Clinical haematology Flashcards

Question

Define anaemia:

Answer 1

Anaemia is a medical condition characterized by a deficiency in the number of red blood cells (RBCs) or a decrease in the concentration of haemoglobin (Hb) in the blood. This deficiency results in reduced oxygen-carrying capacity and impaired oxygen delivery to the body's tissues and organs.

Answer 2

Anaemia can be classified according to the MCV, which is part of the FBC panel

Answer 3

(MCV >100 fl) Morphologically, macrocytic anaemia is usually typified by large RBCs due to abnormal RBC development, giant metamyelocytes and hypersegmented neutrophils (in the peripheral circulation). Macrocytic anaemia may be megaloblastic or non-megaloblastic.

Answer 4

B12 deficiency reduced intake (eg. dietary) reduced absorption (eg. pernicious anaemia, inflammatory bowel disease, gastrectomy) Folate deficiency Drugs hydroxycarbamide (previously called hydroxyurea) azathioprine cytosine arabinoside azidothymidine

Answer 5

Liver disease Alcohol Hypothyroidism Myelodysplastic syndrome Hypothyroidism Pregnancy (usually a mild macrocytosis)

Answer 6

MCV 78–98 fl Causes include: Recent bleeding Anaemia of chronic disease Combined iron & B12/folate deficiency Most non-haematinic-deficiency causes

Answer 7

Microcytic anaemia is defined as the presence of small, often hypochromic, RBCs in a peripheral blood smear Causes include : Iron deficiency α-thalassaemia, β-thalassaemia, HbE, HbC Anaemia of chronic disease (this more often causes normochromic normocytic anaemia) Lead poisoning Sideroblastic anaemias (rare)

Answer 8

Shortness of breath Fatigue Pallor of the conjunctiva Cold extremities Increased cardiac output, palpitations, heart murmurs and cardiac failure Severe anaemia can lead to chest pain and cognitive impairment

Answer 9

Full Blood Count (FBC): This is the initial step in assessing anaemia. It provides information on haemoglobin levels, haematocrit, red blood cell count, and mean corpuscular volume (MCV). Abnormal MCV values help classify anaemia type. Peripheral Blood Smear: A blood smear examination allows a closer look at the size, shape, and color of red blood cells. It can provide valuable clues, such as the presence of abnormal cell shapes (spherocytes, schistocytes) or specific inclusions (Heinz bodies). Reticulocyte Count: Evaluating reticulocytes (immature red blood cells) can determine whether the bone marrow is appropriately responding to anaemia. Low reticulocyte counts may suggest decreased RBC production, while high counts could indicate haemolysis. Iron Studies: Measuring serum iron, ferritin, total iron-binding capacity (TIBC), and transferrin saturation helps diagnose iron-deficiency anaemia and differentiate it from other forms. Vitamin and Folate Levels: Assessing serum vitamin B12 and folate levels is essential for diagnosing megaloblastic anaemias, such as pernicious anaemia or folate deficiency anaemia. Haemoglobin Electrophoresis: This test is crucial for identifying haemoglobinopathies like sickle cell disease and thalassaemia. Specific Tests: In cases of suspected haemolytic anemia or underlying chronic diseases, additional tests may be required, including autoimmune markers, haptoglobin, and direct and indirect bilirubin measurements. Bone Marrow Aspiration and Biopsy: These invasive procedures may be necessary when the underlying cause remains unclear or when bone marrow disorders, myelodysplastic syndromes, or aplastic anemia are suspected.

Answer 10

Nutritional Support: For iron-deficiency anaemia, dietary adjustments or iron supplementation are essential. Correcting vitamin B12 and folate deficiencies through diet or supplements is critical for megaloblastic anaemias. Erythropoiesis-Stimulating Agents: In chronic kidney disease-associated anaemia or anaemia related to chemotherapy, erythropoiesis-stimulating agents (ESAs) may stimulate red blood cell production. Treating Underlying Conditions: Managing chronic diseases, such as inflammatory disorders or cancer, can alleviate anaemia. Specific treatments, such as corticosteroids for autoimmune haemolytic anaemia, may be required. Blood Transfusions: In cases of severe anaemia, significant bleeding, or acute complications, blood transfusions can rapidly improve oxygen delivery. Transfusions are vital in haemolytic crises. Haemolysis Management: When haemolysis is the cause, identifying and treating the underlying haemolytic disorder, along with managing complications like jaundice and anaemia, is crucial. Bone Marrow Stimulants: In some anaemias, such as aplastic anaemia, bone marrow stimulants like granulocyte colony-stimulating factor (G-CSF) or erythropoietin-stimulating agents may be considered. Supportive Care: Providing supportive care, including managing symptoms, optimizing nutrition, and addressing fatigue and quality of life, is a key aspect of anaemia management. Regular Monitoring: Ongoing follow-up and monitoring are vital to track the response to treatment and ensure that haemoglobin levels are stable. Adjustments to the treatment plan may be needed based on patient progress.

Answer 11

Iron deficiency anaemia is a haematological disorder stemming from an insufficient supply of iron, which is vital for the synthesis of haemoglobin—a crucial component of red blood cells. Without adequate iron, the body struggles to produce a sufficient quantity of healthy red blood cells, leading to a reduction in oxygen-carrying capacity and subsequent symptoms of anaemia.

Answer 12

Dietary Insufficiency: Inadequate iron intake, especially in individuals with restrictive diets or limited access to iron-rich foods. Chronic Blood Loss: Gastrointestinal bleeding, heavy menstrual periods, and other sources of chronic blood loss (e.g. angiodysplasia) can deplete iron stores. Malabsorption Disorders: Conditions like coeliac disease, inflammatory bowel disease and atrophic gastritis can hinder iron absorption in the gut. Hookworms are a more prominent cause in tropical setting. Increased Demand: During pregnancy and rapid growth phases, the body's iron requirements can surpass the available supply. This can also occur if there is chronic haemolysis

Answer 13

Tiredness Lethargy Weakness Palpitations: An increased heart rate may be noticeable, especially when at rest. Cognitive Impairment: Some patients may exhibit difficulty concentrating or memory issues. Cold Intolerance Headaches and dizziness Brittle Nails: Changes in the nails, such as brittleness and spoon-shaped deformities (koilonychia), can be observed. Angular stomatitis Atrophic glossitis Pica: Iron-deficiency anaemia may manifest as pica, with cravings for non-food substances like ice (pagophagia) or clay (geophagia). This is more common in children.

Answer 14

Hypochromic, microcytic red cells Additional pencil cells Occasional target cells

Answer 15

Total iron binding capacity (TIBC) – Will typically be high as the body mobilises available iron stores owing to the iron deficiency Ferritin – will be low as available iron stores in the body are mobilised to counteract the iron deficiency Note: Ferritin should be measured alongside B12 and folate to assess possible coexisting haematinic deficiency A low ferritin is diagnostic of iron deficiency; however, a normal or high ferritin does not exclude iron deficiency Ferritin is an acute phase protein so levels can be masked/influenced by other conditions, particularly inflammation – It is good to check a C-reactive protein (CRP) at the same time Iron deficiency anaemia in patients >60y should prompt suspicion colonic malignancy until proven otherwise and prompt FIT testing and subsequent 2 week wait referral if indicated according to NICE guidelines.

Answer 16

Iron Supplementation: Oral or intravenous iron supplements are administered to correct iron deficiency. Intravenous iron is preferred in cases of severe deficiency or malabsorption. Important considerations of oral iron supplementation (usually a 3 month course) include: Side effects - diarrhoea, constipation, black stools, abdominal pain, nausea If it is not tolerated due to SEs, reduce the dose to one tablet on alternate days, or consider alternative oral preparations. Iron supplements should be taken on an empty stomach (preferably one hour before a meal) with a drink containing vitamin C, such as a glass of orange juice or another juice drink with added vitamin C. This aids absorption. Oral iron decreases the absorption of oral Levothyroxine. Therefore if both are prescribed, advise patients to take at least 4 hours apart. Monitoring - recheck FBC within 4 weeks of starting treatment (haemoglobin concentration should rise by about 20 g/L over 3–4 weeks). Then check the FBC again at 2–4 months to ensure that the haemoglobin level has returned to normal. Once Hb is normal can continue supplementation for 3 further months, and then monitor at 3/6/12-monthly intervals.

Answer 17

Pernicious anaemia is a deficiency in RBCs caused by lack of vitamin B12 in the blood In the strictest sense, it is caused by autoimmune impairment of intrinsic factor production The term is also widely used to describe B12 deficiency-related anaemia secondary to other causes as well.

Answer 18

The pathophysiology of pernicious anaemia primarily revolves around the autoimmune destruction of gastric parietal cells, which play a central role in the absorption of vitamin B12. This complex process involves several key factors: Autoimmune Attack: In pernicious anaemia, the body's immune system mistakenly targets and destroys gastric parietal cells. These cells are responsible for producing intrinsic factor, a protein necessary for vitamin B12 absorption. Intrinsic Factor Deficiency: As a result of autoimmune destruction, intrinsic factor levels decrease, leading to impaired vitamin B12 absorption in the ileum, the final part of the small intestine. Vitamin B12 Deficiency: Reduced absorption of vitamin B12 results in a deficiency of this essential nutrient. Vitamin B12 is crucial for erythropoiesis (the formation of red blood cells) and the maintenance of the nervous system. Megaloblastic Changes: Vitamin B12 deficiency leads to impaired DNA synthesis in developing blood cells. This results in megaloblastic changes, causing larger, structurally abnormal red blood cells (megaloblasts) in the bone marrow. These larger cells are less effective at carrying oxygen, leading to anaemia. Haemolysis: Pernicious anaemia can lead to haemolysis (the breakdown of red blood cells) due to their structural abnormalities. .

Answer 19

Fatigue Pallor Glossitis - inflammation of the tongue, leading to a smooth, beefy-red appearance. Neurological Symptoms and subacute combined degeneration of the cord: Pernicious anaemia may cause neuropathy, affecting balance, sensation, and coordination. Jaundice - due to haemolysis Cognitive Impairment - memory problems, confusion, and mood changes may occur

Answer 20

Full Blood Count (FBC): Reveals macrocytic anaemia and may show hypersegmented neutrophils. Low haemoglobin level High MCV High mean corpuscular haemoglobin (MCH) Normal mean corpuscular haemoglobin concentration (MCHC) Low reticulocyte count abnormally large and oval-shaped RBCs

Answer 21

Vitamin B12 Assays: Measure serum vitamin B12 levels, which are typically low in pernicious anaemia. Intrinsic Factor Antibodies: These antibodies help confirm the autoimmune nature of the condition. This test is highly specific. Parietal cell Antibodies: This test is highly sensitive. Bone Marrow Aspiration and Biopsy: May show megaloblastic changes in erythropoiesis. Pernicious anaemia is associated with atrophic body gastritis – diagnostic criteria are based on histologic evidence of gastric body atrophy associated with hypochlorhydria. Note: 'active' vitamin B12 or holotranscobalamin is a more sensitive measure of vitamin B12 deficiency – total vitamin B12 is mostly bound to carrier proteins.

Answer 22

Management of patients with pernicious anaemia is lifelong replacement by quarterly treatment with hydroxycobalamin and close monitoring to ensure early diagnosis of any subsequently unmasked iron deficiency. Folate replacement is also often necessary.

Answer 23

Patients should be advised about possible long-term gastrointestinal consequences, such as gastric cancer and carcinoid. Vitamin B12 is required for the nervous system so, in vitamin B12 deficiency, always consider: Peripheral neuropathy Subacute combined degeneration of the cord Optic atrophy Dementia Vitamin B12 deficiency can be associated with other autoimmune disorders such as hypothyroidism and vitiligo.

Answer 24

Iron Deficiency Anaemia (IDA): IDA is the most common cause of microcytic anaemia. It results from insufficient iron intake, malabsorption, chronic blood loss (e.g. gastrointestinal bleeding), or increased iron requirements (e.g. pregnancy). Thalassaemias: Thalassaemias are a group of inherited haemoglobin disorders characterized by reduced production of normal globin chains, leading to microcytosis. Anaemia of Chronic Disease (ACD): Chronic inflammatory conditions, such as rheumatoid arthritis and chronic infections, can cause ACD, which often presents as microcytic anemia. Lead Poisoning: Exposure to lead, often through contaminated sources, can lead to microcytic anaemia, particularly in children. Sideroblastic Anaemia: Sideroblastic anaemias are a heterogeneous group of conditions characterized by defective haem synthesis and the accumulation of iron within the mitochondria of erythroid precursors.

Answer 25

Thalassaemia is a group of inherited disorders characterised by abnormal haemoglobin production. Defects in the four genes for α-globin result in α-thalassaemia in the two genes for β-globin result in β-thalassaemia The absence/abnormality of the α- or β-globin genes leads to quantitative abnormality in globin chain production and an imbalance of the globin-chain synthesis The clinical severity of the syndrome is proportional to the number of absent or abnormal genes

Answer 26

Autosomal recessive inheritance

Answer 27

α-thalassemia describes the spectrum of diseases caused by nonfunctioning copies of the four α-globin genes on chromosome 16. Symptomatic disease results when two or more copies of the gene are lost Patients with two defective copies have a mild asymptomatic anaemia – so-called α-thalassaemia trait Those with three defective copies have symptomatic haemoglobin H disease Microcytic anaemia (Hb approximately 70 g/l) Haemolysis Splenomegaly Normal survival is to be expected inheritance of four defective copies (hydrops fetalis) is incompatible with life The lack of α-globin chains results in excess γ-chains (creating Hb Barts), which are poor carriers of oxygen owing to their high affinity for oxygen It may affect the fetus in utero - Bart's hydrops fetalis will generally present on antenatal ultrasound scans with increased amniotic fluid, increased nuchal translucency and other features of foetal fluid overload.

Answer 28

Current treatment options for symptomatic thalassaemia include: Blood transfusions Stem cell transplantation A splenectomy is an option, particularly in patients with HbH disease. Regular folic acid can also be given, especially in those who are pregnant.

Answer 29

Autosomal recessive inheritance

Answer 30

β-thalassemia describes the spectrum of diseases caused by nonfunctioning copies of the two β-globin genes The mildest variant of β-thalassaemia is β-thalassaemia minor (also known as thalassaemia trait) Patients typically have one functioning and one dysfunctional copy of the β-globin gene The most severe form of β-thalassaemia (known as β-thalassaemia major) is caused by a complete absence of β-globin synthesis (null mutations in both copies of the β-globin gene)

Answer 31

β-thalassaemia minor - patients are typically asymptomatic β-thalassaemia major: Severe symptomatic anaemia at 3–9 months of age Becomes evident when levels of HbF, which does not contain β-globin, fall and should be replaced by HbA (made up of two α- and two β-globin chains), which is lacking in β-thalassaemia major Ineffective haematopoiesis results in extramedullary haematopoesis, which results in Frontal bossing (hair-on-end appearance on Skull XR) Maxillary overgrowth and prominent frontal/parietal bones (hypertrophy of ineffective marrow) - "Chipmunk facies" Hepatosplenomegaly Failure to thrive in infancy

Answer 32

Isolated microcytosis (MCV approximately 63–77 fl) and mild anaemia (Hb typically not <100 g/l) The degree of anaemia is often less severe than would be expected for the degree of microcytosis Blood film - target cells and basophilic stippling Increased red cell count Hb electrophoresis (diagnostic) shows raised HbA2 (>3.5%) – can be lowered by the presence of iron deficiency Can be confused with iron deficiency – ferritin in β-thalassaemia minor is usually normal or high

Answer 33

Profound microcytic anaemia; reduced MCV and reduced MCHC Increased reticulocytes Blood film – marked anisopoikilocytosis, target cells and nucleated RBCs. Teardrop cells from extramedullary haematopoeisis may also be present Methyl blue stains – RBC inclusions with precipitated α-globin High-performance liquid chromatography (HPLC) or electrophoresis (diagnostic) – mainly shows HbF HbA2 may be normal or mildly elevated Haemolysis

Answer 34

Treatment is with regular blood transfusions The most important long-term consideration in these patients is to reduce the risk of iron overload toxicity A condition which primarily affects the heart, joints, liver and endocrine glands Half of patients with β-thalassaemia major die before the age of 35 years, usually from cardiac failure secondary to iron overload Iron overload can be prevented with iron chelating agents (eg. desferrioxamine/deferiprone/deferasirox) Hydroxycarbamide (previously known as hydroxyurea) can also be used to boost HbF levels Allogeneic bone marrow transplantation (BMT) from a sibling or matched unrelated donor A potentially curative option Should be done before significant organ damage has occurred due to iron overload Risks of transplant include graft rejection, graft vs. host disease, infection and transplant-related mortality These risks must balanced against the long-term benefits of transfusion independence and 'cure'

Answer 35

Cardiomyopathy/cardiac arrhythmia/cardiac failure Older patients are prone to atrial fibrillation Urgent cardiac investigations (eg. ECG, echocardiogram, cardiac monitoring and chest X-ray) may be needed Acute sepsis – bacterial sepsis (risk is further increased after splenectomy) Consider central venous catheter infection (particularly with Klebsiella, Yersinia enterocolitica and encapsulated organisms Give broad-spectrum antibiotics, and consider high-dependency unit input Liver cirrhosis, portal hypertension and acute decompensation Early liver unit input and careful fluid balance are required Endocrine dysfunction Hypocalcaemia with tetany due to hypoparathyroidism Needs cardiac monitoring and IV calcium Diabetes Iron overload due to repeated blood transfusions. Presents similarly to Hereditary Haemochromatosis Death is usually due to heart failure if it goes undiagnosed.

Answer 36

Anaemia of chronic disease is a type of anaemia characterised by low haemoglobin levels, decreased red blood cell production, and altered iron metabolism. It occurs in response to chronic inflammatory or infectious conditions, autoimmune disorders, and malignancies. In ACD, the body's iron is sequestered in storage sites, leading to impaired availability for erythropoiesis, resulting in mild to moderate anaemia.

Answer 37

ACD is a common form of anaemia and frequently occurs in individuals with chronic illnesses. Its prevalence varies based on the underlying diseases. Conditions such as rheumatoid arthritis, chronic kidney disease, cancer, and chronic infections are frequently associated with ACD. It can affect individuals of all age groups and backgrounds, with a higher prevalence in those with multiple comorbidities. Inflammatory Conditions: Rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. Chronic Infections: Tuberculosis, HIV, and osteomyelitis. Malignancies: Leukaemia, lymphoma, and solid tumours. Chronic Kidney Disease: Impaired erythropoietin production and iron metabolism. Autoimmune Disorders: Systemic inflammation can lead to ACD. Chronic Liver Disease: Hepcidin release is altered, impacting iron regulation.

Answer 38

Chronic disease can trigger the formation of inflammatory cytokines such as IL-1 and IL-6. Raised levels of IL-6 stimulate the release of hepcidin from the liver, which inhibits iron absorption by reducing the activity of ferroportin, an iron export channel located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). This leads to a decrease in haemoglobin production and the onset of anaemia. In ACD you have good iron stores, however the chronic inflammation means you can’t access it. This results in a low TIBC, normal/low serum iron and normal/raised ferritin (falsely raised as it is acute phase reactant). See more in the investigations section.

Answer 39

Management of ACD primarily involves treating the underlying condition causing the anaemia. In some cases, erythropoiesis-stimulating agents may be used to stimulate the production of red blood cells. This is because the production of EPO is blunted in ACD. Iron supplementation is generally not effective due to the body's impaired ability to absorb iron in this condition.

Answer 40

Sideroblastic anaemia is a group of blood disorders characterized by an impaired ability of the bone marrow to produce normal red blood cells. Instead, it produces ringed sideroblasts - red blood cells with iron-loaded mitochondria.

Answer 41

Sideroblastic anaemia occurs due to ineffective erythropoiesis, leading to increased iron absorption and deposition within the bone marrow and other organs. The condition can be congenital, with X-linked, recessive, or dominant inheritance patterns depending on the gene involved. Acquired causes may be related to drug toxicity or myelodysplastic syndromes. Toxins and drugs associated with sideroblastic anaemia include chronic alcohol abuse, lead poisoning, and Isoniazid use.

Answer 42

Full blood count: To assess the degree of anaemia and the size of the red blood cells. Serum ferritin and iron levels: Typically elevated in sideroblastic anaemia. Blood film examination: To identify sideroblastic inclusions within the red blood cell cytoplasm (see below). Bone marrow biopsy: Can reveal increased iron deposition and ringed sideroblasts.

Answer 43

Management strategies for sideroblastic anaemia include: Avoidance of triggers: Such as alcohol or other toxins. Chelation therapy: To reduce iron overload. Vitamin B6 (pyridoxine) supplementation: May be beneficial in some patients, particularly those with X-linked sideroblastic anaemia. Blood transfusions: May be necessary in severe cases to manage acute symptoms of anaemia. Stem cell transplant: This may be an option for some patients with severe, refractory disease.

Answer 44

Decreased blood volume or decreased erythropoiesis MCV 80-100

Answer 45

haemolytic and non-haemolytic

Answer 46

Haemoglobinopathies e.g sickle cell disease Enzyme deficiency e.g G6PD membrane defects e.g hereditary spherocytosis Extrinsic defects: Autoimmune haemolytic anaemia

Answer 47

G6PD deficiency results in a reduced ability of red blood cells to neutralise oxidative stress. This deficiency leads to the accumulation of reactive oxygen species, causing damage to the cell membrane and eventual haemolysis. The extent of haemolysis depends on the severity of the deficiency and the presence of triggering factors, such as certain medications, infections, or foods.

Answer 48

Medications: Antibiotics: Antibiotics including sulfamethoxazoles e.g. trimethoprim and quinolones such as ciprofloxacin, Nitrofurantoin Antimalarials: Primaquine, quinidine, and chloroquine. Aspirin: In high doses, aspirin can be problematic. NSAIDs: e.g. ibuprofen and naproxen. Dapsone: Used in the treatment of leprosy and dermatitis herpetiformis. Infections: Viral Infections: Viral illnesses, including hepatitis and some respiratory infections, can trigger haemolysis. Bacterial Infections: Certain bacterial infections, like sepsis, can lead to haemolysis. Fava Beans (Broad Beans): Consumption of fava beans can cause severe haemolysis, and this trigger is often associated with G6PD deficiency. Chemical Exposures: Certain chemicals, such as naphthalene (found in mothballs) and aniline dyes, can trigger haemolysis. Mental and Physical Stress: Stressful situations, including physical and emotional stress, can exacerbate G6PD deficiency. Certain Foods and Beverages: Tonic Water: Contains quinine and can trigger haemolysis. Soy Products: Some individuals with G6PD deficiency may experience haemolysis after consuming large quantities of soy-based foods. Other Medications: Vitamin K Analogues: Medications like menadione, used for various medical conditions, can trigger haemolysis.

Answer 49

Most individuals with G6PD deficiency remain asymptomatic until exposed to triggers Jaundice: Caused by increased bilirubin levels due to haemolysis. Babies may present with neonatal jaundice. Pallor: Resulting from anaemia. Dark Urine: Due to haemoglobinuria, a consequence of haemolysis. Fatigue and weakness: May result from chronic, low-level haemolysis. Gallstones (pigmented)

Answer 50

Bedside: Assess vital signs and perform a physical examination to check for pallor, jaundice, and hepatosplenomegaly. Blood Tests: A full blood count (FBC) may reveal anaemia, reticulocytosis, and elevated bilirubin levels. Blood film shows Heinz bodies +/- bite and blister cells. A G6PD enzyme activity assay confirms the diagnosis, and importantly should be done around 3 months after an acute exacerbation, as if this is done around the time of an acute haemolytic episode, it will be falsely negative.

Answer 51

Avoiding Triggers: Education on avoiding triggers such as specific medications (e.g. sulfonamides, primaquine), infections, and fava beans is essential. Supportive Care: During acute haemolytic episodes, management includes hydration, pain relief, and blood transfusions in severe cases. Monitoring: Regular follow-up to assess haemoglobin levels and ensure avoidance of triggers.

Answer 52

Acute Haemolysis: Severe haemolysis can lead to anaemia, haemoglobinuria, and increased risk of acute kidney injury. Chronic Anaemia: Repeated haemolytic episodes can result in chronic anaemia. Infection Susceptibility: Patients may be more susceptible to infections during haemolytic episodes.

Answer 53

- Blood loss - Aplastic anaemia (parvovirus B19 infection) - Chronic disease e.g. RA

Answer 54

Haemolytic anaemia is a condition characterised by the premature destruction of red blood cells (RBCs), leading to a decrease in their lifespan. This condition can be classified into hereditary and acquired forms, with further subdivisions based on the site of haemolysis, either intravascular or extravascular, and the underlying cause, autoimmune or non-autoimmune.

Answer 55

Sickle cell disease predominantly affects individuals of African descent, and is most prevalent in sub-Saharan Africa. Thalassemias: The distribution of thalassemias is linked to regions with a high prevalence of consanguineous marriages, notably in Mediterranean countries. The prevalence of autoimmune haemolytic anaemia varies, but it is often associated with autoimmune diseases like systemic lupus erythematosus. It can affect individuals of any age and ethnicity. The incidence of intravascular haemolysis may be higher in conditions involving mechanical trauma, such as prosthetic heart valves or microangiopathic disorders. Extravascular haemolysis is often observed in hereditary conditions like hereditary spherocytosis and can affect individuals worldwide - Hereditary spherocytosis is an autosomal dominant disease, treated (in severe cases) with childhood splenectomy. It is also more common in patients from northern Europe - eosin 5-maleimide (EMA) binding test confirm the diagnosis of hereditary spherocytosis.

Answer 56

Includes conditions like sickle cell disease, thalassemias, and hereditary spherocytosis, often caused by genetic mutations affecting RBC structure or function.

Answer 57

Can result from autoimmune disorders, infections (e.g., malaria), medication reactions, or mechanical trauma.

Answer 58

Occurs within the bloodstream, leading to the release of free haemoglobin into the circulation and the excess of haemoglobin is dealt with in many ways: Combination with haptoglobin Combination with albumin (methaemalbuminaemia) Loss in the urine (haemoglobinuria) Storage in tubular epithelial cells as haemosiderin Shedding into the urine (haemosiderinuria) Causes of intravascular haemolytic anaemia include: Intrinsic cellular injury (eg. G6PD deficiency) Intravascular complement-mediated lysis (some autoimmune haemolytic anaemias) Paroxysmal nocturnal haemoglobinuria and acute transfusion reactions Mechanical injury – microangiopathic haemolytic anaemia and cardiac valves Autoimmune haemolytic anaemia (AIHA)

Answer 59

Takes place outside the bloodstream, primarily in the spleen and liver, where RBCs are phagocytosed. It is not associated with dramatic release of free haemoglobin into the circulation. Splenomegaly and hepatomegaly are typical. Causes include: Abnormal red cells (e.g. sickle cell anaemia and hereditary spherocytosis) Normal cells having been marked by antibodies for splenic phagocytosis

Answer 60

Warm AIHA: An IgG-mediated extravascular haemolytic disease, in which the spleen tags cells for splenic phagocytosis. Causes: SLE, idiopathic, lymphoproliferative neoplasms (eg. chronic lymphocytic leukaemia and lymphoma - diagnosed with flow cytometry), drugs (methyldopa) Managed with prednisolone or immunosupression (e.g. AZT) and transfusions if severe Cold AIHA: IgM-mediated haemolytic disease, in which IgM fixes complement causing direct intravascular haemolysis. It includes cold agglutinin disease The IgM agglutinates also cause the hands and feet to become blue in cold conditions (acrocyanosis) Causes: post-infectious (usually after Mycoplasma or EBV), idiopathic, lymphoproliferative disorders Treatment is mostly supportive, warmed blood is transfused if required and resistant cases may trial rituximab

Answer 61

Caused by factors other than autoantibodies, such as infections or mechanical stress: Microangiopathic haemolytic anaemia Paroxysmal nocturnal haemoglobinuria (PNH) Physical lysis of red cells (e.g. malaria, patients with mechanical heart valves) Haemolytic uraemic syndrome (HUS) – often caused by E. coli 0157:H7 Infectious causes of disseminated intravascular coagulation (DIC) such as fulminant meningococcaemia

Answer 62

Fatigue Pallor Jaundice - Haemolysis releases bilirubin into the bloodstream, causing yellowing of the skin and sclera Splenomegaly - The spleen becomes enlarged as it works to remove and destroy the damaged red blood cells. Dark Urine Gallstones - Excess bilirubin can accumulate in the gallbladder, increasing the risk of gallstone formation. Leg Ulcers - In severe cases, reduced blood flow and oxygen supply can lead to painful leg ulcers. Shortness of Breath Heart Palpitations

Answer 63

Supportive Care: Blood transfusions to manage severe anaemia however this won't be curative as there will be ongoing haemolysis if the underlying cause is not managed. Immunosuppressive Therapy: In autoimmune haemolytic anaemia, medications like corticosteroids can reduce antibody production. Splenectomy: May be considered in certain cases, particularly hereditary spherocytosis. Specific management strategies depend on the type of haemolytic anaemia.

Answer 64

x linked recessive

Answer 65

A positive Coombs test (or antiglobulin test) indicates the presence of antibodies or complement proteins bound to red blood cells (RBCs), suggesting an immune-mediated process.

Answer 66

Oral iron supplements, commonly used to treat iron deficiency anaemia, can reduce the absorption of levothyroxine when taken together. To avoid this interaction, it is recommended to take iron at least four hours before or after levothyroxine. This ensures both medications are absorbed properly and can exert their therapeutic effects.

Answer 67

suggests the possibility of lead poisoning.

Answer 68

management of this condition consists of folate supplementation and splenectomy

Answer 69

- Silent carrier (one defective allele) - Alpha thalassaemia trait (two defective alleles) - Haemoglobin H disease (three defective alleles) - Haemoglobin bart disease (four defective alleles)

Answer 70

Haemophilia A and B are both X-linked recessive inherited bleeding disorders, caused by deficiencies in clotting factors VIII and IX respectively, both of which are integral components of the instrinsic pathway of the coagulation cascade.

Answer 71

Factor VIII

Answer 72

They typically presents early in life with spontaneous deep and severe bleeding into soft tissues, joints and muscles – historically, joint damage resulted in a deforming arthropathy Boys often present with excessive bleeding following trauma or surgical intervention (e.g. tonsillectomy) Cerebral haemorrhage was a major cause of mortality in severe haemophilia before the widespread use of blood products

Answer 73

Diagnosis is with a factor VIII/IX assay For boys with severe haemophilia A or B (factor VIII or factor IX <1%, respectively): Two-thirds are diagnosed at birth when the boy is born to a known or suspected carrier The rest are picked up later on in childhood when the baby begins to crawl or fall, or there is an eruption of dentition Some patients have a milder clinical severity – this is directly related to higher factor levels Mild haemophilia >5% Moderate haemophilia 1–5% Blood tests show: Clotting profile - APTT is elevated vWF antigen is normal in haemophilia A Defective platelet function

Answer 74

Minor bleeds in patients with Haemophilia A can be managed with desmopressin (DDAVP) – increases factor VIII sufficiently to deal with the minor bleeding Major bleeds require recombinant factor VIII or IX In patients with severe haemophilia, the use of regular prophylactic recombinant clotting factor treatment, physiotherapy and education in learning how to avoid bleeds have all contributed to the prevention of joint arthropathy Gene therapy has also been shown to be successful Mild and moderate haemophilia require 'on demand' treatment in response to bleeding or in preparation for surgery Supportive management includes: Antifibrinolytics (eg. tranexamic acid) – useful for bleeding wounds but should be avoided in muscle haematomas, haemarthrosis and urinary bleeding as they can lead to fibrosis Vaccination against hepatitis B, hydrotherapy, orthopaedic and dental advice are also beneficial One-third of boys with severe haemophilia A will develop an inhibitor to factor VIII following factor VIII treatment This can worsen bleeding and complicate therapy Treatment of haemophilia with inhibitors should be directed from a specialist centre Life expectancy for patients with haemophilia A and B is well into middle age in this era of blood product-free concentrates

Answer 75

This patient has developed antibodies to Factor VIII as a result of phenytoin use. Prolonged APTT with normal PT suggests involvement of one or more of Factors VIII, IX, XI & XII. APTT does not correct with the mixing studies suggesting that the bleeding disorder is due to antibody action rather than failure to produce clotting factors.

Answer 76

Haemophilia often presents as failure to walk in toddlers due to bleeding into joints (haemarthrosis). This leads to the displacement of normal joint structures, in this case - the patella and quadriceps tendon, as a result of bleeding into the joints.

Answer 77

Desmopressin enhances haemostasis in Haemophilia A by releasing von Willebrand factor from storage sites in endothelial cells to improve Factor VIII activity.

Answer 78

Splenectomy is the surgical removal of the spleen.

Answer 79

Indications for splenectomy can be classified into emergency and elective indications. Indications for emergency splenectomy include trauma and rupture (e.g. in EBV infection). An elective splenectomy may need to be done in cases of hypersplenism, where the spleen has a preference for platelets resulting in increased uptake, which leads to sequestration of cells in the spleen Indications for elective splenectomy include haemolytic anaemia (hereditary or immune) and idiopathic thrombocytopenic purpura. Note: patients post-splenectomy will have Howell-Jolly bodies and Pappenheimer bodies on blood film.

Answer 80

Following splenectomy or in patients with hyposplenism (dysfunctional spleen, e.g. in coeliac disease) there is a reduced immune response against encapsulated organisms (haemophilus, pneumococcus, and meningococcus). What are the most common organisms associated with severe infection? (3) **NHS** - Neisseria meningitidis - Haemophilus influenzae type b (Hib) - Streptococcus pneumoniae (pneumococcus)

Answer 81

Prophylaxis Patients therefore require the following vaccinations: Pneumococcal vaccination (with regular boosters every 5 years). Seasonal influenza vaccination (yearly, typically every autumn). Haemophilus influenza type B vaccination (one-off). Meningitis C vaccination (one-off). Patients also require daily low-dose prophylactic antibiotics, often for life. The typical regimen is with phenoxymethylpenicillin which is also known as penicillin V (clarithromycin or erythromycin if patients are allergic to penicillin). Note: the risk of infection is particularly high in the 2 years following splenectomy, the highest risk being from pneumococcal infection.

Answer 82

Pancytopenia is a haematological condition characterised by reduced counts of all three major cellular components of blood: erythrocytes, leukocytes and thrombocytes.

Answer 83

These can be broadly grouped into three categories: decreased production, increased destruction or sequestration, and peripheral dilution.

Answer 84

Marrow infiltration: Conditions such as leukaemia, lymphoma, myelodysplastic syndromes (MDS), multiple myeloma, metastatic carcinoma or granulomas can infiltrate the bone marrow leading to pancytopenia. Aplastic anaemia: This is a rare condition where the bone marrow fails to produce enough new cells. It can be idiopathic or secondary to exposure to toxins (e.g., benzene), drugs (e.g., chloramphenicol), viral infections (e.g., Hepatitis C) or autoimmune diseases. Nutritional deficiencies: Deficiencies of vitamin B12, folate or iron can impair haematopoiesis resulting in pancytopenia.

Answer 85

Hypersplenism: Conditions causing splenomegaly such as cirrhosis, lymphomas or infectious diseases like malaria can lead to increased sequestration and destruction of blood cells resulting in pancytopenia. Paroxysmal nocturnal haemoglobinuria (PNH): This is a rare acquired disorder that leads to the destruction of red blood cells, white blood cells and platelets.

Answer 86

Dilutional pancytopenia: This can occur in conditions causing overhydration or following transfusion of large volumes of intravenous fluids.

Answer 87

Risk factors for pancytopenia include exposure to certain drugs (e.g., antineoplastics, sulphonamides, anticonvulsants), toxins (e.g., benzene, heavy metals), radiation therapy and certain infections (e.g., HIV, Hepatitis C). Furthermore, individuals with a history of autoimmune diseases, genetic disorders affecting the bone marrow (e.g., Fanconi anaemia) or those who have undergone bone marrow transplantation are at an increased risk. Age is another significant factor as the incidence increases with advancing age due to an increased prevalence of malignancies and myelodysplastic syndromes.Improve

Answer 88

The classification of pancytopenia can be broadly divided into three categories: inherited, acquired, and idiopathic. This categorisation is based on the underlying cause of the condition.

Answer 89

Fanconi Anaemia: This is a rare genetic disorder causing bone marrow failure. It leads to progressive pancytopenia, with aplastic anaemia being a common manifestation. Dyskeratosis Congenita: Another inherited bone marrow failure syndrome, it is characterised by skin pigmentation, nail dystrophy, and oral leukoplakia in addition to pancytopenia. Shwachman-Diamond Syndrome: A rare congenital disorder associated with exocrine pancreatic insufficiency and varying degrees of bone marrow failure leading to pancytopenia.

Answer 90

Aplastic Anaemia: An acquired condition often due to immune-mediated destruction of haematopoietic stem cells, resulting in pancytopenia. Megaloblastic Anaemia: Caused by deficiency of vitamin B12 or folate leading to ineffective erythropoiesis and subsequent pancytopenia. Hypersplenism: Overactivity of the spleen can lead to sequestration and destruction of all blood cell lines causing pancytopenia. Infections: Certain infections such as HIV, hepatitis viruses, Epstein-Barr virus can directly or indirectly cause damage to the bone marrow leading to pancytopenia. Chemotherapy and Radiation: These treatments can cause bone marrow suppression leading to pancytopenia.

Answer 91

Pallor: This is often one of the first signs noted in patients with pancytopenia. It results from reduced oxygen-carrying capacity of the blood due to decreased red blood cell count. Fatigue and weakness: Patients may report feeling tired or weak due to inadequate oxygen supply to tissues. Dyspnoea: Shortness of breath on exertion can occur as the body attempts to compensate for low oxygen levels by increasing respiratory rate. Tachycardia: An increased heart rate may be present as a compensatory mechanism for anaemia.

Answer 92

Infections: Patients are more susceptible to infections due to decreased immune response. These infections can be recurrent and may be caused by organisms which are usually non-pathogenic in individuals with normal immunity. Fever: A persistent or intermittent fever can be a sign of underlying infection in these patients. In severe cases, sepsis may develop.

Answer 93

Bleeding tendencies: This could manifest as petechiae (small red or purple spots on the skin), purpura (larger patches of bleeding into the skin), or ecchymosis (bruises). There could also be spontaneous bleeding from the gums, nosebleeds, or heavy menstrual bleeding in women. Haemorrhagic complications: In severe cases, patients may present with major haemorrhages, such as gastrointestinal bleeding or intracranial haemorrhage.

Answer 94

Full Blood Count (FBC) and Peripheral Blood Smear (PBS) Confirm pancytopenia with repeat FBC. Examine PBS for abnormal cells, including blasts, dysplastic changes, or evidence of haemolysis. Bone Marrow Examination Bone marrow aspirate and trephine biopsy can provide definitive diagnosis in many cases. It is particularly useful when there's suspicion of a primary bone marrow disorder. Serological Studies Perform serological tests for viral infections such as HIV, Hepatitis B and C, Epstein-Barr virus (EBV), and Cytomegalovirus (CMV). Autoimmune Screening An autoimmune screen can be helpful if an autoimmune process is suspected. This includes antinuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), rheumatoid factor (RF), and extractable nuclear antigens (ENA). Biochemical Tests Liver function tests, renal function tests, lactate dehydrogenase (LDH), haptoglobin, direct antiglobulin test (DAT), vitamin B12 levels, folate levels, iron studies including ferritin level should be performed. Cytogenetic and Molecular Studies If myelodysplasia or acute leukaemia is suspected based on the PBS or bone marrow findings, cytogenetic analysis or fluorescence in situ hybridisation (FISH) studies should be carried out. Imaging Chest X-ray and abdominal ultrasound may be useful in certain cases, especially when organomegaly or lymphadenopathy is present.

Answer 95

- RBC and platelet transfusion - Bone marrow and stem cell transplant Growth factor support with erythropoietin or granulocyte colony-stimulating factor in certain circumstances.

Answer 96

Infections: Due to neutropenia, patients are at increased risk of bacterial, fungal, and viral infections. These can range from mild skin infections to severe sepsis. Bleeding: Thrombocytopenia predisposes to spontaneous bleeding. This can manifest as petechiae, purpura, epistaxis or even life-threatening haemorrhage such as intracranial bleeding. Anaemia-related complications: Chronic anaemia can lead to fatigue, pallor and dyspnoea on exertion. Severe anaemia may result in high-output cardiac failure. Organ dysfunction: Persistent cytopenias may contribute to organ dysfunction such as hepatic or renal insufficiency. Malignant transformation: In conditions like myelodysplastic syndromes or aplastic anaemia which often present with pancytopenia, there is a risk of progression to acute myeloid leukaemia.

Answer 97

Polycythaemia is classified as relative or absolute.

Answer 98

Relative polycythaemia (or pseudopolycythaemia) occurs when the haemoglobin is elevated secondary to a low plasma volume rather than an increased number of red cells – remember the haemoglobin level is measured as a concentration.

Answer 99

Dehydration Chronic alcohol intake Excess diuretic use Pyrexia Diarrhoea and vomiting 'Stress polycythaemia' refers to relative polycythaemia that is found predominantly in middle-aged men with stressful occupations and chronically reduced plasma volumes of uncertain cause Gaisböck syndrome is more common in young men, particularly smokers, and is associated with hypertension, which reduces plasma volume, resulting in raised haemoglobin (pseudopolycythaemia)

Answer 100

If the plasma volume is normal, the polycythaemia is an absolute polycythaemia (red cell mass will be raised). Absolute polycythaemia is classified into primary and secondary causes.

Answer 101

In primary polycythaemia, there is excess and uncontrolled erythrocytosis that is independent of erythropoietin (EPO) levels. Most cases of PV are associated with mutations in the JAK2 gene, leading to uncontrolled production of blood cells, especially RBCs. In the majority of cases, it is due to the myeloproliferative condition polycythaemia rubra vera (PRV), which is also known as 'primary proliferative polycythaemia', although there are also some rare familial causes.

Answer 102

In secondary polycythaemia, the excess RBC production is driven by excess EPO. This can be secondary to: An appropriate rise in EPO, as seen in conditions of chronic hypoxia (e.g. COPD or spending time at high altitude) Anabolic steroid use Inappropriate secretion of EPO, which may be seen: In renal neoplasms as a paraneoplastic effect In CKD - impaired renal function can lead to reduced erythropoietin clearance, causing an increase in RBC production In cyanotic heart disease (e.g. tetralogy of Fallot) In high-affinity haemoglobinopathies (e.g. haemoglobin M)

Answer 103

Fatigue Headache Visual disturbances (secondary to hyperviscosity) Pruritus (typically after a hot bath) Erythromelalgia (a painful burning sensation in the fingers and toes) Arterial thrombosis (eg. myocardial infarction or stroke) Venous thrombosis (eg. pulmonary embolus or deep vein thrombosis) Haemorrhage (intracranial or gastrointestinal)- paradoxical increased bleeding risk (due to impaired platelet function) Increased risk of gout (caused by hyperuricaemia secondary to increased cell turnover). Facial redness on examination (plethora) Splenomegaly Hypertension Peptic ulceration

Answer 104

Hyperviscosity symptoms: Chest pain, myalgia, weakness, headache, blurred vision, loss of concentration 'Ruddy complexion' Splenomegaly

Answer 105

Bedside - Pulse oximetry to look for possible secondary polycythaemia Full blood count (FBC) Raised haematocrit Raised haemoglobin Raised red cell mass with low/low–normal plasma volume (ie. true polycythaemia) Raised leukocytes and platelet counts – seen in half of patients In contrast, the neutrophil count and platelet count are usually normal in secondary polycythaemia Renal function and urate (may be raised) Vitamin B12 (often elevated in myeloproliferative disease) EPO levels - often low JAK-2 V617F mutation (>95% of cases) Bone marrow biopsy - Hypercellular bone marrow Abnormal ultrasound – looking for possible abnormalities in kidneys, liver and spleen It is important to exclude chronic myeloid leukaemia, which is done by cytogenetic testing.

Answer 106

Where possible underlying causes of secondary and relative polycythaemia should be corrected The aim should be to maintain: Haematocrit <45% in primary polycythaemia Haematocrit <55% in secondary polycythaemia Venesection is an effective method of lowering the red cell count rapidly and can also be used in the maintenance therapy period Patients need to have reasonable venous peripheral access for this option Repeated venesection may result in iron-deficient RBCs with low haemoglobin content

Answer 107

Regular venesection as above Aspirin 75mg daily Cytoreductive therapy to suppress erythropoeisis in those where venesection isn't sufficient, or those at high risk of thrombosis (most older patients): 1st line: hydroxycarbamide – suppresses erythrocytosis and causes a macrocytosis 2nd line: - Interferon, JAK-2 inhibitors (eg. ruxolitinib) 3rd line: Busulfan can be used but is leukaemogenic. In younger patients, interferon is first line with hydroxycarbamide second line Other interventions: Allopurinol (for gout/hyperuricaemia) Antihistamines, selective serotonin reuptake inhibitors, or interferon (for pruritus)

Answer 108

Acute myeloid leukaemia (AML) Acute lymphoblastic leukaemia (ALL) Chronic myeloid leukaemia (CML) Chronic lymphocytic leukaemia (CLL)

Answer 109

a result of impaired cell differentiation, resulting in large numbers of malignant precursor cells in the bone marrow

Answer 110

the result of excess proliferation of mature malignant cells, but cell differentiation is unaffected

Answer 111

commonly arises from a myeloid precursor cell, such as the cells that produce neutrophils

Answer 112

arises from a lymphoid precursor, such as a B or T cell

Answer 113

Acute myeloid leukaemia It predominantly affects adults, especially older adults, with no geographical variation It can be associated with myelodysplastic syndrome Ionising radiation (like that from a nuclear disaster) has been shown to be associated with the development of leukaemia

Answer 114

- Anaemia- features? **(3)** - Fatigue - Pallor - Weakness - neutropenia (despite high WCC)- leading to frequent infections - Thrombocytopenia- features? **(5)** - Epistaxis - Bleeding gums - Petechiae - Purpura - Easy bruising - splenomegaly → can present as ‘early satiety’ - bone pain

Answer 115

- FBC- what will it show? **(3)** - Neutropenia - Thrombocytopenia - Anaemia - Peripheral blood smear- what will it show? Presence of blast cells (immature WBCs) Myeloblasts and Auer rods Bone marrow biopsy is key to diagnosis, along with other molecular analyses Characteristic findings include: hypercellular marrow the presence of blasts (usually >50%) Sometimes Auer rods

Answer 116

Many different cytogenetic abnormalities can be seen, which are associated with varying effects on prognosis -The translocation t(15;17) – a reciprocal translocation involving the RARA gene – confirms acute promyelocytic leukaemia (APML; M3 subtype) Confers a good prognosis Hypergranular promyelocytes are seen, except in the M3 variant, which is hypogranular T(8;21) seen in M2 subtype Confers better prognosis – chemotherapy may be sufficient, with bone marrow transplantation usually reserved for relapse Cytogenetic abnormalities are the most significant prognostic factors in acute myeloid leukaemia, influencing treatment decisions and patient outcomes.

Answer 117

Chemotherapy regimens (unless the patient is older or unfit) – usually three or four courses of intensive chemotherapy lasting 5–10 days Initial induction chemotherapy is designed to remove the bulk of the leukaemic cells (<5% blasts in the marrow) and subsequent consolidation chemotherapy to remove residual disease A long-term indwelling catheter (i.e. Hickman tunnelled line or PICC) is usually placed to facilitate the administration of chemotherapy and blood products Bone marrow transplantation A powerful and effective therapy that combines: The destruction of leukaemic cells with conditioning chemotherapy and radiotherapy with the aim of clearing the bone marrow before donor stem cells are given The immunogenic response from receiving donor cells that helps to destroy any remaining leukaemic cells (termed the 'graft-versus-leukaemia' effect) Can be risky, with risk increasing in age Complications include relapse and graft-versus-host disease, where the immunogenic response is against the host Prophylactic antimicrobials – given to reduce the risk of infection Blood products and growth hormone therapy – can be given for anaemia, thrombocytopenia and leucopenia as a result of chemotherapy treatments

Answer 118

APML has a high incidence of DIC, so needs aggressive management with platelets and clotting factor support It carries a good prognosis as the translocation t(15;17) translocation makes the disease sensitive to treatment with all-trans retinoic acid (a vitamin A analogue), which is commenced before starting chemotherapy

Answer 119

Death typically occurs within 2 months without treatment Prognosis is still poor in those who undergo treatment 3-year survival rate 20% 30% cure rate with chemotherapy Allogenic transplant can extend this with its curative approach but is usually reserved for younger patients (<50 years) Key survival factors in AML are related to: Age Poor cytogenetics Response to the first dose of induction chemotherapy

Answer 120

Complications include therapy-related long-term side effects such as: Secondary malignancy Cardiorespiratory complications Endocrine dysfunction Infertility Avascular necrosis of the hip – due to prolonged steroid exposure Neuropsychological effects

Answer 121

ALL is a disease of the young (in contrast to AML) It is the most common cancer in childhood – peak incidence at age 4–5 years It can present in adulthood, albeit less commonly It is caused by the abnormal proliferation of lymphoid progenitor cells, which infiltrate the bone marrow and other organs of the body Down syndrome is a well-established risk factor for acute lymphoblastic leukaemia (ALL). Children with Down syndrome have a 10- to 20-fold increased risk of developing ALL compared to the general population.

Answer 122

Symptoms: Of marrow failure, such as fatigue (due to anaemia), abnormal bleeding/bruising (low platelets) and infections (low white cells) From organ infiltration, such as bone pain Signs: Painless lymphadenopathy Hepatosplenomegaly Central nervous system (CNS) involvement (e.g. cranial nerve palsies, meningism) – very common in ALL in contrast to AML Testicular infiltration (resulting in painless unilateral testicular enlargement) causes bone marrow failure leading to a pancytopenia (↓Hb, ↓WCC, ↓platelets). This means that all cell lineages are affected. It can also cause hepatosplenomegaly and lymphadenopathy (superficial or mediastinal). The conjunctival pallor and flow murmur are secondary to the anaemia

Answer 123

Lymphadenopathy and fevers

Answer 124

Leucocytosis on FBC Blast cells on blood film and bone marrow Lymphoblasts are typically large with nucleoli, with very little cytoplasm and no granularity Immunophenotyping can help to differentiate whether the origin is a T or B cell, along with other immunological subtypes Periodic acid–Schiff (PAS) stains for carbohydrate material in ALL

Answer 125

ALL is commonly treated with chemotherapy regimens The treatment strategy is combination chemotherapy that induces remission and then consolidates with stronger chemotherapy CNS prophylactic agents are given to all patients with ALL The CNS is a sanctuary site and many drugs are unable to penetrate the 'blood-brain barrier' – Before this practice, there was a high incidence of CNS relapse Maintenance therapy is delivered to give continuous treatment for 2 years, which has been shown to improve 2-year survival

Answer 126

Blast count in the bone marrow – morphological remission is defined by blast count < 5% Assessment of minimal residual disease (MRD) – greater sensitivity than morphological assessment Uses polymerase chain reaction (PCR) to amplify the characteristic clonal rearrangements of: Immunoglobulin genes in B-cell ALL T-cell receptor genes in T-cell ALL With the detection of 1 leukaemic cell in 10,000 cells in the bone marrow

Answer 127

Children have a cure rate of 70–90% with chemotherapy alone, particularly in good disease-risk groups 20–30% have poor-risk disease with poor-risk prognostic factors including: Age <1 year and >10 years Male sex WCC >50 × 109/l (higher pretreatment WCC predicts poor prognosis) CNS disease poor cytogenetic features, such as t(9;22) T-ALL – prognosis is worse than for B-ALL Incomplete response to therapy In the context of acute lymphoblastic leukaemia (ALL) treatment, hyperdiploidy in blast cells is linked to a more favourable outcome.

Answer 128

CML is most common in middle-aged patients (median age 40–50 years), although any age can be affected Men are slightly more likely to be affected than women It is regarded as sporadic as no significant risk factor has been identified, except for previous high-dose ionising radiation Incidence is 1 per 100,000 of the population It is classically associated with the Philadelphia chromosome

Answer 129

CML usually presents with: Weight loss Tiredness Fever Sweating Common signs include: Massive splenomegaly (>75% of patients) Bleeding (due to thrombocytopenia) Gout The white blood cell count can be very high (>500 × 109/l), which can cause hyperleukocytosis with symptoms, such as: Visual disturbance Confusion Priapism Deafness Hypermetabolism also occurs, with weight loss, sweats and anorexia.

Answer 130

- FBC- what will it show? **(5)** - Leukocytosis - Thrombocytosis - Basophilia - Eosinophilia - High band cells - Blood film- would show what? Left shift (immature granulocytes) → granulocytosis + myeloblasts - Look at leukocyte alkaline phosphatase (LAP)- what will it be? Decreased - Cytogenic testing- for what? For confirmation of Philadelphia chromosome - The protein product of the hybrid BCR-ABL gene has tyrosine kinase activity that leads to uncontrolled cell proliferation and differentiation Bone marrow analysis shows similar findings, plus Marrow hyperplasia Increased reticulin (fibrosis) Granulocytic predominance High vitamin B12 levels can also be present owing to vitamin B12-binding protein being produced by the white cells

Answer 131

CML treatment has been revolutionised by tyrosine kinase inhibitors (eg. imatinib), which have dramatically improved the prognosis of the disease and reduced the incidence of transformation to the acute blast crisis phase, which is often difficult to treat. The treatment strategy is to: Induce clinical remission and thereby reduce hypercatabolic symptoms and splenomegaly Induce haematological remission, with normalisation of the blood count Induce cytogenetic remission, with the elimination of the Philadelphia chromosome from marrow cells and Induce molecular remission, with undetectability of the BCR–ABL fusion gene by PCR The agents used are: Hydroxycarbamide, which may be used to help normalise the blood count while awaiting genetic test results and to reduce splenomegaly It does not modify the underlying molecular/cytogenetic abnormalities or prevent acute transformation Tyrosine kinase inhibitors (eg. imatinib)

Answer 132

Monitoring of BCR–ABL levels is usually performed quarterly Excellent cytogenetic response is defined as a three-log reduction in the BCR–ABL percentage (ie. <0.1% if 100% at presentation) It is expected that tyrosine kinase inhibitors can be continued lifelong – some studies have however shown that patients with well-controlled CML can have their TKI discontinued. Screening for mutations in the BCR–ABL gene that are associated with treatment resistance should be performed in patients who fail to respond to imatinib If found, they can be treated with one of the newer tyrosine kinase inhibitors (eg. nilotinib or dasatinib)

Answer 133

Reversible side effects of tyrosine kinase inhibitors include: Nausea Thrombocytopenia Neutropenia Fluid retention A switch to one of the newer tyrosine kinase inhibitors can be tried if patients have significant side effects.

Answer 134

CLL is most common in men over the age of 60 years – incidence is 50 per 100,000 individuals after the age of 70 years There is some evidence of a familial tendency CLL is caused by the proliferation of functionally incompetent malignant B cells The CLL cells accumulate because they survive for a very long time, rather than because they divide at an accelerated rate It is therefore an indolent disease of deregulated programmed cell death

Answer 135

CLL typically presents asymptomatically, but patients may present with: Non-tender symmetrical lymphadenopathy Hepatosplenomegaly B symptoms – weight loss, night sweats and fever Features of marrow failure (infection, anaemia and bleeding) are less common than in acute leukaemias.

Answer 136

- FBC- what would it show? **(2)** - Persistent lymphocytosis - With high percentage of small sized, mature lymphocytes - Blood smear- what would it show? Smudge cells The most common initial blood result is an incidental lymphocytosis (80% of cases) Blood film shows smudge cells – cells damaged as the film is made because they lack a cytoskeletal protein Immunophenotype of the cells is CD5 and CD23 positive, FMC negative, CD22 and surface immunoglobulin weak Chromosomal abnormalities are found in approximately 50% of patients Direct antiglobulin test can be positive – AIHA can complicate CLL Hypogammaglobulinaemia is common in advanced disease Other tests include bone marrow biopsy, which will show lymphocytic infiltration of mature lymphocytes, with some smear cells

Answer 137

Traditionally, intensive chemotherapy with fludarabine, cyclophosphamide and the addition of rituximab (FCR) is used to form first-line therapy. This has now changed in the world of targeted pathway inhibitors superseding chemotherapy. In a patient with no co-morbidities and TP53 intact, +/- mutated IGHV mutated status, can now start with Venetoclax (selective inhibitor of B-cell lymphoma-2, BCL-2) -Obinutuzumab (anti-CD20 monoclonal antibody) (Ven-O) upfront, before considering FCR upfront alternatively in this patient group. In fit patients with TP53 mutational disruption or any IGHV mutated status or traditionally unsuitable for FCR, frontline therapy is with Acalabrutinib (bruton tyrosine kinase inhibitor) +/- Obinutuzumab or upfront Ibrutinib (tyrosine kinase inhibitor, TKI) monotherapy. Alternatively, this patient group can also be started on upfront Ven-O or Venetoclax monotherapy. BTKi (ibrutinib and acalabrutinib), BCL2i (venetoclax monotherapy or in combination with rituximab) and phosphoinositide 3-kinase inhibitors (PI3Ki) (idelalisib and rituximab) are presently licensed for relapsed/refractory CLL. Allogeneic stem cell transplant should be considered in those fit patients who have failed at least 2 of : chemoimmunotherapy, BTKi, BCL2i or have Richter’s transformation (sudden transformation into a significantly more aggressive form of large cell lymphoma). If they are high-risk patients (TP53 disrupted), then an allogenic transplant can be considered after the failure of these therapies. Steroids and monoclonal antibody treatments (eg. rituximab) may be useful in autoimmune haemolytic disease. Prevention or treatment of infection with antibiotics or immunoglobulins is also part of the management.

Answer 138

CLL is a very variable disease: 1/3 of cases don't progress, 1/3 of cases progress slowly, and 1/3 of cases progress actively. Factors that affect prognosis are Disease stage Atypical lymphocyte morphology Lymphocyte doubling time <12 months Bone marrow trephine showing diffuse involvement Chromosomal/genetic abnormalities, in particular TP53 Unmutated immunoglobulin VH (IGVH) gene status Male sex High expression CD38

Answer 139

Richter’s transformation refers to the development of aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL), in patients with CLL. It is characterised by rapid lymph node enlargement, constitutional symptoms (fevers, night sweats, weight loss), and elevated LDH levels. The systemic and localised symptoms, particularly in the context of CLL, point towards this diagnosis.

Answer 140

B symptoms in leukemia refer to a set of constitutional symptoms that indicate systemic disease activity. They are often associated with lymphoproliferative disorders, including acute leukemia (such as Acute Lymphoblastic Leukemia (ALL)) and chronic leukemia (such as Chronic Lymphocytic Leukemia (CLL)), and may suggest advanced disease or a poor prognosis. The three classic B symptoms are: Fever: Typically unexplained and often low-grade (above 38°C or 100.4°F). This can occur due to cytokine release from leukemic cells or associated infections. Night Sweats: Profuse sweating during sleep, often drenching, which can result from immune activation or increased tumor burden. Unintentional Weight Loss: A loss of more than 10% of body weight over a period of 6 months without trying, often linked to the body's metabolic response to leukemia.

Answer 141

Multiple myeloma is a plasma cell dyscrasia characterised by abnormal clonal proliferation of post-germinal B cells (plasma cells). These plasma cells secrete monoclonal antibodies (most commonly of the Ig subtype) and antibody fragments into the serum and the urine. There is also a relative deficiency of functional antibodies, resulting in a relative hypogammaglobulinaemia. This condition leads to bone destruction, kidney dysfunction, anaemia, and a range of systemic symptoms

Answer 142

Multiple myeloma is the second most common haematologic malignancy, accounting for approximately 1% of all cancers. It predominantly affects older adults, with the median age at diagnosis around 69 years, and those of Afro-Caribbean descent are affected twice as frequently as Caucasians, and men more than women.

Answer 143

The clinical features of multiple myeloma can be remembered by the mnemonic CRAB HAI: HyperCalcaemia – arises primarily owing to increased osteoclast-mediated bone resorption. Results in: moans (painful bones), stones (renal stones), groans (GI symptoms) and psychiatric moans (neurological effects such aslethargy, fatigue, memory loss, psychosis, depression) Renal impairment – occurs because of multiple factors (eg. light chain deposition in the kidneys and hypercalcaemia) Anaemia – other cytopenias (eg. thrombocytopenia and leukopenia) can also occur due to marrow infiltration by the tumour Bone pathology – Back pain is very common. Osteolytic lesions are common, which can lead to pathological fractures and vertebral compression fractures Hyperviscosity – can present with headache, visual disturbance and thrombosis Amyloidosis (AL subtype) – can have multiple sequelae including cardiac failure and neuropathy Infection – recurrent infection occurs secondary to leukopenia and immunoparesis (ie. low levels of functional IgG)

Answer 144

Work-up investigations FBC – may show anaemia U&E – may show renal impairment (particularly raised serum creatinine) and/or hypercalcaemia (with normal ALP), which is a common feature Raised ESR (the positive charge of the protein neutralises the negative charge of the sialic acid on the red cell membrane, reducing the red cells natural tendency to repulse each other, so they fall down the column faster) Skeletal survey – typically done with X-rays, but CT/MRI are more sensitive Findings include osteolytic bone lesions and pathological fractures Diagnostic investigations: Serum protein electrophoresis is the key investigation for confirming multiple myeloma by detecting elevated M protein levels A definitive diagnosis of multiple myeloma requires a bone marrow aspirate and biopsy, revealing over 10% plasma cells to distinguish it from monoclonal gammopathy of unknown significance. Serum and/or urine electrophoresis – This will show a paraprotein spike (typically IgG) Serum free light chain assay (Bence Jones protein) - Can be kappa or lambda - Serum-free light chain levels are high in myeloma can be a useful test in the 1–2% of patients with nonsecretory multiple myeloma (ie. those who do not have a serum/urine monoclonal protein on electrophoresis) Tissue diagnosis typically by bone marrow aspirate and biopsy Myeloma is confirmed if there are >10% plasma cells in the bone marrow Whole body MRI is the first-line imaging in suspected multiple myeloma to assess for bony involvement, as per NICE guidelines. Rouleaux formation on a blood film

Answer 145

Acute renal failure – swift treatment of volume depletion is critical, as well as early involvement of renal physicians Hypercalcaemia – fluid and bisphosphonates needed Hyperviscosity – requires plasmapheresis Spinal cord compression – should be treated as a radiotherapy emergency

Answer 146

Patients will require regular follow-up, with consideration of initiation of therapy when/if signs of active disease appear

Answer 147

Haematopoietic stem cell transplantation The patient will require induction therapy with a nonchemotherapeutic (eg. bortezomib, thalidomide and dexamethasone) (VTD) given together with Daratumumab (monoclonal antibody binding CD38) (DVTD). The standard upfront trajectory for myeloma is DVTD then Autograft then DVTD consolidation then Lenalidomide maintenance. Non-chemotherapeutic options are replacing chemotherapeutic options as they have a lower toxicity rate. A conditioning regimen (high-dose melphalan) followed by autologous stem cell transplant is the preferred option Autologous transplants have a low transplant mortality rate (<1%), but also a lower remission rate (40%) than allogeneic transplants Allogeneic transplants have a higher transplant mortality rate but also a higher remission rate

Answer 148

The standard of care for such patients is melphalan, prednisolone and thalidomide (MPT) This induces good event-free survival Lenalidomide (antiangiogenic) is an alternative to thalidomide Most patients will relapse after initial treatment Further combination therapies of thalidomide, melphalan, lenalidomide, bortezomib (proteasome inhibitor) or dexamethasone can be used such as VMP.

Answer 149

Bone Disease: Multiple myeloma often leads to bone destruction, pathological fractures, and skeletal-related events. Treatment includes bisphosphonates and denosumab to strengthen bones. Renal Dysfunction: Kidney impairment is a common complication, requiring close monitoring and potential interventions. Infections: Patients with myeloma are at increased risk of infections due to weakened immune function. Preventative measures and prompt treatment are essential. Influenza and pneumococcal vaccination should be given for infection prevention. Anaemia: Should be managed with erythropoietin (± transfusion) for anaemia

Answer 150

One significant prognostic tool is the International Staging System (ISS), which stratifies patients into three stages based on the levels of two serum markers: beta-2 microglobulin and albumin. Investigations to inform prognosis include: β2 microglobulin (a very high or very low level confers poor prognosis) - Used in the staging of myeloma by the International Staging System (ISS), which relates to β2 microglobulin and albumin levels LDH (the higher the level, the worse the prognosis) CRP (the higher the level, the worse the prognosis) FISH and cytogenetic analysis – This may also inform the type of treatment used Note: High serum creatinine and low albumin are also poor prognostic markers. Median survival for myeloma is 50% at 5 years. High ISS is associated with poor prognosis.

Answer 151

Essential thrombocytosis is a myeloproliferative disorder caused by dysregulated megakaryocyte (platelet precursor) proliferation. This is often due to a JAK2 V617F mutation, present in over half of patients with the condition.

Answer 152

50% of patients are asymptomatic, with only an incidental FBC finding Thrombosis (arterial or venous) Bleeding (gastrointestinal or intracranial) Hyperviscosity-related - dizziness/syncope, headache Splenomegaly Hyposplenism (caused by multiple splenic infarcts) Erythromelalgia (a red/blue discolouration of the extremities, often accompanied by a burning pain) Livedo reticularis (a net-like purple rash)

Answer 153

The key differential is secondary (reactive) thrombocytosis A transient thrombocytosis triggered by a precipitant (eg. infection, bleeding, thrombosis, iron deficiency, hyposplenism or trauma) – it is important to enquire about possible precipitants in the history Thrombotic complications and bleeding are uncommon in secondary thrombocytosis Most cases with a platelet count >1000 × 109/l are likely due to essential thrombocytosis unless there is a clinically obvious secondary cause A normal platelet count before a possible event/trigger suggests secondary thrombocytosis

Answer 154

FBC – hallmark is persistent platelet count significantly >450 × 109/l. White cell count may be raised with no basophilia If no clear precipitant, which is suggestive of essential (primary) thrombocytosis genetic testing can be done. JAK2 V617F mutation is present in 50–60% of patients. Trephine biopsy - hypercellular marrow and pathological megakaryocytic clumping

Answer 155

Low risk Age <40 years AND: Platelet count <1500 × 109/l No history of thrombosis or haemorrhage No cardiovascular risk factors (diabetes, hypertension, obesity and smoking) Treatment with aspirin alone Essential thrombocythaemia refers to a high platelet count that is not caused by another health condition. If treatment is required, hydroxyurea or anagrelide may be used.

Answer 156

Age >60 years OR has: Platelet count >1500 × 109/l Previous history of thrombosis or haemorrhage Diabetes or hypertension Patients should be treated with hydroxycarbamide and aspirin Patients of childbearing age in this risk group should be counselled about the use of contraception

Answer 157

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by the gradual replacement of normal bone marrow tissue with fibrous tissue. This condition results in bone marrow scarring, peripheral blood abnormalities, and enlarged spleen (splenomegaly).

Answer 158

The development of myelofibrosis is closely associated with genetic mutations, including the Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukaemia virus oncogene (MPL) mutations. These mutations contribute to the dysregulated production of blood cells and the fibrotic changes in the bone marrow.

Answer 159

Constitutional symptoms – weight loss, fever, night sweats Marrow failure – anaemia, recurrent infection, and abnormal bleeding/bruising Bone pain Haemorrhage and thrombosis (less common in myelofibrosis than in other myeloproliferative disorders) Signs include: Splenomegaly (can be massive and painful) – abdominal discomfort, early satiety Hepatomegaly (seen in 50% of patients)

Answer 160

Blood film typically shows poikilocytes (tear-shaped RBCs) and a leucoerythroblastic blood film Platelet count and WCC are often high initially, with pancytopenia occurring later Owing to the marrow fibrosis, it is difficult to aspirate the bone marrow, often resulting in a 'dry tap' Trephine biopsy shows evidence of fibrosis, with hypercellular tissue, reduced fat space and increased reticulin staining Urate and LDH are usually high JAK-2 V617F is positive in 50% of cases

Answer 161

Myelofibrosis is generally an incurable condition Allogeneic stem cell transplantation is the one exception – reserved for patients aged <70 years with good performance status and high-risk disease JAK-2 inhibitors (ruxolitinib) can have a good effect particularly in reducing splenomegaly and treating B symptoms Cytotoxic agents, immunomodulatory drugs (eg. thalidomide), splenic irradiation and splenectomy can be used as treatments to lessen the need for transfusion and improve symptom control

Answer 162

Transformation to Acute Leukaemia: A small percentage of MF patients may experience a transformation to acute leukaemia, which has a poor prognosis. Splenomegaly-related Complications: Enlarged spleen can lead to abdominal discomfort, early satiety, and increased risk of infection. Cardiovascular and Thrombotic Events: Myelofibrosis is associated with an increased risk of thrombotic events, including deep vein thrombosis and pulmonary embolism.

Answer 163

Sickle cell anaemia (SCA) is a genetic condition where normal haemoglobin (where variable HbS is present) tends to form abnormal haemoglobin molecules (HbS) upon deoxygenation leading to distortion of RBCs.

Answer 164

HbS is produced when the glutamic acid at the 6th position of the β chain is replaced by valine In its deoxygenated state, HbS undergoes polymerisation, forming crystals that cause polymers to form, which in turn leads to the development of RBCs with a sickle shape The abnormal shape of the RBCs causes clotting in the microvasculature, which precipitates vaso-occlusive crises, leading to ischaemia of vital organs and pain Deformation of the RBCs leads to chronic haemolysis, which decreases the body's nitric oxide – typically needed for vasoregulation – and this leads to chronic complications such as pulmonary hypertension and leg ulcers

Answer 165

Sickle cell anaemia (HbSS) is an autosomal recessive condition. The most predominant and most severe form, homozygous HbS, represents just one of the sickle cell disease syndromes. Other forms of sickle cell disease involve the coinheritance of HbS with other haemoglobin variants. Most commonly HbC or β-thalassaemia, leading to the HbSC or HbS-βthal forms of sickle cell disease.

Answer 166

In addition, sickled red cells commonly sequester in the spleen, where they undergo phagocytosis by the reticular endothelial system, leading to extravascular haemolysis Initially, this leads to splenic congestion and splenomegaly This is followed by splenic infarction, leading to hyposplenism Because of splenic compromise, there is reduced immune function Individuals with sickle cell disease are prone to bacteraemia – the spleen is necessary for phagocytosis of encapsulated bacteria. This means there is vulnerability to encapsulated organisms such as Haemophilus influenzae type B. Affected individuals should have up to date vaccinations for S. pneumoniae, H. influenzae B and N. meningitidis.

Answer 167

Vaso-occlusive crises Painful vaso-occlusive crises are the most common acute presentation of sickle cell anaemia Primarily caused by microvascular obstruction due to RBC sickling and inflammation May be triggered by local hypoxia (eg. in cold weather) Acute chest crisis Acute chest crises are the most dangerous acute presentation 3% mortality rate, causing 25% of sickle cell-related deaths The cause is often unknown (maybe infectious) Patients present with tachypnoea, wheeze, and cough, with hypoxia and pulmonary infiltrates on chest X-ray Other complications Splenic infarction and subsequent immunocompromise Sequestration crisis Osteomyelitis Stroke Dactylitis Poor growth Chronic renal disease Gallstones Retinal disorders Priapism Pulmonary fibrosis and pulmonary hypertension Iron overload from repeated blood transfusions Red cell aplasia (due to parvovirus B19 infection in the presence of chronic haemolytic anaemia)

Answer 168

Bedside - peak flow, which is essential for monitoring patients with chest crisis FBC may show microcytic anaemia with variable degrees of haemolysis Reticulocytosis and unconjugated hyperbilirubinemia may be noted Typical blood film findings include: characteristic sickle cells target cells reticulocytosis with polychromasia features of functional hyposplenism (Howell–Jolly bodies, nucleated red cells) Definitive diagnosis is with haemoglobin electrophoresis +/– genetic testing. However, many labs use high-performance liquid chromatography (HPLC) and/or isoelectric focusing (IEF) instead of HB electrophoresis. Reticulocyte count is a marker of erythropoiesis and the appropriateness of the bone marrow in responding to anaemia. The baseline reticulocyte count is generally elevated in SCD due to chronic anaemia. In an acute infection, there may be acute-on-chronic anaemia. Reticulocyte count will inform you if there is an appropriate response to the haemoglobin drop.

Answer 169

Treatments include: High-flow oxygen IV fluids and analgesia Top-up transfusions – required in some severe cases Note: ABO-compatible red cells matched for Rhesus and Kell antigens should be given as this will inhibit the development of antibodies that can otherwise complicate future transfusions.

Answer 170

Hydroxycarbamide if frequent crises occur - As one of the indications for hydroxycarbamide therapy is three or more moderate-to-severe sickle cell crises Increases foetal haemoglobin concentrations – needs to be balanced with risks of marrow suppression, reduced fertility and risk of teratogenicity Alternatively regular exchange transfusions may be required for frequent sickle cell crises, acute chest syndrome, priapism and stroke prevention Vaccinations and antibiotic prophylaxis – in view of hyposplenism and subsequent immunocompromise Newer therapies include: crizaniluzumab (p-selectin inhibitor) for treatment of pain crises voxelotor (haemoglobin oxygen-affinity modulator) for haemolytic complications Bone marrow transplant and gene-editing techniques are now becoming possible curative options for some patients

Answer 171

Hodgkin lymphoma is malignant lymphoma characterised by the presence of Reed–Sternberg cells. Peak incidence is in the third decade of life.

Answer 172

Epstein–Barr virus HIV Immunosuppression Cigarette smoking

Answer 173

Hodgkin lymphoma typically presents in young adults with cervical or supraclavicular non-tender lymphadenopathy – although the location of diseased nodes can vary Alcohol-induced painful lymphadenopathy is a suggestive symptom There may be symptoms caused by compression of surrounding structures (eg. shortness of breath or abdominal pain) B symptoms (fever, night sweats, and weight loss) occur in 30% of patients Pruritus can also occur It is important to examine the patient for lymphadenopathy and to check for hepatomegaly or splenomegaly.

Answer 174

Lymphocyte predominant (infiltration of T cells) - better prognosis Nodular sclerosing (bands of fibrous tissue separate nodules of Hodgkin's disease) Mixed picture Lymphocyte depleted (no infiltrating lymphocytes)

Answer 175

Ann Arbor staging system and Lugano Classification

Answer 176

Stage I Involvement of a single lymphatic site Stage II: Involvment of two or more lymph node regions on the same side of the diaphragm. Stage III: Involvement of lymphatic sites on both sides of the diaphragm OR Involvement of lymph nodes above the diaphragm and splenic involvement Stage IV: Disseminated disease involving one or more extra-lymphatic organs with or without associated lymph node involvement. OR Non-contiguous extralymphatic organ involvement in association with nodal stage II disease or any extralymphatic organ involvement in nodal stage III disease. As in the Ann Arbour classification, patients can be further sub-classified as: A: Asymptomatic B: Exhibiting B symptoms (fever, drenching night sweats and/or unexplained weight loss) S: Splenic involvement E: Extranodal contiguous extension

Answer 177

Blood tests Low haemoglobin and raised LDH can predict a poor prognosis – and indicates high red cell turnover Neutrophilia, anaemia of chronic disease, eosinophilia and thrombocytosis are often found ESR and other inflammatory markers are elevated LDH can be raised and is a useful marker of disease activity Further tests: Excisional Lymph node biopsy with evidence of Reed–Sternberg cells is diagnostic Staging scans are required to elucidate the extent of the disease – CT and PET scans are good radiological tools for Hodgkin's disease

Answer 178

Treatment is usually with chemoradiotherapy Classic stage 1 disease can be managed with radiotherapy, with combination chemotherapy given for the more advanced stages The most commonly used chemotherapy is ABVD = Adriamycin® (doxorubicin), bleomycin, vinblastine and dacarbazine Relapsed patients can be salvaged with second-line chemotherapy or an autologous transplant, especially if the relapse occurs >1 year after completion of treatment A common second-line treatment is ESHAP (etoposide, cytosine arabinoside, methylprednisolone (high dose steroids) and cisplatin)

Answer 179

5-year survival rates range from <40% to >95%, depending on: Histopathological disease type – lymphocyte-predominant has the best prognosis; lymphocyte-depleted has the worst prognosis Disease bulk Clinical stage In early-stage Hodgkin's lymphoma, an unfavourable prognosis is associated with higher ESR levels, especially when accompanied by B symptoms.

Answer 180

Non-Hodgkin's lymphoma is a collective term for a variety of malignancies that impact the lymphoid system. The defining characteristic of these lymphomas is the absence of Reed-Sternberg cells.

Answer 181

Non-Hodgkin lymphoma is commonly associated with infection (especially viral) and immunodeficiency: Infectious associations include: Helicobacter pylori – gastric MALT (mucosa-associated lymphoma tissue) lymphoma Epstein–Barr virus/HIV – Burkitt lymphoma (high-grade NHL) (starry sky appearance on biopsy and Translocation between chromosomes 8 and 14) and AIDS-related CNS lymphoma hepatitis C virus – diffuse large B-cell lymphoma and splenic marginal zone lymphoma human T-cell lymphotropic virus type 1 (HTLV1) – T-cell lymphoma Other aetiological associations include: immunodeficiency states (eg. HIV/AIDS and post-organ transplant) autoimmune disorders (eg. Sjögren's disease and coeliac disease) inherited disorders affecting DNA repair (eg. ataxia telangiectasia and Fanconi anaemia)

Answer 182

There are over 30 different types They may be classified according to: cell of origin – B cell or T cell; or pathological grade – high grade (aggressive) or low grade (indolent) The common types of non-Hodgkin’s lymphoma (NHL) are diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL).

Answer 183

a high-grade lymphoma that has an overall 60-70% cure rate and approaching 90% in young, fit patients. Most relapses occur within 3 years. Treatment for DLBCL depends on the bulkiness of the disease but R-CHOP, radiotherapy and high-dose methotrexate for CNS prophylaxis are the mainstay of treatment. Autografts can be used in those with refractory disease in those who are transplant eligible. For those not fit for transplant, R-mini-CHOP or R-GEM-CVP can be considered.

Answer 184

FL is a low-grade lymphoma of the B-cell germinal centre with the median age for presentation being 60-65 years. 85% are advanced disease at presentation. Treatment can begin with watchful monitoring until advancing disease bulk, constitutional symptoms, cytopaenias, and organ/bone compromise.

Answer 185

Painless lymphadenopathy – In contrast to Hodgkin lymphoma, the lymphadenopathy is more likely to be symmetrical, at multiple sites, and spread discontinuously across nodal sites B symptoms (fever, night sweats, and weight loss) – more common in non-Hodgkin lymphoma than in Hodgkin lymphoma, and are a poor prognostic marker Signs on physical examination: There is typically non-tender, firm lymphadenopathy affecting the cervical, axillary and/or inguinal lymph nodes – lymph nodes classically painless There may be splenomegaly and hepatomegaly (more common in NHL) There may be extranodal disease (more common in NHL), the two most common sites being the gut and skin (eg. in cutaneous T-cell lymphoma) Oropharyngeal involvement can also be a feature in NHL

Answer 186

Blood tests: LDH is the most important – an elevated LDH is a poor prognostic marker (reflects greater red cell turnover) Normocytic anaemia or haemolytic anaemia may be found A paraprotein may be present Blood film: Can show nucleated red cells and left shift (the presence of early white blood cell precursors) – particularly in high-grade cancers –occurs due to marrow involvement and increased marrow turnover May also reveal circulating lymphoma cells (ie. abnormal lymphocytes). Biopsy – histopathological assessment will help to define the subtype of the disease Other investigations include: Bone marrow biopsy Staging scans (eg. CT chest, abdomen and pelvis; PET) Cytogenetics (eg. t(11;14) can aid in diagnosing mantle cell lymphoma)

Answer 187

For asymptomatic patients, it may be most appropriate to 'watch and wait' until there is evidence of symptoms/organ failure For stage I disease, local radiotherapy to nodal sites can be used For more advanced systemic disease, immunochemotherapy is usually given – 'rituximab in combination with chemotherapy or obinutuzumab with chemotherapy is now the preferred therapy for most indolent NHLs.

Answer 188

The gold standard therapy is R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) plus the anti-CD20 monoclonal antibody rituximab Autologous and allogeneic transplantation can be used for relapsed disease in patients up to the age of 70 years There is a risk of tumour lysis syndrome, particularly in patients with high disease bulk, and preventive measures should be taken (i.e. hydration and allopurinol/rasburicase) Cell signalling inhibitors (eg. Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib) are also available, used particularly for mantle cell lymphoma. Lymphoblastic NHL has a propensity to penetrate the CNS – treatment is similar to that given for acute lymphoblastic leukaemia and includes CNS prophylaxis akin to CNS prophylaxis used for Burkitt’s Lymphoma and some patients with DLBCL.

Answer 189

Infections: NHL and its treatments can weaken the immune system, increasing the risk of infections. Bacterial, viral, and fungal infections are of concern. Monitoring for signs of infection and administering prophylactic antibiotics or antivirals may be necessary, particularly during chemotherapy cycles. Neurological Complications: Some NHL subtypes can infiltrate the nervous system, leading to neurological symptoms. Peripheral neuropathy, central nervous system involvement, and paraneoplastic syndromes are potential neurological complications. Bleeding and Coagulopathy: NHL can disrupt the normal coagulation process, leading to bleeding and coagulation disorders. This is more common in aggressive subtypes. Patients may experience petechiae, ecchymosis, and, in severe cases, disseminated intravascular coagulation (DIC). Management includes addressing the underlying disease and providing blood products when necessary Secondary Malignancies: Some treatments, particularly radiation and certain chemotherapies, can increase the risk of secondary malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Long-term surveillance is necessary to detect these conditions.

Answer 190

- What is vitamin K responsible for? Production of factors 2, 7, 9, 10 How does it affect PT and APTT? Prolonged PT as it has the biggest affect on factor 7 Normal APTT - What is an advantage of warfarin? Can be directly reversed by replacement of vitamin K - What are disadvantages of warfarin? **(4)** - Long half-life - Regular monitoring of PT and INR - Lots of drug-drug interactions - Not used in PE and DVT - What is the target INRs of patients on warfarin and what is the exception? 2.5 except mitral valve replacement - What is the target in metallic mitral valve replacement? 2.5-3.5 - What is the target following VTE, for AF and for metallic aortic valve replacement? 2.0-3.0 - What is the target for recurrent PEs? 3.5 - What do we do if INR is raised significantly? Indicates high bleeding risk → warfarin reduced/withheld completely and vitamin K may be given and FFP - What do we do 6-8 hours before emergency surgery (if it can wait) in terms of warfarin? Give IV 5mg vitamin K - What if surgery can’t wait? Give 25-50 units/kg four-factor prothrombin complex

Answer 191

- List examples of DOACs **(2)** - Apixaban - Rivaroxaban - How do they work? Factor 10a inhibitors - What about dabigatran? Direct thrombin inhibitor - Why are they preferred to warfarin? Require less monitoring

Answer 192

- What is the short acting heparin called? Unfractionated heparin (standard) - How is it administered? IV - How is it monitored? APTT - What is the long acting heparin called? LMWH - Give an example of LMWH Enoxaparin or dalteparin - How is LMWH administered? Subcutaneous - How is LMWH monitored? Via anti-factor 10a - Which is usually preferable and why? **(2)** LMWH → Preferred as there is a lower risk of heparin-induced thrombocytopenia - How does heparin-induced thrombocytopenia occur? Heparin activates antithrombin III, which forms a complex that inhibits factor 10a - What is the reversal agent for heparin? Protamine sulfate - How is bleeding risk calculated? ORBIT score

Answer 193

- How long before planned surgery must warfarin be stopped? 5 days - When can surgery go ahead? When persons INR is <1.5 - What if INR is >1.5? Give oral vitamin K a day before surgery - When is warfarin contraindicated? Avoid in pregnancy - How long before planned surgery must heparin be stopped? May be stopped on day of surgery, since heparin has a much shorter half-life than warfarin - What things reduce warfarin activity? P450 Inducers (Induce = reduce INR) - Give examples **(5)** **SCARS** - Smoking - Ciroc (alcohol) - Anti-epileptics e.g. Carbamazepine or Phenytoin - Rifampicin - St Johns wart - What things increase warfarin activity? P450 inhibitors increase warfarin activity (increase INR) - Give examples **ASS ZOLES** - Antibiotics- such as? **(4)** - Ciprofloxacin - Isoniazid - Clarithromycin - Erythromycin - SSRIs e.g. fluoxetine, sertraline - Sodium valproate - -zoles → such as? **(3)** - Omeprazole - Ketoconazole - Fluconazole

Answer 194

- How do you manage major bleeding and high INR? **(3)** - Stop warfarin - Oral/IV vitamin K - Prothrombin complex concentrate - How do you manage minor bleeding and INR is >5 (or no bleeding but INR >8)? **(3)** - Stop warfarin - Oral/IV vitamin K - Restart warfarin when INR is <5 - How do you manage no bleeding and INR is 5-8? Withhold 1 or 2 doses of warfarin - What do you do if INR <2? Up warfarin dose and start LMWH

Answer 195

Inhibits COX 1 and 2, hence blocking thromboxane A2 synthesis and reducing **platelet aggregation** - What is it used for? Long-term use of low-dose aspirin is recommended in patients with established cardiovascular disease (secondary prevention)- it is not recommended for primary prevention of CVD - Examples **(6)** - Following coronary bypass surgery - Intermittent claudication - Stable angina - Acute coronary syndromes - Following placement of coronary stents - Stroke - When is aspirin monotherapy indicated? - Following transcatheter aortic valve implantation- what if its not tolerated? Use clopidogrel instead

Answer 196

Inhibits **activation of platelets** - What is clopidogrel used for? Prevention of atherothrombotic events in patients with a history of symptomatic ischaemic disease (e.g. ischaemic stroke) - When is clopidogrel used in combination with low-dose aspirin? For the prevention of atherothrombotic and thromboembolic events in patients with **atrial fibrillation**- use of clopidogrel and aspirin increased bleeding risk - When is monotherapy indicated? When aspirin is CI e.g aspirin hypersensitivity, or aspirin not tolerated despite addition of PPI (pt at high risk of GI bleeding)

Answer 197

Secondary prevention of ischaemic stroke and transient ischaemic attacks

Answer 198

Prevention of atherothrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention; the combination is usually given for up to 12 months

Answer 199

Prevention of atherothrombotic events in patients with acute coronary syndrome; the combination is usually given for up to 12 months

Answer 200

Dual antiplatelet therapy with aspirin and either cangrelor, clopidogrel, prasugrel or ticagrelor- aspirin therapy should continue indefinitely

Answer 201

- What are they? Prevent platelet aggregation by blocking the binding of fibrinogen to receptors on platelets - Example? **(3)** Eptifibatide- (and tirofiban) prevent early myocardial infarction in patients with unstable angina or non-ST-segment-elevation myocardial infarction Tirofiban- for the reduction of major cardiovascular events in patients with ST-segment elevation myocardial infarction intended for primary percutaneous coronary intervention Abciximab- prevention of ischaemic complications in pt undergoing percutaneous transluminal coronary intervention

Answer 202

Blood transfusion reactions may be categorised into acute, subacute, and chronic (long-term) types. Acute complications include allergies, acute haemolytic transfusion reactions, febrile non-haemolytic transfusion reactions, transfusion-related acute lung injury, and transfusion-associated circulatory overload. Late complications include delayed haemolytic transfusion reaction, transfusion-associated graft-versus-host disease and iron overload. Management strategies depend on the specific reaction but generally involve stopping or slowing the transfusion and addressing the resulting symptoms.

Answer 203

Allergy, Acute haemolytic transfusion reaction, Febrile nonhaemolytic transfusion reaction, Transfusion-related acute lung injury, Transfusion-associated circulatory overload

Answer 204

Presentation ranges from urticaria to angioedema and anaphylaxis Management – stop the transfusion, give saline, adrenaline (in case of anaphylaxis), chlorphenamine, and hydrocortisone

Answer 205

Caused by giving an incompatible blood bag to a patient Early signs include fever, hypotension and anxiety Late complications include generalised bleeding secondary to DIC Management – stop the transfusion, give saline, treat DIC

Answer 206

Presents with fever, rigors/chills, but patients are otherwise well Management – Slow the transfusion, give paracetamol

Answer 207

Presents with pulmonary oedema and can cause acute respiratory distress syndrome (ARDS) Management – stop the transfusion, give saline, treat ARDS

Answer 208

Presents with fluid overload Management – Slow the transfusion, give furosemide

Answer 209

Delayed haemolytic transfusion reaction Transfusion-associated graft-versus-host disease Iron Overload

Answer 210

Caused by an exaggerated response to a foreign red cell antigen that the patient has been exposed to before Patients present with jaundice, anaemia, and fever, usually on day 5 post-transfusion

Answer 211

Iron overload may be related to the pathophysiology of the condition (eg. haemochromatosis) or iatrogenic (eg. related to a blood transfusion or excess oral iron) There is no secretion pathway for iron and approximately 1 mg of iron is lost via gut mucosal cells Absorption of luminal iron is mediated by enterocytes, which respond to iron stores in the body The enterocyte is modulated via its transferrin receptor, which regulates transferrin uptake from the plasma In turn, the HFE protein modulates transferrin receptor activity Iron overload usually becomes an issue after 20 units have been given or if serum ferritin rises above 1000 µg/l Subcutaneous desferrioxamine is required regularly to lower iron levels

Clinical haematology Flashcards

(236 cards)