Pregnant - Crohn’s or coeliac disease

Answer 89

- Folate (vitamin B9) is another important molecule which acts as a cofactor in amino acid metabolism and DNA/RNA synthesis. - This DNA impairment will affect all cells, but bone marrow is most affected since its the most active in terms of cell division. This means that folate deficiency can eventually lead to pancytopenia. In response to the anaemia, the bone marrow compensates by releasing megaloblasts into the blood - and the final result is macrocytic, megaloblastic anaemia. - Other rapidly dividing cells, include mucosal epithelial cells of the tongue. These are affected, preventing healing. This leads to glossitis. - Folate is also essential for foetal development - deficiency can result in neural tube defects e.g. spina bifida. So supplementation is essential during pregnancy! - Folate is commonly found in a variety of food sources. - Absorption of folate occurs within the proximal part of the small intestines (e.g. duodenum & jejunum). - There are plenty of hepatic stores of folate (approx. 8-20 mg), but this reserve is lost rapidly from cellular metabolism and the shedding of epithelial cells. There is an estimated loss of 1-2% of stores per day. Therefore, folate deficiency can develop after months, compared to vitamin B12 deficiency, which tends to develop over years.

Answer 90

- Inadequate intake - Malabsorption (e.g. coeliac disease, resection) - Increased requirements (e.g. pregnancy, malignancy disease) - Increased loss (e.g. Chronic liver disease) - Other (e.g. anti-convulsants, alcohol abuse)

Answer 91

- Signs - Pallor - Symptoms - Fatigue - Dyspnoea - Palpitations - Headache - Glossitis - Features of pancytopenia e.g. excessive bleeding and bruising due to thrombocytopenia, recurrent infections due to leukopenia - Symptoms of underlying cause e.g. - Coeliac disease: diarrhoea, bloating, dyspepsia and abdominal discomfort.

Answer 92

- Primary investigations - FBC: high MCV - Blood film: macrocytic, megaloblastic RBC - Haematinics: search for iron, B12 and folate deficiencies - Serum and red cell folate: low

Answer 93

GI investigation e.g. small bowel biopsy to exclude occult GI disease

Answer 94

- Treat underlying cause e.g. stopping drugs or alcohol consumption - Folic acid supplements: always give alongside B12, because replacement of folic acid in the presence of vitamin B12 deficiency may cause significant neurological disease.

Answer 95

In the superior or inferior vena cava and then dumps into the right atrium. From there, the blood goes into RV is pumped into the PA and eventually oxygenated in the lungs.

Answer 96

The process starts with damage to the endothelium or inner lining of blood vessel walls, after which there’s an immediate vasoconstriction or narrowing of the blood vessel, limiting the amount of blood flow. After that, some platelets adhere to the damaged vessel wall, and become activated by collagen and tissue factor. These platelets then recruit additional platelets forming a plug. This is called primary haemostasis.

Answer 97

After that, the coagulation cascade is activated. A set of clotting factors that are made by the liver and are inactive, get proteolytically cleaved. This active protein begins a chain reaction, proteolytically cleaving and activates the next clotting factor and so on. The final step is activation of the protein fibrinogen to fibrin, which deposits and polymerises to form a mesh around the platelet plug. This process is known as secondary haemostasis.

Answer 98

The activation of the cascade is carefully controlled by anticoagulation proteins that target and inactivate key clotting factors. For example, antithrombin inactivates Factors IXa, Xa, XIa, XIIa, VIIa and thrombin, while protein S inactivates Factors Va and VIIIa.

Answer 99

As the clot grows in size, it limits the amount of blood able to pass through, increasing the pressure in that vein. In most cases, the clot starts naturally breaking down: for example, enzymes like plasmin break down fibrin into fragments called D-dimers.

Answer 100

A deep vein thrombosis (DVT) is the formation of a blood clot in the deep veins of the leg or pelvis (as opposed to the superficial veins).

Answer 101

- DVT is a very common medical condition, with the incidence increasing with age. - 65% of below-knee DVTs are asymptomatic and these rarely embolise to the lung

Answer 102

- Age: the risk of DVT is greater after 40 years old - Smoking - Drugs: combined oral contraceptive pill, hormone replacement therapy, tamoxifen - Immobility: surgery, hospitalisation, long-haul travel and bed-bound - Pregnancy - Trauma - Malignancy - Polycythaemia - SLE - Thrombophilia e.g. antiphospholipid syndrome, antithrombin deficiency, protein C or S deficiency, Factor V Leiden - Virchow's triad: hypercoagulability, venous stasis, endothelial damage

Answer 103

Blood flow is normally laminar and ensures platelets and clotting factors are dispersed and not activated. Stasis disrupts this and promotes thrombus formation; immobility and polycythaemia

Answer 104

- Signs - Unilateral swelling - Oedema - Tender and erythematous - Distention of superficial veins - Phlegmasia cerulea dolens: occurs in a massive DVT, resulting in obstruction of venous and arterial outflow (rare). This leads to ischaemia and a blue and painful leg - Symptoms - Unilateral calf pain, redness and swelling

Answer 105

The Wells score calculates the risk of DVT and determines how the patient is investigated and managed. Those with a score ≥ 2 are deemed high risk. Active cancer +1 Bedridden or recent major surgery +1 Calf swelling > 3cm compared to other leg +1 Superficial veins (non-varicose) present +1 Entire leg swollen +1 Tenderness along veins +1 Pitting oedema of the affected leg +1 Immobility of affected leg e.g. plaster +1 Previous DVT +1 Alternative diagnosis likely -2

Answer 106

Examination: measure the circumference of the calf 10cm below the tibial tuberosity. More than 3cm difference between calves is significant.

Answer 107

Duplex ultrasound of leg within 4 hours: this is diagnostic (offer a D-dimer if the scan is negative); if an ultrasound is not possible to arrange within 4 hours: - Perform a D-dimer AND - Offer interim anticoagulation for 24 hours (ideally in a form that can be easily continued) AND - Arrange the ultrasound for the following day

Answer 108

D-Dimer with a result available within 4 hours: if D-Dimer results cannot be obtained within 4 hours, offer interim anticoagulation until the result is available - If D-Dimer is raised: perform a duplex ultrasound within 4 hours - If D-Dimer is normal: a DVT is unlikely and alternative diagnoses should be considered

Answer 109

- Baseline bloods tests: FBC, U&Es, LFTs, PT and APTT - Do not wait for the results of baseline bloods before starting anticoagulation - Review and, if necessary act on, baseline blood results within 24 hours of starting interim anticoagulation

Answer 110

- All patients: all patients with an unprovoked DVT should have a full history, be examined and have blood tests (FBC, U&Es, LFTs, PT and APTT) - Patients do not need further investigation unless they have signs or symptoms of cancer

Answer 111

Do not test if the patient is on lifelong anticoagulation - Antiphospholipid antibodies: considered in people who have an unprovoked DVT and where there is a plan to stop anticoagulation - Thrombophilia screen: considered in people who have an unprovoked DVT and a first-degree relative who has had DVT and where there is a plan to stop anticoagulation

Answer 112

Anticoagulation needed! - No renal impairment - Offer apixaban or rivaroxaban - If neither suitable, offer one of: - LMWH for at least 5 days followed by dabigatran or edoxaban - LMWH and warfarin for at least 5 days (or INR stable at 2.0), then warfarin alone - Renal impairment (estimated creatinine clearance <15 ml/min) - Offer one of: - LMWH - Unfractionated heparin (UFH) - LMWH or UFH and warfarin for at least 5 days (or INR stable at 2.0), then warfarin alone - Active cancer - Consider a DOAC (e.g. rivaroxaban) - Offer anticoagulation for 3 to 6 months, taking into account tumour site, drugs and bleeding risk - If a DOAC is not suitable, consider one of: - LMWH - LMWH and warfarin for at least 5 days (or INR stable at 2.0), then warfarin alone - Other - Inferior vena cava filters: devices inserted into the inferior vena cava designed to filter the blood and catch any blood clots traveling from the venous system towards the heart and lungs.

Answer 113

- Compression stockings - Frequent calf exercises during long periods of immobilisation - Prophylactic anticoagulation with LMWH e.g. in patients who have had surgery and will be immobilised for a long period of time

Answer 114

- Pulmonary embolism: increased pressure in the vein can cause a part of the main clot to break free. Therefore, there is a risk of an embolism to the lungs. Pulmonary embolism can be diagnosed with a CT pulmonary angiogram or ventilation–perfusion (VQ) scan. - Embolic stroke: in patients with an atrial septal defect, the clot may travel to the left atria and then the left ventricle. The clot can then embolise to any part of the body, including the brain causing an embolic stroke - Post-thrombotic syndrome: this is a long term complication caused by chronic obstruction of venous blood, leading to venous hypertension, with pain, swelling, and ulceration - Increased risk of bleeding: patients on anticoagulation are at risk of bleeding - Phlegmasia cerulea dolens: occurs in a massive DVT, resulting in obstruction of venous and arterial outflow (rare). This leads to peripheral limb ischaemia and a blue and painful leg

Answer 115

Patients are at an increased risk of future venous thromboemboli, with a 30% risk of recurrence in the subsequent 5 years. Fatality in these patients is usually either related to a subsequent pulmonary embolism or major haemorrhage as a result of anticoagulation.

Answer 116

Traditional anticoagulants: warfarin, coumarin and heparin Newer anticoagulants, novel oral anticoagulants (NOACs) aka directly acting oral anticoagulants (DOACs): direct thrombin inhibitor (dabigatran) and factor Xa inhibitor (rivaroxaban and apixaban)

Answer 117

Acute myeloid leukaemia (AML) involves the proliferation of myeloblasts (partially developed white blood cells).

Answer 118

M0 - undifferentiated (5%) M1 - AML with minimal maturation (15%) M2 - AML with maturation (25%) M3 - Acute promyelocytic leukaemia (10%) M4 - Acute myelomonocytic leukaemia (20%) M4 eos - Acute myelomonocytic leukaemia with eosinophilia (5%) M5 - Acute monocytic leukaemia (5%) M6 - Acute erythroid leukaemia (10%) M7 - Acute megokaryoblastic leukaemia (5%)

Answer 119

- t(15;17) translocation involves the fusion of retinoic acid receptor (RAR) with promyelocytic protein (PML), blocking maturation of myeloblasts causing promyelocyte accumulation - Presents in younger patients than other subtypes; average age is 44 years old - Demonstrates Auer rods - Abnormal promyelocytes release granules which can cause thrombocytopaenia and disseminated intravascular coagulation (DIC) - Good prognosis (80% cure rate)

Answer 120

- Characterised by monoblast accumulation and usually lack Auer rods - Results in gum infiltration

Answer 121

- It is the most common acute leukaemia in adults - AML is a rare malignancy, with about 3000 new cases every year in the UK - AML is generally a disease of older people and is uncommon before the age of 45. The average age of diagnosis is approximately 68 years old and most common in over 75s.

Answer 122

- Increasing age: AML is generally a disease of older people and is uncommon before the age of 45. The average age of diagnosis is approximately 68 years old - Myelodysplastic syndromes: myelodysplasia evolves to AML in 30% of cases - Myeloproliferative neoplasms: e.g. polycythaemia vera or myelofibrosis - Down's syndrome - Previous chemotherapy or radiation exposure - Benzene: painters, petroleum and rubber manufacturers

Answer 123

Uncontrolled growth of the myeloid cell line in bone marrow causing proliferation of immature, non-functional white blood cells called “Blasts”. Blasts disrupt normal haematopoiesis which causes pancytopenia, a reduction in red blood cells (anaemia), white blood cells (infection) and platelets (bleeding). Immature blast cells can enter the bloodstream and infiltrate the CNS, liver, and skin.

Answer 124

- Signs - Pallor - Lymphadenopathy - Hepatosplenomegaly - Symptoms - Fatigue - Loss of appetite - Weight loss - Fever - Bruising and mucosal bleeding: due to thrombocytopaenia - Recurrent infections: due to leukopaenia - Pain and tenderness in the bones can occur when there’s increased cell production which causes the bone marrow to expand. - Abdominal fullness: due to hepatosplenomegaly - Localised pain in lymph nodes: due to lymphadenopathy - Gingival swelling: swollen gums seen in acute monocytic leukaemia

Answer 125

- FBC: leukocytosis, thrombocytopaenia and anaemia with a low reticulocyte count. Neutropaenia may be present due to failure of myeloblasts to differentiate into functional neutrophils - Blood film: high proportion of blast cells seen. Myeloblasts are usually seen as large cells with nuclei containing fine chromatin and prominent nucleoli, with Auer rods (crystallised aggregates of the myeloperoxidase enzyme.) - Clotting screen: DIC is particularly associated with acute promyelocytic leukaemia - Bone marrow aspirate and biopsy: ≥20% myeloblasts is diagnostic - Cytogenetic and molecular studies: identify specific translocations, e.g. t(15;17) RAR-PML. These studies are also useful to identify myeloid lineage markers such as CD33

Answer 126

- Lactate dehydrogenase (LDH): often raised in leukaemia but is not specific to leukaemia. - Lumbar puncture may be used if there is central nervous system involvement. - Lymph node biopsy can be used to assess lymph node involvement or investigate for lymphoma.

Answer 127

Differentials for bleeding and bruising: - Meningococcal septicaemia - Vasculitis - Henoch-Schonlein Purpura (HSP) - Idiopathic Thrombocytopenia Purpura (ITP) - Non-accidental injury

Answer 128

Induction: - The aim of treatment is to induce clinical and haematological remission (< 5% blast cells) - Chemotherapy: combination of cytarabine and an anthracycline, such as daunorubicin - **All-trans retinoic acid** (ATRA; tretinoin) is added in acute promyelocytic leukaemia (APML). ATRA binds RAR on promyelocytic cells and causes the blasts to mature into neutrophils, which eventually go on to die. Consolidation: - Further chemotherapy is offered - Patients who are high risk may receive stem cell transplantation

Answer 129

- Myelosuppression and neutropaenic sepsis: bone marrow function is disrupted as myeloblasts accumulate, whilst abnormal myeloblasts also fail to differentiate into functional neutrophils. May present with pancytopaenia requiring RBC and platelet transfusion. - Disseminated intravascular coagulation (DIC): blood clots form throughout the body, blocking small blood vessels. Particularly associated with APML and presents with prolonged PT, prolonged APTT, low fibrinogen, elevated D-dimer - Extramedullary involvement: central nervous system involvement is seen in < 5% of patients

Answer 130

- Myelosuppression and neutropaenic sepsis: must be considered in any patient on chemotherapy presenting with a fever. Management will require broad-spectrum antibiotics, such as tazocin, and isolation - Tumour lysis syndrome: treatment with chemotherapy causes rapid cell destruction leading to hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcaemia. This can cause seizures, arrhythmias, and renal failure. Allopurinol can be given to control uric acid levels. Other chemicals must also be monitored and treated. - Infections due to immunodeficiency - Neurotoxicity - Infertility - Secondary malignancy - Cardiotoxicity

Answer 131

In general, the 5-year survival for patients with AML is 25%. However, APML has a favourable prognosis with an 80% cure rate since the introduction of all-trans retinoic acid. Poor prognostic factors include: - > 60 years old - WCC > 100 000 at diagnosis - Secondary haematological pathology which caused AML, such as myelodysplasia - Specific cytogenetic abnormalities, such as deletion of chromosome 5 or 7

Answer 132

You can use the mnemonic “ALL CeLLmates have CoMmon AMbitions” to remember the progressive ages of the different leukaemia from 45-75 in steps of 10 years. - Under 5 and over 45 – acute lymphoblastic leukaemia (ALL) - Over 55 – chronic lymphocytic leukaemia (CeLLmates) - Over 65 – chronic myeloid leukaemia (CoMmon) - Over 75 – acute myeloid leukaemia (AMbitions)

Answer 133

Acute lymphoblastic leukaemia (ALL) involves the proliferation of lymphoblasts, most commonly of the B cell lineage.

Answer 134

B-cell and T-cell ALL can be classified based on the origin (B cell or T cell) and maturity of the malignant cells:

Answer 135

- ALL is the most common childhood malignancy, with 75% of cases occurring in children younger than 6 years old. - Bimodal age distribution: there is one peak at 4-5 years and a second peak after the age of 50 - The most commonly affected demographic is white males.

Answer 136

- t(12;21) is the most common cytogenetic abnormality in children. - In adults, the Philadelphia chromosome is the most common cytogenetic abnormality and describes the translocation t(9;22)

Answer 137

- Previous chemotherapy - Radiation exposure - Down syndrome: 20-fold increased risk - Benzene exposure: painters, petroleum, rubber manufacturers - Family history: there is some evidence of genetic predisposition

Answer 138

Uncontrolled proliferation of lymphocyte precursor cells (B or T). accumulation of lymphoblasts in bone marrow and peripheral blood. Excessive proliferation causes lymphoblasts to replace the other cell type being created in bone marrow leading to pancytopenia. - Common chromosomal translocations include translocation of chromosome 12 and 21 and translocation of chromosome 9 and 22, also called the Philadelphia chromosome.

Answer 139

- Signs - Lymphadenopathy - Hepatosplenomegaly - Pallor - Flow murmur: due to anaemia - Parotid infilitration - Thymus enlargement in T-ALL: mass or growth in the mediastinum - Testicular swelling: due to testicular involvement - CNS involvement: e.g. meningism and cranial nerve palsies - Symptoms - Fatigue - Loss of appetite - Weight loss - Easy bruising, prolonged bleeding and mucosal bleeding: due to thrombocytopaenia - Recurrent infections: due to neutropaenia - Bone pain: due to bone marrow infiltration - Fever - Failure to thrive (children) - Abdominal fullness: due to hepatoslenomegaly - Localised pain in lymph nodes: due to lymphadenopathy

Answer 140

- FBC: lymphocytosis, thrombocytopenia and normocytic anaemia with a low reticulocyte count - Blood film: lymphoblasts - relatively small cells with coarse chromatin, which are clumped together and have small nucleoli. They have very little cytoplasm, which has glycogen granules. - Bone marrow aspiration and trephine biopsy: ≥ 20% lymphoblasts is diagnostic - Immunophenotyping: to identify specific cell surface markers, e.g. TdT, a DNA polymerase that’s present only in the nucleus of the lymphoblast, or CD10 is indicative of B-cell ALL - Cytogenetic and molecular studies: can identify specific translocations, e.g. t(12;21) or t(9;22)

Answer 141

- Lactate dehydrogenase (LDH) often raised in leukaemia but is not specific to leukaemia. - Chest X-ray: may be used to identify a mediastinal mass, e.g. thymus mass - Lumbar puncture: may be indicated to identify CNS involvement - Lymph node biopsy can be used to assess lymph node involvement or investigate for lymphoma. - CT, MRI and PET scans can be used for staging and assessing for lymphoma and other tumours.

Answer 142

Differential diagnosis for bleeding and bruising: - Meningococcal septicaemia - Vasculitis - Henoch-Schonlein Purpura (HSP) - Idiopathic Thrombocytopenia Purpura (ITP) - Non-accidental injury

Answer 143

Pre-phase: - 5 - 7 days of treatment shortly after diagnosis - Treat with corticosteroids, with or without an additional chemotherapy agent Induction: - 4 - 8 week therapy, e.g. corticosteroids, vincristine or doxorubicin (chemotherapy) - Imatinib can be used in addition if Philadelphia chromosome-positive - Intrathecal therapy (administration into CSF) can be used if there is CNS involvement - The aim of treatment is to induce remission, defined as < 5% blast cells in bone marrow Consolidation: - Up to 1 year of high-dose chemotherapy, which is started after complete remission - The aim of treatment is to eliminate clinically undetectable residual leukaemia, hence preventing relapse Maintenance: - 2 years of mercaptopurine and methotrexate therapy - The aim of treatment is to eliminate minimal residual disease (leukemic cells not present on microscopy but cell surface markers still present)

Answer 144

Bone marrow transplantation: may be used as consolidation therapy in people at high risk of relapse, or for treating relapse when it occurs

Answer 145

- Myelosuppression and neutropaenic sepsis: must be considered in any patient on chemotherapy presenting with a fever. Management will require broad-spectrum antibiotics, such as tazocin, and isolation - Tumour lysis syndrome: treatment with chemotherapy causes rapid cell destruction leading to hyperkalaemia, hyperphosphatemia, hyperuricemia, and hypocalcaemia. This can cause seizures, arrhythmias, and renal failure Allopurinol can be given to control uric acid levels. Other chemicals must also be monitored and treated. - Stunted growth and development in children - Infections due to immunodeficiency - Neurotoxicity - Infertility - Secondary malignancy - Cardiotoxicity

Answer 146

Prognosis is dependent on age. 5-year survival in children is generally >90%. Poor prognostic factors include: - Age < 1 year or >10 years - WBC > 30x10^9 at diagnosis - t(9;22) - Presence of extramedullary disease, such as CNS involvement

Answer 147

Chronic myeloid leukaemia (CML) involves the proliferation of partially mature myeloid cells, in particular granulocytes, within the bone marrow and blood.

Answer 148

Chronic phase - lasts many years and may be asymptomatic or with non-specific symptoms, such as fever, weight loss and splenomegaly. Has a cell count of less than 10% blast cells. Accelerated phase - further progression of the disease with 10-19% blast cells and >20% basophils Blast crisis - terminal phase and mimics acute leukaemia. Subtypes: myeloid blast crisis (2/3) or lymphoid blast crisis (1/3) with >20% blast cells

Answer 149

- CML is generally considered a condition of the elderly, with a peak age of diagnosis between 65 and 74 years - Slight male predominance

Answer 150

- Male gender - Radiation exposure

Answer 151

Uncontrolled growth of myeloid cells interferes with production of normal blood cells in the bone marrow. Abnormal myeloid cells spill out of bone marrow into peripheral blood, causing abnormally high levels of granulocytes (neutrophils, basophils, eosinophils) Translocation 9:22 – Philadelphia chromosome. BCR-ABL gene fusion acts as a tyrosine kinase and speeds up cell division. It also inhibits DNA repair.

Answer 152

- As the CML cells divide quicker than they should, there’s a high chance that further genetic mutations can happen! - If this occurs, CML might progress and accelerate into a more serious acute leukaemia which is called a **blast crisis.** - A lot of cases of these blast crises include the formation of a trisomy on chromosome number 8, or the doubling of the Philadelphia chromosome.

Answer 153

- Signs - Hepatosplenomegaly - Abdominal tenderness - Pallor - Pyrexia - Symptoms - Fatigue - Weight loss - Fever - Night sweats - Shortness of breath - Easy bruising and bleeding, e.g. epistaxis: due to thrombocytopenia - Recurrent infections: due to leukopenia - Bone pain: due to marrow expansion - Abdominal fullness: due to hepatosplenomegaly

Answer 154

- FBC: leukocytosis, granulocytosis, anaemia with a reduced reticulocyte count, and reduced leukocyte ALP may be seen. Thrombocytosis is found in 30% of patients. - Blood film: an increase in all stages of maturing granulocytes. Precise findings depend on the disease phase (e.g. blast transformation) - Bone marrow biopsy: myeloblast infiltration in the bone marrow - Cytogenetic and molecular studies: Philadelphia chromosome t(9;22)(q34;q11) - Lactate dehydrogenase (LDH) often raised in leukaemia but is not specific to leukaemia.

Answer 155

Differential diagnosis of bleeding and bruising: - Meningococcal septicaemia- Vasculitis - Henoch-Schonlein Purpura (HSP) - Idiopathic Thrombocytopenia Purpura (ITP) - Non-accidental injury

Answer 156

Chronic or accelerated phase: - Tyrosine kinase inhibitor: imatinib is generally considered first-line - Hydroxyurea may be used prior to confirmation of the BCR–ABL1 fusion, following which patients are then switched to a tyrosine kinase inhibitor! - Tyrosine kinase inhibitor may be combined with interferon-alpha if required - High dose induction chemotherapy and allogeneic stem cell transplantation if the above fails Blast phase: - Tyrosine kinase inhibitor plus high dose induction chemotherapy, followed by stem cell transplantation - Patients may have pancytopaenia requiring blood and platelet transfusion - If remission is not achieved through the above measures, death is imminent

Answer 157

- Myelosuppression and neutropaenic sepsis: must be considered in any patient on chemotherapy presenting with a fever. Management will require broad-spectrum antibiotics, such as tazocin, and isolation - Gout: an increased turnover of cells results in the release of uric acid which can deposit in joints as urate crystals - Tumour lysis syndrome: treatment with chemotherapy causes rapid cell destruction leading to hyperkalaemia, hyperphosphatemia, hyperuricemia, and hypocalcaemia. This can cause seizures, arrhythmias, and renal failure Allopurinol can be given to control uric acid levels. Other chemicals must also be monitored and treated. - Infections due to immunodeficiency - Neurotoxicity - Infertility - Secondary malignancy - Cardiotoxicity

Answer 158

- Myelosuppression and neutropaenic sepsis: lymphoblasts invade the bone marrow, disrupting function. - Predisposition to infection - Blast crisis: conversion to acute leukaemia and seen in the terminal phase of CML. May result in pancytopaenia

Answer 159

CML has a good prognosis due to the introduction of targeted tyrosine kinase inhibitors, with a 75% 5-year survival rate. Patients respond particularly well to imatinib during the chronic phase. Prognosis is poorer with accelerated and blast phases.

Answer 160

Chronic lymphocytic leukaemia (CLL) describes the neoplastic proliferation of mature B lymphocytes.

Answer 161

- CLL is the most common adult leukaemia - In the UK, there are approximately 3800 diagnoses each year - Median age at diagnosis is 70 - M>F

Answer 162

- Age: median age at diagnosis is 70 - Family History - Male sex: twice as common in men - White - Imunnocompromised - Pneumonia

Answer 163

Pathophysiology Uncontrolled proliferation and accumulation of mature B lymphocytes which have escaped apoptosis. Lymphocytes accumulate in bone marrow and then spread to lymphoid tissues causing hepatosplenomegaly. Abnormal haemolysis can occur causing anaemia

Answer 164

- Signs - Lymphadenopathy - Hepatosplenomegaly: neoplastic cells invade the liver and spleen - Pallor - Symptoms - Fatigue - Loss of appetite - Weight loss - Fever - Easy bruising and bleeding: due to thrombocytopaenia - Recurrent infections: due to hypogammaglobulinaemia - Abdominal fullness: due to hepatosplenomegaly - Localised pain at lymph nodes: due to lymphadenopathy

Answer 165

- FBC: lymphocytosis - Thrombocytopaenia and anaemia may also be seen as leukaemic cells infiltrate the bone marrow - Blood film: increased number of premature lymphocytes and **smudge cells** (immature B cells that have broken during the smear). - Immunophenotype: CD5, CD19, CD20, CD23 -Immunoglobulins: hypogammaglobulinemia - Genetic analysis: identify chromosomal deletions, e.g. del 17p, which helps guide treatment

Answer 166

- Bone marrow biopsy: increased number of mature lymphocytes and few immature cells. Not necessary for a diagnosis - Lymph node biopsy: conduct if lymphadenopathy is present - Chest x-ray may show infection or mediastinal lymphadenopathy - CT, MRI and PET scans can be used for staging and assessing for lymphoma and other tumours - Coombs’ test: also known as the direct antiglobulin test (DAT). Conducted if an autoimmune haemolytic anaemia is suspected - Lactate dehydrogenase (LDH) often raised in leukaemia but is not specific to leukaemia

Answer 167

Differential diagnosis of bleeding and bruising: - Meningococcal septicaemia - Vasculitis - Henoch-Schonlein Purpura (HSP) - Idiopathic Thrombocytopenia Purpura (ITP) - Non-accidental injury

Answer 168

- Early-stage disease - Monitor: blood counts and clinical examinations carried out every 3-12 months - Evidence shows chemotherapy in early-stage disease does not confer a survival advantage - Active and/or advanced disease The management is dependent on chemotherapeutic agents and some regimes are listed below: - FCR: fludarabine, cyclophosphamide and rituximab are used in patients with good performance status - Chlorambucil and rituximab: used in patients with poor performance status - Other chemotherapeutic agents: tyrosine kinase inhibitors, such as ibrutinib, are considered in those with del(17p) - Allogenic stem cell transplant: considered in a specific subset of patients with a good performance status

Answer 169

Complications secondary to chemotherapy: - Myelosuppression and neutropaenic sepsis: lower risk compared to acute leukaemias - Gout: an increased turnover of cells results in the release of uric acid which can deposit in joints as urate crystals. Lower risk compared to acute leukaemias - Tumour lysis syndrome: lower risk compared to acute leukaemias - Infections due to immunodeficiency - Neurotoxicity - Infertility - Secondary malignancy - Cardiotoxicity

Answer 170

- Hypogammaglobulinaemia: dysfunctional neoplastic B cells exhibit impaired immunoglobulin production - Autoimmune haemolytic anaemia: occurs in up to 25% of patients and most typically is of the warm subtype - The mechanism is thought to involve neoplastic cells inducing normal B cells to release autoantibodies - Richter transformation: transformation into a non-Hodgkin lymphoma, most commonly a diffuse large B-cell lymphoma. Presents with rapidly progressing lymphadenopathy, B-symptoms (fever, night sweats, weight loss), and a raised lactate dehydrogenase (LDH)

Answer 171

5-year survival is 70-75% and early-stage disease is associated with a median survival of over 10 years. However, Richter transformation occurs in 2-8% of cases and is associated with a poor prognosis.

Answer 172

B- cell development begins in the bone marrow, which is a primary lymphoid organ. Here, young precursor B-cells mature into naive B-cells The naive B-cells then leave the bone marrow and circulate in the blood and eventually settle down in lymph nodes (secondary lymphoid organs). Each lymph node has B-cells which group together in follicles in the cortex or outer part of the lymph node, along with T-cells in the paracortex just below the cortex. B-cells differentiate into plasma cells, which are found in the medulla or centre of the lymph nodes. Plasma cells release antibodies or immunoglobulins. Antibodies bind to pathogens to help destroy or remove them. Various immune cells, including B-cells have surface proteins e.g. CD19 or CD21. A B-cell is activated when it encounters an antigen that binds to its surface immunoglobulin. Some of these activated B-cells mature directly into plasma cells and produce IgM antibodies. Other activated B-cells go to the centre of a primary follicle in the lymph node and they differentiate into B-cells called centroblasts and start to quickly proliferate or divide. These proliferating centroblasts form a germinal center, located in the center of the follicle of the lymph node. These centroblasts have a rearrangement of their immunoglobulin genes, and some of them undergo a class switch where they change from producing IgM antibodies to producing IgG or IgA antibodies. Within the germinal center, centroblasts mature into centrocytes; and the centrocytes that make antibody with high affinity for the antigen, differentiate into either plasma cells which go to the medulla of the lymph node, or memory B-cells which circulate in the blood and reside in lymph nodes, spleen, and mucosa-associated lymphoid tissue, also called MALT.

Answer 173

Lymphoma is a lymphoproliferative disorder (specifically B-cells) which can be divided into Hodgkin and Non-Hodgkin Lymphoma. The differentiating factor between the two is the presence of pathognomonic Reed-Sternberg cells in Hodgkin lymphoma

Answer 174

- HL is a rare malignancy. - In the UK, there were 2107 new cases of HL between 2015 and 2017, accounting for < 1% of total cancer cases. - Bimodal age distribution: 15-35 years and > 60 years - M>F

Answer 175

- Bimodal age distribution: 15-35 years and > 60 years - EBV infection: mixed cellularity subtype - HIV infection: lymphocyte-deplete subtype - Autoimmune conditions such as rheumatoid arthritis and sarcoidosis - Family history

Answer 176

The difference between Hodgkin's and non-Hodgkin's Lymphoma is the presence of pathognomonic Reed-Sternberg cells in Hodgkin lymphoma. These are large B cells with prominent ‘owl’s eye nuclei’ which secrete inflammatory cytokines and attract reactive inflammatory cells, resulting in ‘B symptoms’.

Answer 177

Mutation of B lymphocytes leading to the presence of large, multi-nucleated giant cells called Reed-Sternberg cells and large mono-nucleated cells called malignant Hodgkin cells.

Answer 178

- Lymphadenopathy (may be cervical, axillary, or inguinal) - Painless - Hard - Rubbery - Fixed - Contiguous spread (to nearby nodes) unlike in NHL - Splenomegaly: rarer compared to NHL - Symptoms - B symptoms: occur in around 30% of cases - Fever - Weight loss - Night sweats - Pel-Ebstein fever: an intermittent fever every few weeks - Alcohol-induced lymph node pain - Pruritus - Dyspnoea: due to mediastinal lymphadenopathy

Answer 179

- FBC: may demonstrate leukocytosis but can also present with pancytopaenia if the bone marrow is involved - LDH: often elevated and may be used to monitor treatment response and recurrence - Ultrasound of lymph nodes: an initial ultrasound of the lymph node region will indicate whether there are any concerning features of malignancy - Excisional lymph node biopsy: this is diagnostic and will show the presence of multinucleated Reed-Sternberg cells (Owl’s eye nuclei), indicating HL. The exact histological pattern depends on the subtype. - Staging imaging: chest X-ray, CT neck, chest and abdomen, and PET scan are all conducted to evaluate the extent of the disease - Immunophenotyping: Reed-Sternberg cell is CD15 and CD30 positive, in classical HL.

Answer 180

Lymph node biopsy (Reed-Sternberg cells – multi-nucleated giant cells with an owl face appearance)

Answer 181

Stage 1 - involvement of a single lymph node region Stage 2 - involvement of 2 or more lymph node regions on the same side of the diaphragm Stage 3 - involvement of lymph node regions or structures on both sides of the diaphragm Stage 4 - diffuse involvement of one or more extralymphatic organs

Answer 182

Depends on stage, severity, age etc - Chemotherapy - Radiotherapy: usually administered after completing a number of cycles of chemotherapy - Rituximab: monoclonal antibody targets CD20 on lymphocytes and is used in CD20+ lymphoma, i.e. nodular lymphocyte-predominant HL (atypical). It is often used alongside chemotherapy and/or radiotherapy

Answer 183

Complications secondary to chemotherapy: - Myelosuppression and neutropaenic sepsis: must be considered in any patient on chemotherapy presenting with a fever. Management will require broad-spectrum antibiotics, such as tazocin, and isolation - Tumour lysis syndrome: treatment with chemotherapy causes rapid cell destruction leading to hyperkalaemia, hyperphosphatemia, hyperuricemia, and hypocalcaemia. This can cause seizures, arrhythmias, and renal failure Complications secondary to HL: - Impaired immunity: impaired cell-mediated immunity due to dysfunctional lymphoid tissue means that patients are prone to recurrent infections

Answer 184

The prognosis is dependent on the stage and histological subtype. Early-stage disease has a 5-year survival of 90%. However, in advanced disease, this reduces to 75%. Lymphocyte-rich HL has the best prognosis, whilst lymphocyte-depleted HL is associated with the poorest prognosis. Other poor prognostic factors include age over 45 years, male gender, stage IV disease, Hb <10.5 g/dL, WCC >15,000/µl, lymphocyte count < 600/µl or < 8%, and albumin <40 g/L

Answer 185

T-cell development starts in the thymus from precursors that arise in the bone marrow. In the thymus, these precursor T-cells mature and express either CD4 on helper T-cells or CD8 on cytotoxic T-cells. Mature T-cells circulate in the blood and are found in the paracortex of the lymph nodes.

Answer 186

Lymphoma is a lymphoproliferative disorder (B and T-cells) which can be divided into Hodgkin (HL) and Non-Hodgkin lymphoma (NHL). The differentiating factor between the two is the presence of Reed-Sternberg cells found in Hodgkins Lymphoma. Lymphoma differs from leukaemia in that neoplastic cells predominantly involve the lymph nodes and extranodal sites, unlike leukaemia which predominantly involves the bone marrow and blood.

Answer 187

- NHL is far more common than HL - Diffuse large B-cell lymphoma is the most common haematological malignancy overall - B-cell lymphomas are more common than T-cell lymphomas

Answer 188

- Age: >50 years - Male - Family history - Infection: HIV, HTLV-1, EBV, H.pylori, Hep B and C - Autoimmunity: Hashimoto's thyroiditis and Sjogren’s syndrome are implicated in marginal zone lymphoma - Immunodeficiency: HIV as well as hereditary immunodeficiency syndromes, e.g. Wiskott-Aldrich syndrome - Exposure to pesticides and a specific chemical called trichloroethylene used in several industrial processes

Answer 189

- In non-Hodgkin lymphoma, there is usually a genetic mutation in a lymphocyte - either a B- or a T-cell. Instead of undergoing apoptosis, they divide uncontrollably becoming a neoplastic cell. - Lymphomas are cancers of lymphocytes in the lymphatic system, causing proliferation of lymphocytes in lymph nodes. Hodgkin’s lymphoma is a specific disease. Non-Hodgkin’s lymphoma is all the other lymphomas (no Reed-Sternberg cells).

Answer 190

By cell types (proliferation of B cells, T cells or NK cells) and grade (high or low)

Answer 191

- Signs - Lymphadenopathy - Painless - Hard - Rubbery - Fixed - Non-contiguous spread unlike in HL - Splenomegaly: more common in NHL compared to HL - Extranodal disease: bone marrow, thyroid, salivary gland, GI tract, CNS - Symptoms - B symptoms: - Fever - Weight loss - Night sweats - Related to extranodal involvement: - GI tract: bowel obstruction - Bone marrow: fatigue, easy bruising, or recurrent infections - Spinal cord: weakness and a loss of sensation - usually in the legs

Answer 192

- FBC: may demonstrate leukocytosis but can also present with pancytopenia if the bone marrow is involved - Blood film: certain lymphomas, such as hairy cell leukaemia, are associated with a characteristic blood film finding - LDH and uric acid: often elevated and used as prognostic markers - Ultrasound of lymph nodes: an initial ultrasound of the affected lymph nodes will indicate whether there are any concerning features of malignancy e.g. disruption of normal morphology - Excisional lymph node biopsy: this is diagnostic and will show distorted lymph node architecture - Skin biopsy: useful if a T-cell lymphoma is suspected - Bone marrow biopsy: useful in staging disease

Answer 193

- Staging imaging: CT neck, chest, abdomen and pelvis and/or PET-CT are usually the methods of choice - Genetic testing: assess for chromosomal translocations - Immunophenotype: determine if the neoplasm is from the B cell or T cell lineage through assessing cell surface markers

Answer 194

Dependent on staging, severity, age etc - Chemotherapy e.g. RCHOP, R-CVP, RCODOX-M - Radiotherapy - Rituximab: monoclonal antibody targets CD20 on lymphocytes and is used in CD20+ lymphoma - Stem cell transplant - Antibiotics, if any infection e.g. H.pylori eradication in gastric MALToma

Answer 195

Complications secondary to chemotherapy: - Myelosuppression and neutropenic sepsis: must be considered in any patient on chemotherapy presenting with a fever. Management will require broad-spectrum antibiotics, such as tazocin, and isolation - Tumour lysis syndrome: treatment with chemotherapy causes rapid cell destruction leading to hyperkalaemia, hyperphosphatemia, hyperuricemia, and hypocalcaemia. This can cause seizures, arrhythmias, and renal failure Complications secondary to NHL: - Impaired immunity: impaired cell-mediated immunity due to dysfunctional lymphoid tissue means that patients are prone to recurrent infections

Answer 196

The prognosis depends on the subtype of NHL. Overall 5-year survival is approximately 70%. In general, high-grade lymphomas are curable, unlike low-grade lymphomas. However, high-grade lymphomas are more aggressive as cells divide quickly. Poor prognostic factors include: - Age >60 years - Stage III or IV - Extranodal disease - Poor performance status - High LDH

Answer 197

Myeloma describes the malignant monoclonal proliferation of plasma cells in the bone marrow, resulting in the production of various types of monoclonal proteins, most commonly immunoglobulins (usually IgG and IgA) and free light chains. Multiple myeloma is where the myeloma affects multiple areas of the body.

Answer 198

- The median age of diagnosis is 72 years in Europe - More common in Afro-Caribbeans than caucasians

Answer 199

- Increasing age: the incidence rises steeply from around age 65 to 69 - Monoclonal gammopathy of uncertain significance (MGUS): a pre-malignant, asymptomatic, plasma cell disorder characterised by an excess of monoclonal protein. The risk of progressing to myeloma is 1% per year. - Smouldering myeloma: progression of MGUS with higher levels of antibodies or antibody components. More likely to progress to myeloma than MGUS - Family history - Male - Black African ethnicity - Radiation exposure

Answer 200

There is an excess of plasma cell formation during haematopoiesis. This also leads to the formation of abnormal antibodies (only consisting of light chains rather than a light and heavy chain). These are known as paraproteins. Myeloma differs from leukaemias and lymphomas as the malignant cell in myeloma is the plasma cell, rather than the lymphoblast. Furthermore, in myeloma, light chains can form amyloid proteins, resulting in amyloidosis. The pathogenesis underlying the symptoms can be remembered with the mnemonic, CRAB: - Calcium: hypercalcaemia is caused by neoplastic cells releasing cytokines (e.g. IL-1), causing activation of osteoclasts via the RANK receptor. There is also osteoblastic suppression from stromal cells. This leads to bone resorption, resulting in bone pain and lytic lesions on imaging - Renal insufficiency: this is caused by the deposition of light chains (Bence Jones proteins) in the kidney tubules disrupting renal function. Additionally, nephrocalcinosis (calcium deposition in the renal parenchyma) also causes renal failure - Anaemia: bone marrow infiltration by plasma cells results in reduced haematopoiesis and subsequent anaemia, as well as thrombocytopaenia and leukopaenia - Bone lesions: bone lesions, fractures and pain are caused by osteoclast activation and osteoblastic suppression which leads to bone breakdown. Common places for myeloma bone disease to happen are the skull, spine, long bones and ribs.

Answer 201

- Signs - Pallor: due to anaemia - Signs due to amyloidosis: - Macroglossia - Carpal tunnel syndrome: Tinel’s and Phalen’s sign positive - Peripheral neuropathy - Symptoms - Related to hypercalcaemia: - Bones: bony pain with back pain being common - Stones: renal stones and renal colic - Abdominal groans: abdominal pain and constipation - Thrones: urinary frequency - Psychiatric overtones: confusion, depression, psychosis - Related to anaemia: - Fatigue - Related to thrombocytopaenia: - Bleeding and bruising - Related to a reduction in normal immunoglobulins: - Recurrent infections

Answer 202

- Urine electrophoresis: Bence-Jones proteins, which are immunoglobulin (monoclonal) light chains - Serum electrophoresis: paraprotein band, or ‘M’ spike (usually IgG or IgA) - Bone marrow aspirate and trephine biopsy: ≥ 10% plasma cell infiltration. - FBC and blood film: anaemia due to disrupted erythropoiesis. - U&Es: renal failure - Bone profile: hypercalcaemia and raised ALP - Beta-2-microglobulin: a higher concentration is associated with poorer prognosis - Imaging: conducted to ascertain bone marrow infiltrative lesions - Whole-body MRI: first-line imaging; CT is second-line - Skeletal survey (whole-body X-ray): used historically, but less frequently now - X-rays: ‘raindrop skull’ due to lytic lesions is a characteristic finding; it differs subtly from ‘pepperpot’ skull seen in hyperparathyroidism

Answer 203

Bone marrow plasma cells ≥ 10% (or biopsy-proven bony / extramedullary plasmacytoma) AND a myeloma-defining event Myeloma defining event: one or more biomarkers - bone marrow plasma cells >=60% - >1 focal lesion on MRI - Involved:uninvolved serum free light chain ratio >=100 OR evidence of end-organ damage: CRAB - hypercalcaemia - renal insufficiency - anaemia - bone lesions

Answer 204

- MGUS - Smouldering myeloma - Solitary plasmacytoma - Amyloidosis

Answer 205

1st line – chemotherapy with thalidomide and dexamethasone bortezomib. Venous thromboembolism prophylaxis while on chemo. Stem cell transplant. Myeloma bone disease – bisphosphonates to suppress osteoclast activity, analgesics, radiotherapy

Answer 206

- Myelosuppression and neutropaenic sepsis: must be considered in any patient on chemotherapy presenting with a fever. Management will require broad-spectrum antibiotics, such as tazocin, and isolation - Recurrent infections: due to dysfunctional plasma cells; offer annual influenza vaccination and consider offering pneumococcal vaccination to under 65s. IVIg may be required - Pancytopenia: due to bone marrow infiltration - Fatigue: may require erythropoietin analogues in symptomatic anaemia - AL amyloidosis: can have a multitude of effects including renal failure, carpal tunnel syndrome, peripheral neuropathy, or cardiomyopathy (dilated or restrictive) - Plasmacytoma: individual tumours made up of the cancerous plasma cells - Pathological fracture: a significant cause of morbidity and mortality, particularly vertebral fractures due to osteolytic lesions; prevented with zoledronate - Renal failure - Hyperviscosity: headaches, neurological symptoms, VTE, easy bruising and bleeding, loss of sight due to vascular disease in the eye, heart failure - Chronic pain: requires analgesia as per WHO analgesic ladder and NICE guidance

Answer 207

Myeloma is an incurable disease and patients inevitably relapse a few years post-treatment. Poor prognostic factors: - Raised LDH - Raised beta-2-microglobulin - Reduced albumin - Specific chromosomal abnormalities, e.g. del(17p)

Answer 208

- Malaria begins when a plasmodium-infected female Anopheles mosquito hunts for a blood meal. - At this point, the Plasmodium is in a stage of development called a sporozoite, in the mosquito’s salivary gland. - When the mosquito pierces a person’s skin with its proboscis, the sporozoites spill out of the mosquito’s saliva and make it into the bloodstream.

Answer 209

Malaria is a parasitic infection caused by protozoa of the genus Plasmodium.

Answer 210

- Malaria is a serious global health problem that affects millions of people, particularly: - Young children under the age of 5 - Pregnant women - Patients with other health conditions like HIV and AIDS - Travellers who have had no prior exposure to malaria - Prevalent in tropical and subtropical regions e.g. latin america, sub-saharan africa, south asia, and southeast asia. - Certain conditions e.g. sickle cell anaemia, thalassaemia and G6PD deficiency are thought to be protective against malaria - The most severe and dangerous member of the family is Plasmodium falciparum. This accounts for about 75% of the cases of malaria in the UK.

Answer 211

- Protozoa of the plasmodium genus: - Plasmodium falciparum - Plasmodium vivax - Plasmodium malariae - Plasmodium ovale - Plasmodium knowlesi

Answer 212

Malaria is spread through bites from the female Anopheles mosquitoes that carry the disease. Once the plasmodium gets into the bloodstream, it starts to infect and destroy mainly liver cells and red blood cells, which causes a variety of symptoms and sometimes even death. Malaria takes a blood meal, infected blood is taken up by mosquito and transformed to sporozoites in the gut. Mosquito bites another human and injects sporozoites. Sporozoites travel to the liver of the newly infected person. They can lie dormant for several years as hypnozoites in p. vivax and p. ovale. The mature in the liver to merozoites which enter the blood and infect RBCs. Merozoites > trophozoites >schizont. RBCs rupture causing haemolytic anaemia and systemic infection.

Answer 213

Plasmodium falciparum is known for causing the worst infections. Most plasmodium-infected red blood cells get screened and destroyed by the spleen. Plasmodium falciparum avoids this fate by generating a sticky protein that coats the surface of the infected red blood cells. The protein causes the red blood cells to clump together and occlude tiny blood vessels - a process called cytoadherence. This blocks the flow of blood so that infected cells aren’t able to flow into the spleen, and it also blocks blood flow from reaching other vital organs which can cause ischaemia. This can eventually lead to organ failure (refer to complications). This is known as complicated malaria.

Answer 214

- Signs - Pallor: due to anaemia - Jaundice: due to unconjugated bilirubin from destruction of RBCs - Hepatosplenomegaly: due to compensation for anaemia - Symptoms - Fever, sweats and rigors (occurs in spikes) - Fatigue: due to anaemia - Headaches - Myalgia - Vomiting

Answer 215

- FBC, U&E, LFT: thrombocytopenia, elevated lactate dehydrogenase levels due to haemolysis, and normochromic, normocytic anaemia - Malaria blood film: will show the parasites, the concentration and also what type they are.

Answer 216

Non-falciparum = chloroquine Falciparum: non-complicated = chloroquine/hydroxychloroquine. Complicated = artesunate, quinine sulfate

Answer 217

- Full body clothing - Mosquito repellent - Sleeping in insecticide covered mosquito nets - Indoor insecticide sprays - Clean water - Use antimalarials e.g. malarone, mefloquine, doxycycline

Answer 218

- Complicated malaria due to plasmodium falciparum: - Cerebral malaria: altered mental status, seizures and coma - Bilious malaria: diarrhoea, vomiting, jaundice and liver failure - Acute kidney injury - Pulmonary oedema - Disseminated intravascular coagulopathy (DIC) - Severe haemolytic anaemia - Multi-organ failure and death

Answer 219

Zika virus, yellow fever, COVID-19

Answer 220

Primary polycythaemia – polycythaemia vera caused by JAK2 mutation. Secondary – caused by hypoxia, increased erythropoietin, dehydration (alcohol)

Answer 221

Proliferation of the erythrocyte cell line. Increase in RBC count and haematocrit

Answer 222

- The peak incidence of PCV is 50-70 years old - It is slightly more common in men

Answer 223

Requires both criteria: A1: raised haematocrit (>0.52 in men or >0.48 in women) OR raised red cell mass (>25% above predicted). A2: Mutation in JAK2

Answer 224

A non-receptor tyrosine kinase that is involved in the control of cellular growth and proliferation.

Answer 225

- Age > 40 years - Family history - JAK2 mutation

Answer 226

Normally, kidneys produce erythropoietin which activates JAK2 gene on haematopoietic stem cells, causing cell to divide and produce more RBCs. mutation in JAK2 gene means it is always activated so it produces more RBCs without erythropoietin.

Answer 227

Conjunctival plethora (excessive redness of conjunctiva), splenomegaly, “ruddy” complexion (like sunburn), itching skin especially after warm water, erythromelalgia (burning sensation in fingers and toes)

Answer 228

Signs: Prone to clotting (stroke, MI, DVT), blurred visions Symptoms: Fatigue, dizziness, sweating, headache

Answer 229

Genetic testing (JAK2 mutation)

Answer 230

FBC (raised Hb, haematocrit, WCC, platelets), low erythropoietin

Answer 231

1st line – venesection/phlebotomy (removes blood to keep Hb in a normal range) Myelosuppressive medication – hydroxycarbamide/hydroxyurea or JAK2 inhibitor. Aspirin to prevent clotting.

Answer 232

Risk of clotting (stroke, MI, PE, Budd Chiara – liver clot), progression to acute myeloid leukaemia

Answer 233

Secondary polycythaemia to hypoxia, alcohol, erythropoietin

Answer 234

- After damage to the endothelium, there’s an immediate vasoconstriction which limits the amount of blood flow. - After that some platelets adhere to the damaged vessel wall, and become activated and then recruit additional platelets to form a plug. This is known as primary haemostasis. - After that, the coagulation cascade is activated. There are a set of clotting factors, most of which are proteins synthesised by the liver, and usually these are inactive. The coagulation cascade starts when one of these proteins gets proteolytically cleaved. - This active protein then proteolytically cleaves and activates the next clotting factor, and so on. - The final step is activation of the protein fibrinogen to fibrin, which deposits and polymerises to form a mesh around the platelets. This is known as secondary haemostasis. - The coagulation cascade is started in one of two ways: - The extrinsic pathway: starts when tissue factor gets exposed by the injury of the endothelium. - The intrinsic pathway: starts when platelets near the blood vessel injury activate factor XII into factor XIIa

Answer 235

Haemophilia A and haemophilia B are inherited severe bleeding disorders.

Answer 236

Almost exclusively affects males (X-linked recessive)

Answer 237

- Inherited - Acquired: - Liver failure - Vitamin K deficiency - Autoimmunity against a clotting factor - Disseminated intravascular coagulation

Answer 238

In most cases of haemophilia there is a decrease in the amount or function of one or more of the clotting factors which makes secondary haemostasis less effective and allows more bleeding to happen. Haemophilia A is caused by a deficiency in factor VIII. Haemophilia B (also known as Christmas disease) is caused by a deficiency in factor IX. Haemophilia usually refers to inherited deficiencies of coagulation factors, which could be either quantitative or qualitative. The mutated genes in haemophilia A are called F8, and in haemophilia B they’re called F9. These are both on the X chromosome. There are also many acquired causes: - Liver failure: as the liver is responsible for many of the clotting factors - Vitamin K deficiency: as vitamin K is needed by many enzymes to synthesise a lot of the clotting factors - Autoimmunity against a clotting factor - Disseminated intravascular coagulation

Answer 239

- Abnormal bleeding: - Gums - Gastrointestinal tract - Urinary tract causing haematuria - Retroperitoneal space - Intracranial - Following procedures - Excessive bleeding - Ecchymosis: easy bruising - Spontaneous haemorrhage - Haematomas: collections of blood outside the blood vessels - Haemoarthrosis: bleeding into joint

Answer 240

- Diagnosis is based on bleeding scores, coagulation factor assays and genetic testing. - Platelets count: usually normal - Prothrombin time: tests the extrinsic and common pathway and so is normal - Activated partial thromboplastin time: tests the intrinsic and common pathways, usually prolonged

Answer 241

- Von Willebrand Disease: can present similarly to haemophilia - Platelets dysfunction

Answer 242

- Avoid contact sports and medicines that promote bleeding e.g. aspirin - IV infusion of deficient clotting factor (either prophylactic or in response to bleeding) - Complication: if patients initially had very low levels of the clotting factor, the immune system might mount an attack against the IV clotting factors, potentially leading to anaphylaxis - Desmopressin: to stimulate the release of von Willebrand Factor - Antifibrinolytics e.g. tranexamic acid

Answer 243

- Bleeds into the brain are a dangerous complication: can cause a stroke or increased intracranial pressure - Haemarthrosis: can cause problems with joints

Answer 244

- vWf plays a key role in forming clots. - It is synthesised and stored in the endothelial cells and megakaryocytes. - Synthesis is regulated by von Willebrand gene on chromosome 12. - When there is injury, histamine and thrombin stimulate the endothelial cells and megakaryocytes to produce vWF. - vWf then attaches to the exposed collagen fibres, which allows platelets to adhere. - In addition to this, vWF is also needed as a carrier for factor VIII and protects it from degradation.

Answer 245

Von Willebrand disease (VWD) is the most common inherited cause of abnormal bleeding. It is usually due to a reduced quantity or reduced quality of von Willebrand factor.

Answer 246

Family history

Answer 247

There are many different underlying genetic causes, most of which are autosomal dominant. The causes involve a deficiency, absence or malfunctioning of von Willebrand factor (VWF). There are three types based on the underlying cause and ranging from type 1 to type 3. Type 3 is the most severe. - Type I: most common, autosomal dominant condition and can lead to reduced or defective production of vWF - Type II: quantity of vWF is fine but quality is affected. 4 sybtypes - A: vWF can attach to collagen and factor VIII, but unable to bind platelets - B: vWF binds to platelets in the bloodstream, without injury. These platelets are cleared by the liver and spleen causing thrombocytopenia - M: vWF can attach to collagen and factor VIII, but unable to bind platelets - N: vWF binds to collagen and platelets, but not to factor VIII - Type III: rarest and most severe, autosomal recessive, individuals may have no vWF factor! von Willebrand disease may also be acquired: - Autoimmune conditions e.g. SLE - Certain drugs e.g. valproic acid, cirpofloxacin

Answer 248

- Easy, prolonged or heavy bleeding e.g. - Bleeding gums with brushing - Nose bleeds (epistaxis) - Heavy menstrual bleeding (menorrhagia) - Heavy bleeding during surgical operations - Easy bruising - Severe cases: - Joint bleeding - Muscle bleeding - GI bleeding

Answer 249

Diagnosis is based on a history of abnormal bleeding, family history, bleeding assessment tools and laboratory investigations. - Platelets count: usually normal except in type IIB - Prothrombin time: tests the extrinsic and common pathway and so is normal - Activated partial thromboplastin time: tests the intrinsic and common pathways, usually prolonged - Measurement of vWF antigen

Answer 250

Management is required either in response to major bleeding or trauma (to stop bleeding) or in preparation for operations (to prevent bleeding): - Desmopressin: can be used to stimulates the release of VWF - VWF can be infused - Factor VIII is often infused along with plasma-derived VWF - Management of women with heavy periods Managed by a combination of: - Tranexamic acid (antifibrinolytic agent) - Mefanamic acid - Norethisterone - Combined oral contraceptive pill - Mirena coil Hysterectomy may be required in severe cases.

Answer 251

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterised by activation of coagulation pathways, resulting in formation of intravascular thrombi and depletion of platelets and coagulation factors.

Answer 252

- Disseminated intravascular coagulation describes a situation in which the process of haemostasis starts to run out of control. - Normally, the formation of new clots and the process of fibrinolysis are in a steady balance. In serious medical conditions e.g. sepsis, malignancy, serious trauma, obstetric complications, or intravascular haemolysis, there can be a release of a procoagulant e.g. tissue factor, that tips the scales in favour of clot formation. - When this occurs, lots of blood clots start to form in blood vessels serving various organs, leading to ischaemia, necrosis, and eventually organ damage. - DIC is also known as consumption coagulopathy, because the excess clotting consumes platelets and clotting factors. - Without enough platelets circulating in the blood, other parts of the body begin to bleed with even the slightest damage to the blood vessel walls. - To make things worse, as the clots are broken down through fibrinolysis, fibrin degradation products are released into the circulation and these interfere with platelet aggregation and clot formation, making haemostasis even more difficult. - So paradoxically, patients have too much and too little clotting. - In some cases, disseminated intravascular coagulation can be a more chronic process e.g. in individuals with certain solid tumours and large aortic aneurysms. In these situations, there may be physiologic compensation making the lab results look relatively normal.

Answer 253

- Patient is often acutely ill and shocked - Bleeding may occur from the mouth, nose and venepuncture sites and there may be widespread ecchymoses - Confusion - Bruising - Thrombotic events occur as a result of vessel occlusion by fibrin and platelets - any organ may be involved but the skin, brain and kidneys are most affected

Answer 254

Diagnosis can be suggested from history e.g severe sepsis, trauma or malignancy, clinical presentation and thrombocytopenia - Platelet count: low - Fibrinogen: low - D-dimer: breakdown product of fibrin, raised - Prothrombin time: prolonged - Partial thromboplastin time: prolonged

Answer 255

- Treat underlying cause - Supportive measures for complications - Replacement of platelets with transfusion - Fresh Frozen Plasma (FFP) to replace the coagulation factors - Cryoprecipitate to replace fibrinogen and some coagulation factors - Red cell transfusion in patients who are bleeding - Other e.g. ventilator support

Answer 256

Thrombocytopenia describes a low platelet count. The normal platelet count is between 150 to 450 x 109/L.

Answer 257

Causes of thrombocytopenia can be split into - Problems with production - Sepsis - B12 or folic acid deficiency - Liver failure causing reduced thrombopoietin production in the liver - Bone marrow suppression - Leukaemia - Myelodysplastic syndrome - Splenic sequestration - In liver cirrhosis, portal hypertension causes blood to back up into the spleen, causing congestive splenomegaly. - The spleen physically enlarges and also starts to hyperfunction - hypersplenism. - Here, the spleen generously allows up to 90 percent of the total platelets in, which means that nearly none are left in the blood. - Problems with destruction - Non-immune - Thrombotic thrombocytopenic purpura - Haemolytic Uraemic Syndrome - Disseminated Intravascular Coagulopathy (DIC) - Immune - Immune thrombocytopenic purpura - Heparin-induced thrombocytopenia - Other causes include: - Medications (sodium valproate, methotrexate, isotretinoin, antihistamines, proton pump inhibitors) - Alcohol

Answer 258

- A mild thrombocytopenia may be asymptomatic and found incidentally on a full blood count. - Platelet counts below 50 x 109/L will result in easy or spontaneous bruising and prolonged bleeding times. They may present with nosebleeds, bleeding gums, heavy periods, easy bruising or blood in the urine or stools. - Platelet counts below 10 x 109/L are high risk for spontaneous bleeding. Spontaneous intracranial haemorrhage or GI bleeds are particularly concerning.

Answer 259

- Platelet concentration can fall as a result of large volume transfusions of platelet-free products - Pseudothrombocytopenia: clotting of platelet factors can falsely make platelet count appear low - Haemophilia A and haemophilia B - Von Willebrand Disease

Answer 260

ITP is a condition where antibodies are created against platelets. This causes an immune response against platelets, resulting in the destruction of platelets and a low platelet count. Also known as autoimmune thrombocytopenic purpura, idiopathic thrombocytopenic purpura and primary thrombocytopenic purpura.

Answer 261

- Primary ITP: when ITP occurs by itself - Secondary ITP: triggered by another condition e.g. hepatitis C, HIV, or lupus

Answer 262

ITP is caused by autoantibodies that bind to the platelet receptor Gp2B3A, and target platelets for destruction in the spleen. ITP is like the platelet equivalent of autoimmune haemolytic anemia. Some patients develop both conditions together - Evan’s syndrome.

Answer 263

- Most of the time, ITP is asymptomatic, but in severe cases it can cause: - Petechiae - Purpura (red or purple spots on the skin caused by bleeding underneath skin) - Easy bruising - Epistaxis (nose bleed) - Menorrhagia (heavy menstruation) - Gum bleeding - Major haemorrhage is rare - Splenomegaly is rare

Answer 264

- FBC: isolated thrombocytopenia, with a normal haematocrit and leukocyte count - Blood film: - Megakaryocytes start releasing large platelets, which makes the mean platelet volume increase - Minority of patients who have concurrent autoimmune haemolytic anemia, there can be spherocytes present - Platelet autoantibodies (present in 60-70%) - not needed for diagnosis - Abdominal ultrasound can be done to rule out splenomegaly, and hepatitis C virus and HIV, since ITP is being triggered by those infections.

Answer 265

- Secondary ITP: treat underlying cause - Prednisolone (steroids) - IV immunoglobulins - Rituximab (a monoclonal antibody against B cells) - Splenectomy - Vaccinations should be arranged for patients undergoing a splenectomy - Additional measures such as carefully controlling blood pressure and suppressing menstrual periods are also important.

Answer 266

The platelet count needs to be monitored and the patient needs education about concerning signs of bleeding such as persistent headaches and melaena and when to seek help.

Answer 267

TTP is a condition where tiny blood clots develop throughout the small vessels of the body using up platelets and causing thrombocytopenia, bleeding under the skin and other systemic issues. It affect the small vessels so it is described as a microangiopathy.

Answer 268

The blood clots develop due to a problem with a specific protein called ADAMTS13 (there can be a genetic deficiency of ADAMTS-13, or an autoantibody against ADAMTS-13). This protein normally inactivates von Willebrand factor and reduces platelet adhesion to vessel walls and clot formation. A shortage in this protein leads to von Willebrand factor overactivity and the formation of blood clots in small vessels. This causes platelets to be used up leading to thrombocytopenia. The blood clots in the small vessels break up red blood cells, leading to haemolytic anaemia. Deficiency in the ADAMTS13 protein can be due to an inherited genetic mutation or due to autoimmune disease where antibodies are created against the protein.

Answer 269

Patients classically develop five symptoms: - Thrombocytopenia - Microangiopathic hemolytic anaemia - Fatigue - Fever - Renal insufficiency: which can cause haematuria and decreased urine output; and neurologic symptoms like headache and confusion.

Answer 270

- FBC: thrombocytopenia and normocytic normochromic anaemia - Blood film: schistocytes (fragmented red blood cells) - Unconjugated bilirubin: raised - Lactate dehydrogenase: raised - Haptoglobin levels: decreased, because haptoglobin binds to free haemoglobin in the circulation - Creatinine levels: may be elevated if there is kidney damage - Coombs test: checks for immune mediated causes, negative - Prothrombin time: normal - Partial thromboplastin time: normal

Answer 271

- Plasma exchange: gets rid of the patient’s plasma along with all of the large von willebrand factor multimers, and replaces it with new plasma - Steroids - Rituximab (a monoclonal antibody against B cells).

Answer 272

Heparin induced thrombocytopenia (HIT) involves the development of antibodies against platelets in response to exposure to heparin.

Answer 273

Heparin induced antibodies specifically target a protein on the platelets called platelet factor 4 (PF4). These are anti-PF4/heparin antibodies. The HIT antibodies bind to platelets and activate clotting mechanisms. This causes a hypercoagulable state and leads to thrombosis. They also break down platelets and cause thrombocytopenia. Therefore there is an unintuitive situation where a patient on heparin with low platelets forms unexpected blood clots. Patients are more at risk when taking unfractionated heparin as opposed to LMWH heparin.

Answer 274

- Some patients develop life-threatening thrombotic events, which are most often venous - causing deep vein thrombosis, pulmonary embolism, or cerebral venous sinus thrombosis or less often arterial - causing limb gangrene, stroke, or myocardial infarction. - Other patients simply have thrombocytopenia on a FBC.

Answer 275

- FBC: thrombocytopenia - Check for HIT antibodies

Answer 276

Stopping use of heparin and using an alternative anticoagulant

Answer 277

Haemoglobin is made up of four globin chains, each bound to a heme group. There are four major globin chain types - alpha (α), beta (β), gamma (γ), and delta (δ). These four globin chains combine in different ways to give rise to different kinds of haemoglobin.

Answer 278

Thalassaemia is an autosomal recessive haemoglobinopathy which causes a microcytic anaemia. In adults, blood primarily consists of the following isoforms: - HbA (2alpha2beta): >95%, reduced alpha thalassaemia and reduced beta thalassaemia - HbA2 (2alpha2beta): 2%, reduced alpha thalassaemia and increased beta thalassaemia - HbF (2alpha2gamma): <2%, reduced alpha thalassaemia and increased beta thalassaemia

Answer 279

- Thalassaemia is prevalent in areas with malaria as there is evidence to suggest that thalassaemic red cells provide immunity against the parasite. - Alpha thalassaemia: Asian and African descent - Beta thalassaemia: South-East Asian, Mediterranean, and Middle Eastern descent

Answer 280

Family history

Answer 281

Patients with alpha or beta thalassaemia trait have a normal life expectancy. Beta thalassaemia major is fatal in the first few years of life if untreated, and the leading cause of death is heart failure. If treated appropriately with transfusion and chelation, patients can have near-normal life expectancy. In alpha thalassaemia, Hb Barts is fatal *in utero*, whilst HbH patients have near-normal life expectancy

Answer 282

Alpha-thalassemia is a genetic disorder where there's a deficiency in production of the alpha globin chains of haemoglobin. This is an autosomal recessive conditions

Answer 283

Common in individuals of Asian and African descent

Answer 284

Family history

Answer 285

Alpha thalassaemia occurs due to impaired synthesis of α-globin due to genetic deletions. 4 alleles (on chromosome 16) are responsible for alpha chain synthesis: - Silent carrier: one gene deletion does not cause symptoms and patients have normal electrophoresis - Alpha thalassaemia trait: people with 2 gene deletions are mildly anaemic with near-normal haemoglobin electrophoresis. This can either be caused by a ‘cis’ deletion, where mutated genes are on the same chromosome; or a ‘trans’ deletion when the mutated genes are on two different chromosomes. - HbH: people with 3 gene deletions are unable to form alpha chains. The beta chains form tetramers (HbH), which damage erythrocytes causing moderate to severe disease - HbH cause damage by causing haemolysis as well as having a high affinity for O2 and not releasing O2 to tissues. - Hb Barts (alpha thalassaemia major): people with 4 gene deletions die in utero because the gamma chains form tetramers (Hb Barts), which cannot carry oxygen efficiently - Severe hypoxia leads to high-output cardiac failure and massive hepatosplenomegaly, resulting in oedema all over the body, called hydrops fetalis. A consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of RBCs. This may cause bones containing bone marrow, as well as the liver and spleen, to enlarge.

Answer 286

Patients with alpha thalassaemia trait are usually asymptomatic. Clinical features of HbH disease are highly variable and generally develop in the first years of life - Signs - Pallor: due to anaemia - Jaundice: due to unconjugated bilirubin - Chipmunk faces: compensatory extramedullary hematopoiesis in the skull causes marrow expansion - Hepatosplenomegaly - Failure to thrive - Symptoms - Shortness of breath: due to anaemia - Palpitations: due to anaemia - Fatigue: due to anaemia - Swollen abdomen: due to hepatosplenomegaly

Answer 287

- FBC: microcytic anaemia with reticulocytosis as the marrow compensates to produce more erythrocytes - Blood film: microcytic, hypochromic erythrocytes, as well as target cells (look like bullseyes due to scrunching up of the cell membrane) and nucleated RBCs (Howell-Jolly bodies). With moderate alpha thalassaemia, there may be golf-ball like RBCs, due to precipitated HbH molecules. - Hb electrophoresis: this is diagnostic. The pattern depends on the type of thalassaemia. HbH (beta chain tetramers) would be present in alpha thalassaemia

Answer 288

- Patients with alpha thalassaemia trait don't require treatment - Regular blood transfusions: may be required and will be guided by the Hb level. - Iron chelation: desferrioxamine acts as an iron chelator and can be given to treat or prevent iron overload in patients with regular transfusions - Folate supplementation: haemolysis leads to increased cell turnover and a state of folate deficiency - Splenectomy: patients with thalassaemia develop splenomegaly due to extramedullary erythropoiesis. This leads to hypersplenism which, in turn, causes haemolysis and pancytopenia. Splenectomy is recommended if there is massive splenomegaly or hypersplenism - Stem cell transplantation: the only curative option recommended in those with severe disease

Answer 289

- Heart failure: severe anaemia can lead to high output cardiac failure - Hypersplenism: compensatory extramedullary hematopoiesis takes place in the spleen leading to splenomegaly and hypersplenism. This, in turn, can cause pancytopaenia - Aplastic crisis: associated with parvovirus B19 infection and can result in pancytopaenia with reduced reticulocytes - Iron overload due to regular transfusions: excess iron leads to secondary haemochromatosis which can affect the liver, heart, pancreas, skin, and joints - Complications due to haemochromatosis: arrhythmias, pericarditis, cirrhosis, hypothyroidism and diabetes mellitus - Gallstones: haemolysis results in haemoglobin being broken down to bilirubin and forming pigmented gallstones

Answer 290

Beta thalassaemia is a genetic disorder where there’s a deficiency in the production of the β-globin chains of haemoglobin. It is an autosomal recessive condition.

Answer 291

Most commonly seen in Mediterranean, African and South East Asian populations.

Answer 292

Family history

Answer 293

- 2 alleles (on chromosome 11) are responsible for chain synthesis. - In beta thalassaemia, there’s either a partial or complete β-globin chain deficiency, due to a point mutation in the beta globin gene present on chromosome 11. Most often, these mutations occur in two regions of the gene - the promoter sequences and splice sites - which affects the way the mRNA is read. - The result is either a reduced, or completely absent beta globin chain synthesis. - When there’s a β-globin chain deficiency, free α-chains accumulate within red blood cells, and they clump together to form intracellular inclusions, which damage the red blood cell’s cell membrane, causing haemolysis - This causes haemoglobin to spill out of RBCs. Haemoglobin can then be recycled into iron and unconjugated bilirubin. - The excess unconjugated bilirubin leads to jaundice, and excess iron deposits leads to secondary hemochromatosis. - The haemolysis can also lead to hypoxia. - A consequence of hypoxia is that it signals the bone marrow, and extramedullary tissues like the liver and spleen, to increase red blood cell production, which may cause bone marrow containing bones, like those in the skull and face, as well as the liver and spleen, to enlarge.

Answer 294

Beta thalassaemia minor is usually asymptomatic. Patients with beta thalassaemia major almost always present < 2 years old. - Signs - Jaundice: due to unconjugated bilirubin - Pallor: due to anaemia - Hepatosplenomegaly - Chipmunk facies: enlarged forehead and cheekbones - Failure to thrive - Symptoms - Shortness of breath: due to anaemia - Palpitations: due to anaemia - Fatigue: due to anaemia - Swollen abdomen: due to hepatosplenomegaly - Growth retardation

Answer 295

- 1st line - FBC: microcytic anaemia with reticulocytosis as the marrow compensates to produce more erythrocytes; in beta thalassaemia trait, microcytosis is disproportionate to anaemia (characteristic) - Lab work may also show high serum iron, high ferritin, and a high transferrin saturation level. - Blood film: microcytic, hypochromic erythrocytes, as well as target cells (look like bullseyes due to scrunching up of cell membrane) and nucleated RBCs (Howell-Jolly bodies) - Hb electrophoresis: this is diagnostic. Reduced HbA and elevated HbA2 would be expected in beta thalassaemia - Other - Skull X-ray: a ‘hair-on-end’ appearance is seen in beta thalassaemia intermedia and major due to marrow hyperplasia - DNA testing can be used to look for the genetic abnormality

Answer 296

- Beta thalassemia minor usually doesn’t require any treatment. - Regular blood transfusions: may be required and will be guided by the Hb level. - Iron chelation: desferrioxamine acts as an iron chelator and can be given to treat or prevent iron overload in patients with regular transfusions - Folate supplementation: haemolysis leads to increased cell turnover and a state of folate deficiency - Splenectomy: patients with thalassaemia develop splenomegaly due to extramedullary erythropoiesis. This leads to hypersplenism which, in turn, causes haemolysis and pancytopenia. Splenectomy is recommended if there is massive splenomegaly or hypersplenism - Stem cell transplantation: the only curative option recommended in those with severe disease

Answer 297

- Heart failure: severe anaemia can lead to high output cardiac failure - Hypersplenism: compensatory extramedullary hematopoiesis takes place in the spleen leading to splenomegaly and hypersplenism. This, in turn, can cause pancytopaenia - Aplastic crisis: associated with parvovirus B19 infection and can result in pancytopaenia with reduced reticulocytes - Iron overload due to regular transfusions: excess iron leads to secondary haemochroatosis which can affect the liver, heart, pancreas, skin, and joints - Complications due to haemochromatosis: arrhythmias, pericarditis, cirrhosis, hypothyroidism and diabetes mellitus - Gallstones: haemolysis results in haemoglobin being broken down to bilirubin and forming pigmented gallstones

Answer 298

- Can be therapeutic e.g. DVT and PE - OR prophylactic e.g. prevention of DVT/PE, stroke etc

Answer 299

- Inactivates factor Xa but not thrombin - Has a longer half-life than standard heparin - Monitoring not usually required

Answer 300

- Works on antithrombin and increases its affinity for its target. Antithrombin binds excess factor X as well as excess thrombin to make it unavailable. This ultimately prevents fibrin formation. Antithrombin also plays a role in inhibiting factors VII, IX, XI and XII. Thrombin also has additional roles apart from the cleaving of fibrinogen to fibrin. It is involved in activating platelets, activating factor V, VIII and IX and XIII (stabilising factor that reinforces the fibrin mesh). When heparin inactivates thrombin via antithrombin, it will also have an effect on the thrombin-induced activation of these other factors. - Has a rapid onset and short half-life - Monitoring needed; dose adjusted based on APTT

Answer 301

Increased bleeding, heparin-induced thrombocytopenia (HIT), osteoporosis with long term use, hyperkalaemia

Answer 302

bleeding disorders, low platelets, previous HIT, peptic ulcer, cerebral haemorrhage, severe hypertension, neurosurgery

Answer 303

- Warfarin inhibits the activation of vitamin K (by inhibiting vitamin K epoxide reductase complex I), this depletes vitamin K as vitamin K is no longer recycled. This results in the reduced synthesis of active clotting factors. Vitamin K is involved in the conversion of coagulation factors (II, VII, IX and X) into their mature forms, as the conversion uses an enzyme that requires vit K. This inactivation affects the extrinsic, intrinsic and common pathways.

Answer 304

haemorrhage, mild rash, hair loss

Answer 305

peptic ulcer, bleeding disorders, severe hypertension, pregnancy

Answer 306

- e.g. rivaroxaban and apixaban (factor Xa inhibitors); dabigattran (direct thrombin inhibitor) - Do not require monitoring or dose adjustment

Answer 307

severe renal impairment, active bleeding, lesion at risk of bleeding, reduced clotting factors

Answer 308

- Pentasaccharide Xa inhibitor - Used in acute coronary syndrome or in place of LMWH for prophylaxis

Answer 309

- Raising the INR puts patient at risk of haemorrhage - Stop anticoagulant - If heparin overdose: can use protamine sulphate to counteract this - If warfarin: vitamin K1 can be used as antidote - Prothrombin complex concentrate or fresh frozen plasma

Haematology Flashcards

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