Haematology Flashcards

Question

Primary investigations for anaemia

Answer 1

FBC - haem and MCV Blood film Reticulocyte count Ferritin B12 and folate Bilirubin Direct Coombs test Haemoglobin electrophoresis

Answer 2

- 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 3

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 4

Most common

Answer 5

Vegetarian, H.pylori infection, Pregnant, Young children and adolescents, IBD, Coeliac, Certain drugs (e.g. PPI's)

Answer 6

Bone marrow requires iron to produce haemoglobin. There are several scenarios where iron stores can be used up and the patient becomes iron deficient: - 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. 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. 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 7

Pallor, Conjunctival pallor, Glossitis, Koilonychia, Angular stomatits

Answer 8

Fatigue, Dyspnoea, Dizziness, Headache, Nausea, Bowel disturbance, Hair loss, Pica, Exacerbation of other cardiac syndromes

Answer 9

- 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 10

Ferritin: 12 - 200 ug/l Iron: 14 - 31 umol/l Total iron binding capacity: 54 - 75 umol/l

Answer 11

Treat cause, oral iron (ferrous sulphate or ferrous fumarate), Iron infusion (cosmofer), Blood transfusion if severe

Answer 12

Constipation, black coloured stools, diarrhoea, nausea and dyspepsia/epigastric discomfort

Answer 13

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 14

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

Answer 15

- 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 16

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

Answer 17

- 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 18

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

Answer 19

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 20

- 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 21

Family history, Northern European descent

Answer 22

- 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 23

Splenomegaly, Pallor, Jaundice, Tachycardia, Flow murmur

Answer 24

Fatigue, Dizziness, Palpitations, RUQ pain, Neonatal jaundice, Failure to thrive

Answer 25

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 26

- 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 27

- 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 28

- 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 29

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

Answer 30

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

Answer 31

- 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 32

- 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 33

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. Triggers: 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 34

Jaundice, pallor, Splenomegaly, Dark tea-like coloured urine

Answer 35

Shortness of breath, Fatigue, Dizziness, Headaches, Palpitations

Answer 36

FBC, Blood film, LDH, Bilirubin, Haptoglobin, Coomb's test, G6PD enzyme assay

Answer 37

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

Answer 38

Gallstones, Kidney damage

Answer 39

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 40

- 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 41

- 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 42

Fatigue, Palpitations, dizziness, Headaches, Chest pain and SOB, Increased bleeding, recurrent infections

Answer 43

FBC, Erthyropoetin, Bleeding time, Bone marrow biopsy

Answer 44

Removal/treatment of cause, Tranfusions, Stem cell transplant, Immunosuppressive treatments

Answer 45

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 46

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 47

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

Answer 48

- Sickle cell is a genetic disease where red blood cells can take the shape of a crescent, or sickle, and that change allows them to more easily be destroyed. - Sickle cell disease is caused by defective haemoglobin. Specifically, the β-globin chains end up misshapen. This is because of a mutation in the beta globin gene, or HBB gene. A point mutation results in a hydrophilic glutamic acid being substituted for a hydrophobic valine, changing the structure of the beta chain. - If only one gene is mutated, this is called sickle cell trait. If both are mutated, this is known as sickle cell disease. - Due to the abnormal beta chain, patients with the sickle trait have reduced levels of HbA, whilst those with sickle cell disease have absent HbA. Instead, sickle patients have the abnormal HbS isoform consisting of 2 alpha chains and 2 abnormal beta chains. HbS is prone to sickling and haemolysis. - HbS carries oxygen perfectly well, but when deoxygenated, HbS changes its shape, which allows it to aggregate with other HbS proteins and form long polymers that distort the red blood cell into a crescent shape, a process called sickling. Sickling is triggered by dehydration, acidosis, infection, and hypoxia. HbAS (trait) patients sickle at PaO2 2.5 - 4 kPa, whilst HbSS (disease) patients at PaO2 5 - 6 kPa. - Repeated sickling of red blood cells damages their cell membranes and promotes premature destruction - haemolysis This destruction of red blood cells leads to anaemia as well as increased free haemoglobin. Free haemoglobin in the plasma is bound by haptoglobin and gets recycled; which is why a low haptoglobin level is a sign of intravascular haemolysis. Recycling of that heme group yields unconjugated bilirubin, which at high concentration can cause scleral icterus, jaundice, and gallstones. - To counteract the anaemia of sickle cell disease, the bone marrow makes increased numbers of reticulocytes. This can cause the bones to enlarge. Extramedullary hematopoiesis can also happen - leading to splenomegaly. - In sickled form, red blood cells tend to get stuck in capillaries, called vaso-occlusion. This can lead to vaso-occlusive crisis causing symptoms e.g. dactylitis, priapism, acute chest syndrome, stroke, depending on where the occlusion is. - 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 49

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

Answer 50

Sequestrian, Aplastic, Haemolytic and Vaso-occlusive

Answer 51

- 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 52

- 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 53

Increased rate of intravascular and extravascular haemolysis; rare

Answer 54

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

Answer 55

- 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 56

- 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 57

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 58

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 59

Sickle cell crises, Anaemia, Increased risk of infection

Answer 60

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 61

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

Answer 62

- 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 63

- 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 - 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 64

pallor, Signs of neurological deficit e.g. confusion, ataxia etc

Answer 65

SOB, Fatigue, Palpitations, Headaches, Glossitis, Personality change, Depression, Memory loss, Visual disturbances, Numbness, Weakness, paraesthesia, Ataxia, Loss of vibration sense or proprioception, Autonomic dysfucntion

Answer 66

1st line: FBC, Blood film, Haematinics, Lactate dehydrogenase (may be elevated), LFT Other: Bone marrow aspirate, Schillings test, serological assessment, gastroscopy

Answer 67

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

Answer 68

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

Answer 69

- 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 70

Elderly, Poverty, Alcoholic, Pregnant, Crohns or coeliac

Answer 71

- 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. - Causes of folate deficiency: - 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 72

Fatigue, Dyspnoea, Palpitations, Headache, Glossitis, Feature of pancytopenia, Symptoms of underlying cause

Answer 73

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

Answer 74

- 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 75

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 76

- 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 77

Age, Smoking, Drugs (the pill, hormone replacement therapy), Immobility, Pregnancy, Trauma, Malignancy, Polycythaemia, SLE, Thrombophilia, Virchow's triad (hypercoagulability, Venous stasis and endothelial damage)

Answer 78

Unilateral swelling, Oedema, tender and erthymatous, Distension of superficial veins, Phlegmasia cerulea dolens, Unilateral calf pain, Redness and swelling

Answer 79

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. +1 point: Active cancer, bedridden or recent surgery, Calf swelling, superficial veins, entire leg swollen, tenderness along veins, Pitting oedema, immobility of affected leg e.g. plaster, previous dvt, Alternative diagnosis likely

Answer 80

Examination and Wells score, investigate for cancer and thrombophilia

Answer 81

- **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 - 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 - **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 82

- 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 83

- **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 84

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 85

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 86

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

Answer 87

- 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) Acute monocytic leukaemia (M5): - Characterised by monoblast accumulation and usually lack Auer rods - Results in gum infiltration

Answer 88

- 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 89

- 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 90

- A myeloblast is an immature white blood cell. Physiologically, myeloblasts become mature white blood cells called **granulocytes** (neutrophils, eosinophils and basophils). - Acute leukaemias are caused by a mutation in the precursor blood cells in the bone marrow. - AML is caused by a wide variety of abnormalities e.g. chromosomal translocations, which are used to subclassify AML into a few different types. - Acute promyelocytic leukaemia is an important subtype. It is characterised by translocation of chromosome 15 and 17 which disrupts the retinoic acid receptor alpha gene, which is required for normal cell division. - There are also certain conditions that can actually lead to AML, like myelodysplastic syndrome, which is characterised by defective maturation of myeloid cells and buildup of blasts in the bone marrow. - Another condition often associated with both AML and ALL is Down syndrome, which is caused by an extra 21st chromosome - trisomy 21. - The mutation does two things. It causes these precursor blood cells to lose their ability to differentiate into mature blood cells and it makes the blast cells divide uncontrollably, and in the process take up a lot of space and nutrition in the bone marrow. - This causes cytopenias - a reduction in the number of healthy blood cells, like anaemia, thrombocytopenia, and leukopenia. - As the number of blast cells in the bone marrow keep increasing, they spill out into the blood. Some of the cells, especially lymphoblasts, settle down in organs and tissues across the body, like the liver and spleen. - Additionaly, in acute promyelocytic leukemia, the promyelocytes activate the clotting process, and this combined with the already decreased platelets, results in disseminated intravascular coagulation

Answer 91

Pallor, Lymphadenopathy, Hepatosplenomegaly

Answer 92

- 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 93

- 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 94

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

Answer 95

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 96

**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 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 Complications secondary to AML: - 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 97

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 98

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 99

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

Answer 100

- 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 101

- 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 102

- 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 103

- In acute leukaemias there’s uncontrolled proliferation of partially developed white blood cells (blast cells). It is caused by a mutation in the precursor blood cells in the bone marrow. - In ALL, it’s usually due to a chromosomal translocation or due to an abnormal chromosome number. - Common chromosomal translocations include translocation of chromosome 12 and 21 and translocation of chromosome 9 and 22, also called the Philadelphia chromosome. - These result in production of abnormal intracellular proteins, which affect the cell’s function and cell division. - A condition often associated with both AML and ALL is Down syndrome, which is caused by an extra 21st chromosome - trisomy 21. - ALL can further be classified into T-cell ALL and B-cell ALL - The mutation does two things. It causes these precursor blood cells to lose their ability to differentiate into mature blood cells and it makes the blast cells divide uncontrollably, and in the process take up a lot of space and nutrition in the bone marrow. - This causes cytopaenias like anaemia, thrombocytopenia, and leukopenia. - As the number of blast cells in the bone marrow keep increasing, they spill out into the blood. - Some of these cells, especially lymphoblasts, settle down in organs and tissues across the body, e.g. liver, spleen, kidneys, testicles and meninges. - Sometimes, pre-T-cells migrate to the thymus or lymph nodes like normal T-cells do, and settle down there, causing these structures to enlarge.

Answer 104

- 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

Answer 105

Fatigue, Loss of appetite, Weight loss, Easy bruising, prolonged bleeding and mucosal bleeding, recurrent infection, Bone pain, Fever, Failure to thrive, Abdominal fullness, Localised pain in lymph nodes

Answer 106

- 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 107

- 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 108

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

Answer 109

**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 110

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

Answer 111

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 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 Complications secondary to ALL: - Myelosuppression and neutropaenic sepsis: lymphoblasts invade the bone marrow, disrupting function, and may present with pancytopaenia requiring RBC and platelet transfusion. - Extramedullary involvement: CNS, testicular, and renal involvement - Infertility: due to lymphoblast invasion

Answer 112

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 113

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

Answer 114

Chronic, Accelerated, Blast

Answer 115

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

Answer 116

Male gender, Radiation exposure

Answer 117

CML: - In chronic leukemia there are lots of partially developed white blood cells in the blood over a long period of time. - Both CML and CLL cause cells to mature only partially, and that’s a key distinction from acute leukemias where the cells don’t mature at all. As a result, these abnormal, premature leukocytes don’t work effectively, which weakens the immune system. - Chromosomal abnormality in hematopoietic stem cells that are destined to become leukocytes is the most common cause of chronic leukemia. Some examples of abnormalities include a chromosomal deletion, a trisomy, and a translocation. - Chronic myeloid leukemia, CML, is caused by a particular chromosomal translocation that affects granulocytes. The most common cause is a chromosome translocation which results in a Philadelphia chromosome. - A portion of chromosome 9’s long arm switches with a portion of chromosome 22’s long arm - t(9;22) - So, a chromosome 22 gene, which is the BCR gene, ends up sitting right next to a chromosome 9 gene, the ABL gene. - When they’re combined it forms a fusion gene called BCR ABL, which codes for the BCR ABL protein, which is a constitutively active (always turned on) tyrosine kinase - Since BCR ABL helps control various cellular functions like cell division, having it always “on” forces myeloid cells to keep dividing quicker than they should, which causes a buildup of the premature leukocytes in the bone marrow, that eventually spill into the blood. - Some cells settle in organs and tissues across the body, but others keep circulating in the blood. Due to the extra cells in the blood, all the healthy cells get “crowded out”, making it tougher for them to survive. - This causes cytopaenias, like anaemia, thrombocytopenia, and leukopenia. Progression to AML: - 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 118

- Hepatosplenomegaly - Abdominal tenderness - Pallor - Pyrexia

Answer 119

Fatigue, Weight loss, Fever, Night sweats, Shortness of breath, Easy bruising and bleeding, Recurrent infections, Bone pain, Abdominal fullness

Answer 120

- 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 121

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

Answer 122

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 123

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 124

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

Answer 125

- 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 126

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

Answer 127

**CLL:** - In chronic leukaemia there are lots of partially developed white blood cells in the blood over a long period of time. - Both CML and CLL cause cells to mature only partially, and that’s a key distinction from acute leukemias where the cells don’t mature at all. As a result, these abnormal, premature leukocytes don’t work effectively, which weakens the immune system. - Chromosomal abnormality in haematopoietic stem cells that are destined to become leukocytes is the most common cause of chronic leukaemia. Some examples of abnormalities include a chromosomal deletion, a trisomy, and a translocation. - Chronic lymphocytic leukaemia, CLL, is caused by a variety of chromosomal mutations that affect lymphocytes, in particular B cells. - In CLL the most likely cause is a mutation in the cells’ chromosomes - but the exact mutation isn't known - B-cells start to interfere with the pathways of B-cell receptors, which should only be signalled during infection to activate a few specific tyrosine kinases. - Interference with Bruton’s tyrosine kinase, for example, is what stops CLL cells from maturing fully, and it’s similar interference with other tyrosine kinases allows them to die slower than they divide, which is why they build up. - These premature cells always express particular proteins on their surfaces including CD5, CD19, and CD23. - These premature leukocytes build up in the bone marrow and eventually settle into organs and tissues or circulate in the blood. With a bunch of extra cells in the blood, all the healthy cells get “crowded out”, as it's tougher for them to survive. - This causes cytopaenias, like anaemia, thrombocytopaenia, and leukopaenia. **Small lymphocytic lymphoma (SLL):** - Some cells then move to the lymphatic system. This causes swelling of the lymph nodes, or “lymphadenopathy”. - The B-cells in these nodes will accumulate into distinct masses, or “lymphomas” - known as SLL **Richter transformation:** - The small harmless lymphomas collect into sizable masses that damage the body. **Autoimmune haemolytic anaemia:** - Reduced functioning of CLL cells result in autoimmune haemolytic anaemia as B-cells produce autoantibodies. This results in the cells attacking the body’s own red blood cells and killing them off **Hypogammaglobinaemia** - The cells don’t produce enough gamma globulins.

Answer 128

- **Lymphadenopathy** - **Hepatosplenomegaly:** neoplastic cells invade the liver and spleen - **Pallor**

Answer 129

- **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 130

- **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 131

- **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 132

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

Answer 133

- **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

Answer 134

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 135

**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** **Complications secondary to CLL:** - **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 136

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 137

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 138

- 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 139

- **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 140

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’. In classical Hodgkin lymphoma a B-cell in the germinal centre has an abnormal antibody gene rearrangement. Instead of undergoing apoptosis, the cell starts to divide uncontrollably - becoming a neoplastic cell. These neoplastic cells are abnormal and don't produce antibodies. The exact mechanism of how this happens is unclear, but in some people there seems to be a link with viruses like HIV and EBV. In Hodgkin lymphomas, neoplastic cells are large mononuclear cells called Hodgkin cells or multi-nucleated cells called Reed-Sternberg cells. In classical HL these cells don't express CD45 or CD20, which are typically seen on B-cells. These neoplastic cells are also usually surrounded by non-neoplastic inflammatory cells - mostly T cells - which are attracted by chemokines. The neoplastic cells also activate fibroblasts which make collagen, as well as eosinophils. Hodgkin Lymphoma can be split into classical HL (expressing CD15 and CD30), and lymphocyte predominant (non classical, expressing CD45 and CD20) HL. Classical HL is further subdivided into 4 categories. *Lymphocyte predominant cells are variants of reed-sternberg cells that look like popcorn.

Answer 141

- Signs - **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 142

- **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 143

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

Answer 144

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 145

**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 146

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 147

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 148

- 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 149

- **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 150

- 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. - Usually, lymphomas develop in lymph nodes - nodal lymphomas. - Lymphomas can happen anywhere in the body, and when they develop in other tissues or organs - like the stomach or skin - they are known as extranodal lymphomas. - Lymphoma cells can also get into the blood and can spread to other parts of the body. If lymphoma cells get into the GI tract they can grow and cause bowel obstruction. If they go to the bone marrow, they can crowd out normal bone marrow progenitor cells and cause pancytopenia. If they go to the spinal cord they can cause spinal cord compression. NHLs can be divided by cell type (proliferation of B cells, T cells, or NK cells), and grade (high or low).

Answer 151

- 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 152

- **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 153

- **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 154

**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 155

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 156

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 157

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

Answer 158

- **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 159

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 160

- 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 161

- **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 162

Bone marrow plasma cells ≥ 10% (or biopsy-proven bony / extramedullary plasmacytoma) AND a myeloma-defining event: - Bone marrow plasma cells > 60% - > 1 focal lesion on MRI - Involved:univolved serum free light chain ratio >100 OR Evidence of end organ damage (CRAB): - Hypercalcaemia - Renal insufficiency - Anaemia - Bone lesions

Answer 163

- MGUS - Smouldering myeloma - Solitary plasmacytoma - Amyloidosis

Answer 164

Generally, **chemotherapy +/- stem cell transplantation** - Induction therapy - Patients with good performance status and < 70 years: **bortezomib and dexamethasone +/- thalidomide, followed by stem cell transplantation. This is followed by maintenance therapy** - Patients with poor performance status and > 70 years: **bortezomib, prednisolone, and melphalan (an alkylating agent)** - Monitoring - **Repeat blood tests, including serum and urine electrophoresis,** every 2-3 months - **Bortezomib monotherapy** is recommended first-line following a first relapse - Certain patients may be suitable for a **second autologous stem cell transplant,** if required - Other - **Bisphosphonates**: zoledronate is first-line and started on all patients to protect against bone disease - **Radiotherapy:** to bone lesions can improve bone pain - **Orthopaedic surgery:** can stabilise bones or treat fractures - **Cement augmentation:** involves injecting cement into **vertebral fractures** or **lesions** and can improve spine stability and pain - Anaemia may require **transfusion of RBCs and erythropoietin** - **Venous thromboembolism prophylaxis:** with aspirin or low molecular weight heparin whilst on certain chemotherapy regime

Answer 165

- **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 166

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 167

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

Answer 168

- 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 169

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

Answer 170

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. **Active infection:** The incubation time, which is the period of time between infection and symptom onset, varies depending on the plasmodium species. Plasmodium falciparum incubates for a few days, whereas Plasmodium malariaie incubates for a few weeks. The release of tumour necrosis factor alpha and other inflammatory cytokines, causes fevers that typically occur in paroxysms or short bursts, and correspond to the rupture of the infected red blood cells, which happens in waves of reproductive cycles unique for each plasmodium species. The haemolytic anaemia, also causes symptoms e.g. extreme fatigue, headaches, jaundice, and splenomegaly. Most plasmodium infections have a mild course of symptoms and are generally regarded as uncomplicated malarial infections. These typically resolve with treatment. **Recurrence:** After recovery, some individuals can get symptoms after a period of time - this is called recurrent malaria and it’s broadly divided into three underlying causes: recrudescence, relapse, and reinfection. - Recrudescence refers to ineffective treatment that didn’t completely clear the infection - Relapse refers to situations where the blood was cleared of merozoites but hypnozoites persisted in the liver, and then emerged to cause more problems - Reinfection is when an individual was effectively treated, but a completely new infection caused a new bout of malaria **Plasmodium falciparum:** 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 171

- 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 172

- **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 173

- **Uncomplicated malaria** Oral: 1. Artemether with lumefantrine (**Riamet**) 2. Proguanil and atovaquone (**Malarone**) 3. **Quinine sulphate** 4. **Doxycycline** - **Complicated or severe malaria** IV: 1. **Artesunate:** this is the most effective treatment but is not licensed. 2. **Quinine dihydrochloride**

Answer 174

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

Answer 175

- **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 176

Polycythaemia vera (PCV) is a myeloproliferative disorder characterised by neoplasia of mature myeloid cells, in particular those involved in the red cell lineage, within the bone marrow.

Answer 177

- Can also be referred to erythrocytosis - an increase red blood cell mass - Defined as an increase in haemoglobin, packed cell volume (PCV) known as haematocrit and red cell count - these measurement are all concentrations and are directly dependent on plasma volume as well as RBC mass - Can be divided into: - **Absolute** i.e. due to increase in RBC mass **Primary:** - Polycthaemia Vera (PV) or - Mutations in erythropoietin receptor or - High oxygen affinity haemoglobin **Secondary:** - Hypoxia e.g. high altitude, chronic lung disease, cyanotic congenital heart disease or heavy smoking - Inappropriately high erythropoietin secretion e.g. in renal carcinoma and hepatocellular carcinoma - **Relative** i.e. decreased plasma volume and normal RBC mass: **Apparent polycythaemia:** - Chronic form associated with obesity, hypertension and a high alcohol and tobacco intake **Dehydration:** - Acute and due to dehydration e.g. alcohol or diuretics

Answer 178

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

Answer 179

JAK2 +ve requires both: A1: Raised haematocrit (> 0.52 in men and > 0.48 in women) or raised red cell mass (25% above predicted) A2: Mutation in JAK2 JAK2 -ve requires A1-A4 plus another A or two B criteria: A1: Raised haematocrit or red cell mass A2: Absence of mutation in JAK2 A3: No cause of secondary erythrocytosis A4: Bone marrow histology consistent with PCV A5: Palpable splenomegaly A6: Presence of an acquired geentic abnormality (excluding BCR-ABL1) in haemaopoetic cells B1: Thrombocytosis B2: Neutrophilia B3: Radiological evidence of splenomegaly B4: low serum ertythropoetin

Answer 180

- **Age > 40 years** - **Family history**

Answer 181

- In polycythaemia vera, there are increased blood cell levels (particularly RBCs) due to overproduction by the bone marrow. - It typically begins with a mutation in a single haematopoietic stem cell. In 90% of the affected individuals there is a mutation of the Janus Kinase 2 or JAK2 gene. - Normally, the kidneys produce erythropoietin which binds to receptors on the hematopoietic stem cells and activates JAK2 gene. This causes the cell to divide and thus produce more blood cells. - However, when there’s a mutation, it keeps JAK2 gene activated, and these cells are able to divide even in the absence of erythropoietin. The mutated cells proliferate, and rapidly become the predominant hematopoietic cells in the bone marrow. - PCV is a primary polycythaemia that results in increased red blood cells (polycythaemia) as well as increased neutrophils (neutrophilia) and platelets (thrombocytosis). This causes hyperviscosity, increasing the risk of thrombosis. - Platelets are often dysfunctional in PCV, which also increases the risk of bleeding, although major bleeding is rare. **Myelofibrosis:** - In time these cells start to die out and scar tissue forms. At that point, the bone marrow can no longer produce blood cells, leading to anaemia, thrombocytopenia, and leukopenia. This is known as the spent phase (myelofibrosis). - Scarring is usually in response to cytokines that are released from the proliferating cells. One particular cytokine is fibroblast growth factor. - When the bone marrow is replaced with scar tissue the production of blood cells (haematopoiesis) starts to happen in other areas such as the liver and spleen. This is known as extramedullary haematopoiesis and can lead to hepatomegaly and splenomegaly.

Answer 182

- Signs - **Splenomegaly:** because the excess red blood cells buildup in the spleen, which usually helps with removing excess cells. - **Conjunctival plethora** (excessive redness to the conjunctiva in the eyes) - **Plethoric appearance** - **Palmar erythema** - **Hypertension** - Symptoms - **Fatigue** - **Dizziness** - **Headache** - **Blurred vision** - **Increased sweating** - **Facial flushing** - **Pruritus:** characteristically exacerbated by hot water, such as after a bath. This is due to the increased number of basophils and mast cells which contain histamine. - **Erythromelalgia:** pain, redness and swelling esp in hands and feet

Answer 183

- Primary investigations - **FBC:** elevated Hb, elevated haematocrit (males > 0.52; females > 0.48), whilst leukocytes and platelets may also be raised; haematocrit is more sensitive than Hb - **U&Es and LFTs:** renal and hepatic disease may cause secondary polycythaemia - **ABG:** useful to exclude secondary polycythaemia. PO2 is normal in PCV but reduced in secondary polycythaemia due to respiratory causes such as COPD - **Ferritin:** iron deficiency anaemia can mask polycythaemia so ferritin should be checked - **Erythropoietin (EPO):** to distinguish **primary** polycythaemia (EPO is **low**) from **secondary** polycythaemia (EPO is **raised**), which may be caused by hypoxia, COPD, high altitude and renal cell carcinoma - **JAK2 V617F mutation**: a positive finding is **definitive** for PCV. A negative finding **does not** rule out PCV, as 5% of cases involve other mutations - **Bone marrow biopsy:** shows prominent erythroid, granulocytic and megakaryocytic proliferation. Can show scarring in myelofibrosis. - Investigations to consider **If JAK2 negative, perform additional investigations:** - **Red cell mass:** increased > 25% - **Abdominal ultrasound:** splenomegaly may not be palpable if mild, therefore ultrasound is performed to elucidate this. - **If EPO is normal or low**: **JAK2 exon 12 analysis** and **bone marrow biopsy** - **If EPO is high**: further imaging (e.g. CT head and neck) to exclude a rare tumour - Other - **ESR**: may be raised - **Leukocyte ALP**: may be raised

Answer 184

- **Venesection**: first-line, offered to all patients to maintain haematocrit below 0.45 - **Hydroxycarbamide (hydroxyurea):** the first-line cytoreductive agent to reduce thrombosis risk and is only used in patients with a high risk of thrombosis, e.g. > 60 years old or background of thrombosis - **Aspirin:** 75 mg daily dose of aspirin for all patients - **Ruxolitinib (JAK2 inhibitor)**: used as a second-line cytoreductive agent. Can also help with itching symptoms - **Radioactive phosphorus-32**: less commonly used and may be considered if not suitable for other cytoreductive agents or in the very elderly - **Modifiable risk factors:** NICE recommends that cardiovascular risk factors are managed, such as diabetes, hyperlipidaemia, hypertension and smoking

Answer 185

- **Thrombosis:** increased risk due to hyperviscosity - **Stroke** - **MI** - **Deep vein thrombosis** - **Budd-Chiari syndrome**: this is the obstruction of the hepatic veins that normally drain the liver and most commonly occurs due to thrombosis. - **Haemorrhage:** paradoxically, the risk of haemorrhage is also increased, although patients rarely present with major bleeding - **Gout/ kidney stones:** buildup of uric acid due to high turnover of RBCs - **Leukaemia:** 1-3 ****% ****risk of progression to acute leukaemia - **Treatment-induced leukaemia**: radioactive phosphorus-32 increases the risk so is rarely used, whilst there is a slight increased risk with hydroxycarbamide - **Myelofibrosis:** 2-8% risk of progression to myelofibrosis

Answer 186

The most common cause of death in these patients is related to cardiovascular complications. The overall survival rate varies in the literature but is approximately 19 years from diagnosis. Up to 15% of patients progress to acute leukaemia, whilst thromboembolic disease is a significant cause of morbidity and mortality in patients (e.g. stroke).

Answer 187

Haemophilia A and haemophilia B are inherited severe bleeding disorders.

Answer 188

Almost exclusively affects males (X-linked recessive)

Answer 189

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

Answer 190

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 191

- **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 192

- 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 193

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

Answer 194

- **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 195

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

Answer 196

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 197

- 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 carried for factor VIII and protects it from degradation.

Answer 198

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 199

- **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 200

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 201

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 202

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 203

- 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 204

- 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 205

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 206

- **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 207

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

Answer 208

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 - Immune - Immune thrombocytopenic purpura - Heparin-induced thrombocytopenia - Other causes include: - Medications (sodium valproate, methotrexate, isotretinoin, antihistamines, proton pump inhibitors) - Alcohol

Answer 209

- 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 210

- **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 211

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 212

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

Answer 213

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 214

- 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 215

- **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 216

- 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 217

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 218

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 219

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 220

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 221

- **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 222

- **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 223

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

Answer 224

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 225

- 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 CBC

Answer 226

- **FBC:** thrombocytopenia - **Check for HIT antibodies**

Answer 227

Stopping use of heparin and using an alternative anticoagulant

Answer 228

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 229

Thalassaemia is an autosomal recessive haemoglobinopathy which causes a microcytic anaemia.

Answer 230

- 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 231

Family history

Answer 232

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 233

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 234

Common in individuals of Asian and African descent

Answer 235

Family history

Answer 236

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 237

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 facies:** 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 238

- **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 239

- 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 240

- **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 241

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 242

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

Answer 243

- 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. EY: β = normal beta chain; β+ = reduced beta chain; β0 = absent beta chain - 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 244

- **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 245

- **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 246

- 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 247

- **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 248

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

Answer 249

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

Answer 250

- 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 *SE: increased bleeding, heparin-induced thrombocytopenia (HIT), osteoporosis with long term use, hyperkalaemia* *Contraindications: bleeding disorders, low platelets, previous HIT, peptic ulcer, cerebral haemorrhage, severe hypertension, neurosurgery*

Answer 251

- 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. *SE: haemorrhage, mild rash, hair loss* *Contraindications: peptic ulcer, bleeding disorders, severe hypertension, pregnancy*

Answer 252

**DOACs (direct oral anticoagulants)** - e.g. rivaroxaban and apixaban (factor Xa inhibitors); dabigattran (direct thrombin inhibitor) - Do not require monitoring or dose adjustment *Contraindications: severe renal impairment, active bleeding, lesion at risk of bleeding, reduced clotting factors*

Answer 253

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

Answer 254

**Over anticoagulation** - 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

(281 cards)