Haematology Flashcards
- Anaemia
A Iron deficiency anaemia B Beta-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
1 A 35-year-old man presents to his GP with a 1-month history of increased tiredness. The patient also admits to diarrhoea and minor abdominal pain during this period. His blood tests reveal the following:
Hb 9.5 (13–18g/dL) MCV 64 (76–96fL) Fe 12.2 (14–31μmol/L) TIBC 74 (45–66μmol/L) Ferritin 9.2 (12–200μg/L)
Hb (haemoglobin); MCV (mean cell volume); Fe (iron); TIBC (total iron-binding capacity)
1) A
Iron deficiency anaemia (IDA; A) causes a hypochromic (pallor of the red blood cells on blood film due to reduced Hb synthesis), microcytic (small size) anaemia (low haemoglobin). A reduction in serum iron can be caused by a number of factors, including inadequate intake, malabsorption (coeliac disease; most likely cause in this case given diarrhoea and abdominal pain), increased demand (pregnancy) and increased losses (bleeding and parasitic infections). Further studies are required to distinguish IDA from other causes of microcytic anaemia: serum ferritin will be low, while total iron binding capacity (TIBC) and transferrin will be high.
Blood loss (D) will result in a normocytic anaemia as a consequence of a reduced number of circulating red blood cells. Common causes include gastrointestinal blood loss, heavy menstrual bleeding and certain surgical procedures.
Chronic alcohol (E) consumption directly causes a non-megaloblastic macrocytic anaemia. A poor diet in such patients also leads to folate and vitamin B12 deficiency which exacerbates the anaemia.
Chronic renal failure (G) is caused by the reduced production of red blood cells due to diminished secretion of erythropoietin by the damaged kidneys. This results in a normocytic, normochromic anaemia.
Lead poisoning (I) causes dysfunctional haem synthesis resulting in a microcytic anaemia. Lead poisoning leads to basophilic stippling, reflecting RNA found in red blood cells due to defective erythropoiesis.
- Anaemia
A Iron deficiency anaemia B Beta-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
2 A 56-year-old vagrant man presents to the accident and emergency department with weakness in his legs. The patient has a history of poorly controlled Crohn’s disease. His blood tests demonstrate Hb 9.4 (13–18 g/dL) and MCV 121 (76–96 fL). A blood film reveals the presence of hypersegmented neutrophils.
2) F
The majority of cases of vitamin B12 deficiency (F) occur secondary to malabsorption: reduced intrinsic factor production due to pernicious anaemia or post-gastrectomy, as well as disease of the terminal ileum. Clinical features will be similar to those of anaemia in mild cases, progressing to neuropsychiatric symptoms and subacute degeneration of the spinal cord (SDSC) in severe cases. Vitamin B12 deficiency results in a macrocytic megaloblastic anaemia as a result of inhibited DNA synthesis (B12 is responsible for the production of thymidine). Hypersegmented neutrophils are pathognomonic of megaloblastic anaemia.
Blood loss (D) will result in a normocytic anaemia as a consequence of a reduced number of circulating red blood cells. Common causes include gastrointestinal blood loss, heavy menstrual bleeding and certain surgical procedures.
Chronic alcohol (E) consumption directly causes a non-megaloblastic macrocytic anaemia. A poor diet in such patients also leads to folate and vitamin B12 deficiency which exacerbates the anaemia.
Chronic renal failure (G) is caused by the reduced production of red blood cells due to diminished secretion of erythropoietin by the damaged kidneys. This results in a normocytic, normochromic anaemia.
Lead poisoning (I) causes dysfunctional haem synthesis resulting in a microcytic anaemia. Lead poisoning leads to basophilic stippling, reflecting RNA found in red blood cells due to defective erythropoiesis.
- Anaemia
A Iron deficiency anaemia B Beta-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
3 A 65-year-old man is referred to the haematology department by his GP after initially presenting with tiredness, palpitations, petechiae and recent pneumonia. His blood tests reveal Hb 9.8 (13–18 g/dL), MCV 128 (76–96 fL), reticulocyte count 18 (25–100 × 109/L), 1.2 (2–7.5 × 109/L) and platelet count 125 (150–400 × 109/L).
3) H
Aplastic anaemia (H) is caused by failure of the bone marrow resulting in a pancytopenia and hypocellular bone marrow. Eighty per cent of cases are idiopathic, although 10% are primary (dyskeratosis congenita and Fanconi anaemia) and 10 per cent are secondary (viruses, SLE, drugs and radiation). The pathological process involves CD8+/ HLA-DR+ T cell destruction of bone marrow resulting in fatty changes. Investigations will reveal reduced Hb, reticulocytes, neutrophils, platelets and bone marrow cellularity as well as a raised MCV. Macrocytosis results from the release of fetal haemoglobin in an attempt to compensate for reduced red cell production.
Blood loss (D) will result in a normocytic anaemia as a consequence of a reduced number of circulating red blood cells. Common causes include gastrointestinal blood loss, heavy menstrual bleeding and certain surgical procedures.
Chronic alcohol (E) consumption directly causes a non-megaloblastic macrocytic anaemia. A poor diet in such patients also leads to folate and vitamin B12 deficiency which exacerbates the anaemia.
Chronic renal failure (G) is caused by the reduced production of red blood cells due to diminished secretion of erythropoietin by the damaged kidneys. This results in a normocytic, normochromic anaemia.
Lead poisoning (I) causes dysfunctional haem synthesis resulting in a microcytic anaemia. Lead poisoning leads to basophilic stippling, reflecting RNA found in red blood cells due to defective erythropoiesis.
- Anaemia
A Iron deficiency anaemia B Beta-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
4 A 56-year-old woman presents to her GP with increased tiredness in the past few weeks. A past medical history of rheumatoid arthritis is noted. Her blood tests demonstrate the following:
Hb 8.6 (11.5–16g/dL) MCV 62 (76–96fL) Fe 10.2 (11–30μmol/L) TIBC 38 (45–66μmol/L) Ferritin 220 (12–200μg/L)
4) C
Anaemia of chronic disease (ACD; C) occurs in states of chronic infection and inflammation, for example in tuberculosis (TB), rheumatoid arthritis, inflammatory bowel disease and malignant disease. ACD is mediated by IL-6 produced by macrophages which induces hepcidin production by the liver. Hepcidin has the effect of retaining iron in macrophages (reduced delivery to red blood cells for erythropoiesis) and reduces export from enterocytes (reduced plasma iron levels). Laboratory features of ACD include a microcytic hypochromic anaemia, rouleaux formation (increased plasma proteins), raised ferritin (acute phase protein) as well as reduced serum iron and TIBC.
Blood loss (D) will result in a normocytic anaemia as a consequence of a reduced number of circulating red blood cells. Common causes include gastrointestinal blood loss, heavy menstrual bleeding and certain surgical procedures.
Chronic alcohol (E) consumption directly causes a non-megaloblastic macrocytic anaemia. A poor diet in such patients also leads to folate and vitamin B12 deficiency which exacerbates the anaemia.
Chronic renal failure (G) is caused by the reduced production of red blood cells due to diminished secretion of erythropoietin by the damaged kidneys. This results in a normocytic, normochromic anaemia.
Lead poisoning (I) causes dysfunctional haem synthesis resulting in a microcytic anaemia. Lead poisoning leads to basophilic stippling, reflecting RNA found in red blood cells due to defective erythropoiesis.
- Anaemia
A Iron deficiency anaemia B Beta-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
5 A 12-year-old Mediterranean boy presents to his GP with increased tiredness over the past few weeks which is affecting his ability to concentrate at school. Examination is normal. Blood tests demonstrate the following:
Hb 9.5 (13–18g/dL) MCV 69 (76–96fL) Fe 18.2 (14–31μmol/L) TIBC 54 (45–66μmol/L) Ferritin 124 (12–200μg/L)
5) B
Beta-Thalassaemia (B) is a genetic disorder characterized by the reduced or absent production of Beta-chains of haemoglobin. Mutations affecting the Beta-globin genes on chromosome 11 lead to a spectrum of clinical features depending on the combinations of chains affected. Beta-Thalassaemia minor affects one Beta-globin chain and is usually asymptomatic, but may present with mild features of anaemia. Haematological tests reveal a microcytic anaemia but iron studies will be normal, differentiating from iron deficiency anaemia. Beta-Thalassaemia major occurs due to defects of both Beta-globin chains and results in severe anaemia requiring regular blood transfusions, as well as skull bossing and hepatosplenomegaly.
Blood loss (D) will result in a normocytic anaemia as a consequence of a reduced number of circulating red blood cells. Common causes include gastrointestinal blood loss, heavy menstrual bleeding and certain surgical procedures.
Chronic alcohol (E) consumption directly causes a non-megaloblastic macrocytic anaemia. A poor diet in such patients also leads to folate and vitamin B12 deficiency which exacerbates the anaemia.
Chronic renal failure (G) is caused by the reduced production of red blood cells due to diminished secretion of erythropoietin by the damaged kidneys. This results in a normocytic, normochromic anaemia.
Lead poisoning (I) causes dysfunctional haem synthesis resulting in a microcytic anaemia. Lead poisoning leads to basophilic stippling, reflecting RNA found in red blood cells due to defective erythropoiesis.
- Blood transfusion (1)
A 22-year-old motorcyclist is involved in a road traffic accident, and is transfused two units of blood. 4 hours later he develops acute shortness of breath and hypoxia, and despite attempts at ventilation deteriorates rapidly and goes into respiratory arrest. An autopsy shows evidence of massive pulmonary oedema with granulocyte aggregation within the pulmonary microvasculature.
The most likely diagnosis is:
A Anaphylaxis B ABO incompatible blood transfusion C Fluid overload D Transfusion related acute lung injury E Air embolism
D
Transfusion related acute lung injury (TRALI) (D) is rare but is one of the leading causes of transfusion related mortality. It can present with acute shortness of break and hypoxia, as in this case, typically within 6 hours of receiving the transfusion. The classic presentation to look out for is that of non-cardiogenic pulmonary oedema, i.e. pulmonary oedema that is not due to fluid overload.
The underlying mechanism is not fully understood, but it is thought to involve HLA antibodies in the blood donor reacting with corresponding HLA antigens on the patient’s white blood cells. This leads to the formation of aggregates of white blood cells which become stuck in small pulmonary capillaries. The release of proteolytic enzymes from neutrophils and toxic oxygen metabolites causes lung damage, and subsequent non-cardiogenic pulmonary oedema which can be fatal. Treatment is essentially supportive, and includes stopping the transfusion, giving
IV fluids and ventilation if needed. TRALI can occur with platelets and FFP, as well as with packed red cells as in this case. You might find it helpful to remember the mechanism by rearranging ‘TRALI’ to form the word ‘TRAIL’, and think of the blood donor leaving a ‘trail’ of antibodies in the recipient.
An anaphylactic reaction (A) can also present immediately following a blood transfusion, but look out for clues such as a rash, urticaria and a wheeze to point you towards this diagnosis.
ABO incompatible transfusions (B) present with symptoms and signs of acute intravascular haemolysis, such as restlessness, chest or loin pain, fever, vomiting, flushing, collapse and haemoglobinuria. Shortness of breath and acute hypoxia are less common with this, and the pathological description given here at autopsy is characteristic of TRALI. The use of the term ‘pulmonary oedema’ in the question may have misled you to think of fluid overload (C). Whilst fluid overload is much more common, this patient has only received two units of blood and fluid overload would be less likely to cause such a rapid deterioration. These patients might have pedal oedema and bilateral crepitations on examination, and can be treated with diuretics.
An air embolism (E) can rarely occur if air is introduced into the blood bag, and can present with circulatory collapse. Again, the findings on autopsy from this case would not correlate with this diagnosis.
- Anaemia (2)
A 24-year-old unemployed man presents to his GP with a 4-week history of flu-like symptoms and a persistent dry cough. On examination he has a maculopapular rash. A blood film reveals a haemolytic anaemia, and he is positive for cold agglutinins. The most likely organism implicated is:
A Streptococcus pneumoniae B Mycoplasma pneumoniae C Legionella pneumophilia D Chlamydophila psittaci E Borrelia burgdorferi
B
Autoimmune haemolytic anaemia is a form of mainly extravascular haemolysis, which is mediated by autoantibodies.
It is classified into warm and cold autoimmune haemolytic anaemia, according to the optimal temp at which the antibodies bind to RBCs.
This activates the classical pathway in the complement system, resulting in haemolysis. Cold AIHA is mediated by IgM antibodies, and as the name suggests these antibodies bind optimally at lower temperatures (28-31°C), resulting in anaemia that is aggravated in cold conditions. In severe cases, patients may suffer from Raynaud’s or acrocyanosis (purplish discolouration of peripheries). Most cases are idiopathic, but there are some specific causes worth remembering, as ‘Cold LID’:
- -> Lymphoproliferative disease, e.g. CLL, lymphomas
- -> Infections – mycoplasma, as in this case (B), EBV
- -> Do not know, i.e. idiopathic!
This patient has typical features of mycoplasma pneumonia including a protracted history of flu-like symptoms (such as myalgia, arthralgia, headache) and a non-productive cough. Tx: includes avoiding cold conditions, use of chlorambucil, and treating the underlying cause. The other infectious agents listed here do not typically cause a cold haemolytic anaemia.
Warm AIHA on the other hand is mostly IgG mediated, and these anti- bodies have maximal reactivity at body temperature of 37°C. These antibodies attach to the membrane of red blood cells, and the ‘Fc’ portion is recognized by splenic macrophages. These remove part of the RBC membrane, which leads to the formation of spherocytes. Secondary causes may again include lymphoproliferative disease, but also drugs such as penicillin and autoimmune diseases such as SLE.
Tx: steroids, immunogolobulins and possibly splenectomy.
- Haematology of systemic disease
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection
1 A 56-year-old woman visits her GP for a regular check-up for a chronic condition she suffers from. On examination, she has signs of long-term steroid therapy. There is ulnar deviation at her metacarpophalangeal joints. Blood tests reveal a microcytic hypochromic anaemia, low iron and total iron binding capacity, but a raised ferritin level.
1) D
Rheumatoid arthritis (RA; D) is an inflammatory disease that mainly affects the small joints of the hands but systemic involvement can be a feature, manifesting in the lungs (fibrosis), heart (pericarditis) and eyes (scleritis). RA is a cause of anaemia of chronic disease (ACD), which is mediated by IL-6 produced by macrophages. IL-6 induces hepcidin production by the liver which has the effect of retaining iron in macrophages (reduced delivery to red blood cells for erythropoiesis) and decreases export from enterocytes (reduced plasma iron levels). Laboratory features of ACD include a microcytic hypochromic anaemia, rouleaux formation and raised ferritin (acute phase protein).
Colorectal cancer (C) may result in iron deficiency anaemia (IDA) secondary to bleeding. IDA will demonstrate a microcytic anaemia, reduced ferritin and iron count and raised total iron binding capacity.
Miliary tuberculosis (E) may cause infiltration of the bone marrow leading to a leuko-erythroblastic picture on blood film. Other causes of a leuko-erythroblastic film include myelofibrosis, leukaemia, lymphoma and non-haemopoietic cancers (for example, breast cancer).
Acute pancreatitis (F) can result in a neutrophilia as a result of tissue inflammation. Other causes of neutrophilia include ulcerative colitis and corticosteroids.
Epstein–Barr virus (EBV; I) results in a reactive lymphocytosis. Other causes include cytomegalovirus, toxoplasmosis, hepatitis, rubella and herpes virus infection. Autoimmune disorders and neoplasia can also be causative.
- Haematology of systemic disease
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection
2 A 45-year-old man presents to accident and emergency with an excruciating headache. Blood tests show an erythrocyte sedimentation rate of 110 mm/hour.
2) A
Temporal arteritis (A) is a vasculitis most commonly affecting the medium and large arteries of the head. It is also known as giant cell arteritis due to the inflammatory cells that are visualized on biopsy. Prominent temporal arteries with regional tenderness, coupled with an erythrocyte sedimentation rate (ESR) of more than 60mm/hour is highly suggestive of temporal arteritis. ESR may be raised due to increase plasma proteins (fibrinogen, acute phase proteins or immunoglobulin) or due to reduced packing of red blood cells (anaemia). Other causes of a raised ESR include myeloma, polymyalgia rheumatica and autoimmune disease.
Colorectal cancer (C) may result in iron deficiency anaemia (IDA) secondary to bleeding. IDA will demonstrate a microcytic anaemia, reduced ferritin and iron count and raised total iron binding capacity.
Miliary tuberculosis (E) may cause infiltration of the bone marrow leading to a leuko-erythroblastic picture on blood film. Other causes of a leuko-erythroblastic film include myelofibrosis, leukaemia, lymphoma and non-haemopoietic cancers (for example, breast cancer).
Acute pancreatitis (F) can result in a neutrophilia as a result of tissue inflammation. Other causes of neutrophilia include ulcerative colitis and corticosteroids.
Epstein–Barr virus (EBV; I) results in a reactive lymphocytosis. Other causes include cytomegalovirus, toxoplasmosis, hepatitis, rubella and herpes virus infection. Autoimmune disorders and neoplasia can also be causative.
- Haematology of systemic disease
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection
3 A 38-year-old man from Nigeria presents to his GP with progressive shortness of breath, cough and painful rashes on his lower legs. Blood tests reveal a monocytosis. Chest X-ray demonstrates bihilar lymphadenopathy.
3) H
Sarcoidosis (H) is a granulomatous disease characterized by the presence of non-caseating granulomas in multiple organs, most commonly affecting the lungs. Diagnosis of sarcoidosis is usually a matter of excluding other diseases but chest X-ray (bihilar lymphadenopathy), CT scanning and lung biopsy can all help. Blood tests commonly reveal a monocytosis; monocytes are contributory to the pathogenesis of granulomatous disease. Other causes of monocytosis include brucellosis, typhoid, vari- cella zoster infection and chronic myelo-monocytic leukaemia (CMML).
Colorectal cancer (C) may result in iron deficiency anaemia (IDA) secondary to bleeding. IDA will demonstrate a microcytic anaemia, reduced ferritin and iron count and raised total iron binding capacity.
Miliary tuberculosis (E) may cause infiltration of the bone marrow leading to a leuko-erythroblastic picture on blood film. Other causes of a leuko-erythroblastic film include myelofibrosis, leukaemia, lymphoma and non-haemopoietic cancers (for example, breast cancer).
Acute pancreatitis (F) can result in a neutrophilia as a result of tissue inflammation. Other causes of neutrophilia include ulcerative colitis and corticosteroids.
Epstein–Barr virus (EBV; I) results in a reactive lymphocytosis. Other causes include cytomegalovirus, toxoplasmosis, hepatitis, rubella and herpes virus infection. Autoimmune disorders and neoplasia can also be causative.
- Haematology of systemic disease
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection
4 A 66-year-old presents to his GP with severe weight loss over 1 month as well as tiredness. Blood tests reveal an increased erythrocyte, haemoglobin and erythropoietin count.
4) B
Renal cell carcinoma (RCC; B) is the most common type of renal cancer. Secondary polycythaemia may be associated with RCC as a result of increased erythropoietin (EPO) production. Secondary polycythaemia can be distinguished from primary polycythaemia as in the former there is an increase in blood EPO levels, whereas in the latter EPO levels decrease. Other causes of secondary polycythaemia include chronic hypoxia (high altitude, smoking, lung disease, cyanotic heart disease), renal disease (cysts, renal artery stenosis, hydronephrosis) and solid tumours (renal cell carcinoma and hepatocellular carcinoma).
Colorectal cancer (C) may result in iron deficiency anaemia (IDA) secondary to bleeding. IDA will demonstrate a microcytic anaemia, reduced ferritin and iron count and raised total iron binding capacity.
Miliary tuberculosis (E) may cause infiltration of the bone marrow leading to a leuko-erythroblastic picture on blood film. Other causes of a leuko-erythroblastic film include myelofibrosis, leukaemia, lymphoma and non-haemopoietic cancers (for example, breast cancer).
Acute pancreatitis (F) can result in a neutrophilia as a result of tissue inflammation. Other causes of neutrophilia include ulcerative colitis and corticosteroids.
Epstein–Barr virus (EBV; I) results in a reactive lymphocytosis. Other causes include cytomegalovirus, toxoplasmosis, hepatitis, rubella and herpes virus infection. Autoimmune disorders and neoplasia can also be causative.
- Haematology of systemic disease
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection
5 A 24-year-old man has recently returned from a trip to Kenya. He presents to his GP with abdominal pain, fever and on examination has hepatosplenomegaly. Blood tests reveal a marked eosinophilia.
5) G
Schistosomiasis (G) is a parasitic disease caused by Schistosoma spp. It is particularly common in Asia, Africa and South America. The risk of bladder cancer is increased in urinary forms of schistosomiasis. The immune response to parasitic infection involves eosinophils and hence a marked eosinophilia is characteristic. Other causes of eosinophilia besides parasitic infection include allergic disease (asthma, rheumatoid arthritis, polyarteritis), neoplasms (Hodgkin’s lymphoma, non-Hodgkin’s lymphoma) as well as certain drugs (NSAIDs).
Colorectal cancer (C) may result in iron deficiency anaemia (IDA) secondary to bleeding. IDA will demonstrate a microcytic anaemia, reduced ferritin and iron count and raised total iron binding capacity.
Miliary tuberculosis (E) may cause infiltration of the bone marrow leading to a leuko-erythroblastic picture on blood film. Other causes of a leuko-erythroblastic film include myelofibrosis, leukaemia, lymphoma and non-haemopoietic cancers (for example, breast cancer).
Acute pancreatitis (F) can result in a neutrophilia as a result of tissue inflammation. Other causes of neutrophilia include ulcerative colitis and corticosteroids.
Epstein–Barr virus (EBV; I) results in a reactive lymphocytosis. Other causes include cytomegalovirus, toxoplasmosis, hepatitis, rubella and herpes virus infection. Autoimmune disorders and neoplasia can also be causative.
- Anaemia (3)
A 7-year-old boy is taken ill from school on a cold December day, with a presumed viral infection. On returning home that day, he beings to feel even more unwell with a very high fever, headache and abdominal pain. His father begins to worry that his skin has taken on a yellow tinge, and the boy says his urine is now a dark reddy-brown colour. He is taken to the GP and after several tests the presence of ‘Donath–Landsteiner antibodies’ is reported. This child is suffering from:
A Paroxysmal cold haemoglobinuria B Paroxysmal nocturnal haemoglobinuria C Sickle cell disease D Acute intermittent porphyria E Epstein–Barr virus
A
Paroxysmal cold haemoglobinuria (A) is a rare form of autoimmune haemolytic anaemia. It usually affects children in the acute setting after an infection, and the key in this case is the presence of sudden haemoglobinuria and jaundice after exposure to a cold temperatures. IgG autoantibodies usually form after an infection, and bind to red blood cell surface antigens, inducing variable degrees of intravascular haemolysis in the cold. The antibodies are known as ‘Donath–Landsteiner antibodies’.
Analysis of the urine will confirm the presence of haemaglobinuria, and blood tests often reveal a normocytic or macrocytic anaemia. It is possible to test indirectly for the IgG antiglobulins at a low temperature, as in this case. Blood transfusion may be required if the anaemia is severe, but in children who have an acute onset with an antecedent infection, it is usually a transient and self limiting condition.
Paroxysmal nocturnal haemoglobinuria (B) is another rare acquired dis- ease, but one that is potentially life threatening. The resulting defect in the red cell membrane leads to intravascular haemolysis. The disease has three aspects: the most common way for it to present is with a haemolytic anaemia, which may cause haemoglobinuria, especially overnight. The second aspect is thrombophilia, which can present with visceral thrombosis (e.g. CNS, pulmonary, mesenteric). The third aspect is deficient haematopoiesis which can cause a pancytopenia with aplastic anaemia. You can remember this as PNH = Pancytopenia – New thrombus – Haemolytic anaemia. The latest diagnostic test is flow cytometry, which can detect absent membrane proteins on red blood cells. This has largely replaced the ‘Ham’s test’ (which was used to show that a patient’s eryth- rocytes are lysed if the blood is acidified). Treatment is with thrombo- prophylaxis, and the monocolonal antibody eculizumab may have a role.
Sickle cell disease (C) can lead to vaso-occlusive crises precipitated by the cold, but this would present with severe pain due to microvascular occlusion and Donath Landsteiner antibodies would not be present.
Acute intermittent porphyria (D) is an autosomal dominant condition caused by deficiency of an enzyme involved in haem synthesis (porphobilinogen deaminase). This can lead to accumulation of toxic haem precursors, which cause neurovisceral symptoms. The urine can characteristically turn a deep red colour on standing.
Epstein–Barr virus (E) alone would not cause the symptoms described in this case, though it can trigger paroxysmal cold haemoglobinuria.
- Anaemia (4)
A 21-year-old student has recently been diagnosed with coeliac disease. She presents to her GP complaining of increased tiredness and shortness of breath on climbing stairs.
Which of the following are most likely to be raised in this patient?
A Serum iron B Haematocrit C Transferrin D Ferritin E Mean cell haemoglobin
C
This patient is suffering from iron deficiency anaemia, a common complication in coeliac disease. The tiredness and shortness of breath are common symptoms. Causes can include blood loss (e.g. upper or lower GI bleeding, menstruation), malabsorption (as in this case), dietary deficiency (rare in adults but can be seen in children) or infestation with parasitic worms (the most common cause worldwide). Blood tests characteristically reveal a low mean cell volume, mean cell haemoglobin (E) and mean cell haemoglobin concentration. A blood film may reveal hypochromic red blood cells with anisocytosis (variation in cell size) and poikilocytosis (variation in cell shape). The red blood cell distribu- tion width (RDW) (a measure of the variation of the width of red blood cells) may be increased initially.
Serum iron levels (A) can be measured directly, but are unreliable and may be increased if the patient has started on iron supplements, as the levels increase straight away. Levels of ferritin (D), the intracellular protein that stores iron, may also be low and this is the most sensitive test. However, it is also an acute phase protein, and so may be falsely elevated in the presence of inflammation or malignancy which coexists with the iron deficiency anaemia (therefore a normal ferritin level cannot exclude IDA). The haematocrit (B) is the percentage of red blood cells in the blood, and it may be reduced in IDA.
Transferrin (C) is a glycoprotein that binds to iron in the blood, and lev- els may be increased in IDA as the liver produces greater amounts (you can think of this as the liver trying to compensate for the little iron it has available, so it makes more of the binding carrier for iron). Total iron-binding capacity (TIBC) is a laboratory test used to give a measure of the capacity of the blood to bind iron with transferrin, and it too would be raised in IDA. The TIBC is reduced in anaemia of chronic disease, possibly because the body produces less transferrin to prevent the pathogens that require iron for metabolism obtaining it.
IDA can be treated with oral iron supplements, with an expected rise in the haemoglobin of 1g/dL per week. Do not forget that iron supplements characteristically lead to production of black stools.
- Anaemia (5)
A 34-year-old woman with known Addison’s disease is brought to the GP by her husband, as he is concerned that she keeps falling over at night. On examination the GP notes that she has conjunctival pallor. A thorough neurological examination reveals absent knee jerks, absent ankle jerks and extensor plantars bilaterally. Which of the following is the most sensitive test for the condition she has developed?
A Anti-intrinsic factor antibodies B Anti-endomysial cell antibodies C Anti-smooth muscle antibodies D Anti-parietal cell antibodies E Anti-voltage gated calcium channel antibodies
D
This woman has developed pernicious anaemia leading to vitamin B12 deficiency. It can be associated with other autoimmune conditions, such as Addison’s disease or thyroid disease. Specifically, she has developed a condition called subacute combined degeneration of the cord (SACD) which has led to symmetrical loss of dorsal columns (resulting in loss of touch and proprioception leading to ataxia, and LMN signs) and cor- ticospinal tract loss (leading to UMN signs), with sparing of pain and temperature sensation (which is carried by spinothalamic tracts). The ataxia and loss of joint position sense have resulted in her falling at night, which may be exacerbated by optic atrophy – another manifestation of vitamin B12 deficiency.
Remember that vitamin B12 is found in meat, fish and dairy products. More common causes of vitamin B12 deficiency can be related to diet (e.g. vegans) or to malabsorption. It is absorbed in the terminal ileum after binding to intrinsic factor produced by the parietal cells in the stomach. Causes of malabsorption can therefore be related to the stomach (e.g. post gastrectomy, pernicious anaemia), or due to the terminal ileum (e.g. Crohn’s, resection of the terminal ileum, bacterial overgrowth).
Pernicious anaemia is caused by an autoimmune atrophic gastritis when autoantibodies are produced against parietal cells and intrinsic factor itself. The lack of B12 impairs DNA synthesis in red blood cells, leading to the production of large, megaloblastic erythrocytes.
Blood tests and a blood film may reveal several features that are worth remembering:
- Low haemoglobin
- High MCV
- Low platelets and WCC if severe
- Low serum B12
- Hypersegmented neutrophils
- Megaloblasts in the bone marrow
- Cabot rings in RBCs (remnants of the nuclear membrane seen in pernicious anaemia, lead poisoining and other forms of megaloblastic anaemia)
Intrinsic factor antibodies (A) can be found in approximately 50% of patients, and are specific for pernicious anaemia but not as sensitive as anti-parietal cell antibodies (D) which are found in >90% of patients. However, anti-parietal cell antibodies can also be found in approximately 10% of normal people, and 40 per cent of people who have atrophic gastritis without pernicious anaemia. The Schilling test is no longer commonly used for diagnosis.
Anti-endomysial cell antibodies (B) are found in coeliac disease (with a specificity of approximately 95%), anti-smooth muscle cell anti- bodies (C) are found in autoimmune hepatitis and primary biliary cirrhosis, and anti-voltage gated calcium channel antibodies (E) are found in Lambert–Eaton syndrome (a variant of myasthenia gravis).
- Macrocytic anaemia
A 58-year-old woman is referred to a haematology clinic following repeated chest infections and epistaxis. On examination she has conjunctival pallor and some petechial rashes on her forearms, but no organomegaly. Her blood tests reveal a pancytopenia, and an MCV of 112. Her drug history includes omeprazole, carbamazepine, gliclazide, metformin, paracetamol, and simvastatin. BM biopsy reveals a hypocellular marrow. The most likely diagnosis is:
A Aplastic anaemia B Myelodysplasia C Hypothyroidism D Chronic myeloid leukaemia E Myeloma
A
Causes of macrocytosis can be divided into:
1 Megaloblastic, e.g. folate and B12 deficiency
2 Non-megalobastic, causes of which can be remembered as RALPH = reticulocytosis (e.g. in haemolysis), alcohol, liver disease, pregnancy and hypothyroidism)
3 Other haematological disorders, e.g. myelodysplasia, aplastic anaemia, myeloma, myeloproliferative disorders
This woman is suffering from aplastic anaemia (A), where the bone marrow stops producing cells leading to a pancytopenia. Bone marrow examination is needed to confirm the diagnosis, and shows a hypocellular bone marrow. Causes of aplastic anaemia can be primary or secondary. Primary causes can be congenital (e.g. Fanconi’s anaemia) or idi- opathic acquired aplastic anaemia. Secondary causes include drugs (all the Cs – cytotoxics, carbamazepine, chloramphenicol, anticonvulsants such as phenytoin), ionizing radiation and viruses (e.g. hepatitis, EBV). This woman’s aplastic anaemia is secondary to long-term carbamaz- epine therapy for hypothyroidism. Hypothyroidism (C) alone may lead to macrocytosis, but is not the underlying cause for her pancytopenia. Patients with aplastic anaemia can present with features of the pancyto- penia, such as recurrent infections (from a low white cell count), bleed- ing and petechial rashes (from a low platelet count) and features of anaemia.
Treatment of aplastic anaemia is with supportive therapy, such as red cell transfusions and platelets, allogenic bone marrow transport which can be curative, or immunosuppression with, for example, ciclosporin and antithymocyte globulin (ATG).
Myelodysplasia (B) is a group of disorders caused by ineffective haema- topoeisis, so results in pancytopenia with increased marrow cellularity. Chronic myeloid leukaemia (D) would typically result in a very high white blood cell count, and a hypercellular bone marrow as there is active pro- duction of cells. Myeloma (E) can also cause a macrocytic or normocytic anaemia, but a bone marrow biopsy would show increased plasma cells.
- Hepatomegaly
A 50-year-old diabetic man sees his GP complaining of generalized tiredness and a painful right knee. He is found on examination to have 5 finger breadths of hepatomegaly. An X-ray of his right knee is reported as showing chondrocalcinosis. His blood tests are likely to reveal:
A Raised MCV B Raised total iron binding capacity C Reduced serum ferritin D Reduced iron level E Raised transferrin saturation
E
This man has hereditary haemachromatosis, an inherited disorder of iron metabolism. It is particularly common in those of Celtic descent, and the gene responsible for the majority of cases is the HFE gene on chromosome 6.
Increased iron absorption leads to deposition to multiple organs including:
- the liver (hepatomegaly, deranged LFTs)
- joints (arthralgia, chondrocalcinosis)
- pancreas (diabetes)
- heart (dilated cardiomyopathy)
- pituitary gland (hypogonadism and impotence)
- adrenals (adrenal insufficiency)
- skin (slate grey skin pigmentation)
Blood tests can show deranged LFTs as in this case, as well as a raised serum ferritin, raised serum iron, reduced or normal total iron binding capacity and raised transferrin saturation (E) (>80%).
Remember that the TIBC measures the blood’s capacity to bind iron with transferrin. The transferrin saturation is the ratio of serum iron to TIBC ×100, and represents the percentage of iron binding sites on transferrin that are occupied by iron. It is typically 20–40%, but is raised in haemachromatosis. This is because TIBC is usually low or normal whilst serum iron levels are high, so the percentage of transferrin occupied by iron is increased.
The following table summarizes the common laboratory findings for various conditions:
Liver biopsy with Perl’s staining or Prussian blue staining can demon- strate iron overload in haemachromatosis. This can be used to quantify iron loading and determine the severity of the disease. MRI is also a less invasive way to accurately gauge iron concentrations in the liver.
Treatment options include lifetime regular venesection to reduce iron levels, maintenance of a low iron diet, and treatment with iron chelators if venesection is not possible. Patients with haemachromatosis who have developed liver cirrhosis are at increased risk of developing hepatocellular carcinoma.
- Plasma cell disorders (1)
A 64-year-old woman is seen in the haematology clinic with generalized bone pain and recurrent infections. Following a set of blood tests, a skeletal survey reveals multiple lytic lesions and a bone marrow biopsy reports the presence of >10% plasma cells. Her blood tests are most likely to have shown:
A Raised calcium, normal alkaline phosphatase, raised ESR
B Normal calcium, raised alkaline phosphatase, normal ESR
C Raised calcium, raised alkaline phosphatase, raised ESR
D Raised calcium, normal alkaline phosphatase, raised CRP
E Normal calcium, normal alkaline phosphatase, raised CRP
A
This woman has multiple myeloma, a cancer of plasma cells. The symptoms can be remembered using the mnemonic BRAIN:
- Bone pain (due to osteoclast activation leading to hypercalcaemia and the presence of lytic lesions on a skeletal survey, characteristically with a ‘pepperpot skull’ appearance),
- Renal failure (which can be secondary to one or a combi- nation of: hypercalcaemia, tubular damage from light chain secretion, or secondary amyloidosis),
- Anaemia (typically normocytic),
- Infections (particularly pneumonias and pyelonephritis), and
- Neurological symp- toms (such as a headache and visual changes from hyperviscosity, or confusion and weakness from the hypercalcaemia).
Diagnostic criteria for symptomatic myeloma:
- > Clonal plasma cells >10% on bone marrow biopsy
- > A paraprotein in the serum or urine – most commonly IgG
- > Evidence of end-organ damage related to the plasma cell disorder (commonly referred to by the acronym ‘CRAB’):
- Calcium – high
- Renal insufficiency
- Anaemia
- Bone lesions (e.g. lytic lesions, or osteoporosis with compression factors)
Blood tests may reveal a high calcium but the alkaline phosphatase is often normal (A) (in contrast to other malignancies, with osteolytic metastases and raised alkaline phosphatase).
The bone disease in myeloma is thought to be mediated by over- expression of the ‘RANK ligand’ by bone marrow stroma, which activates osteoclasts. Peripheral blood films can reveal the presence of rouleaux formation (stacks of red blood cells which occur because high plasma protein concentrations make the cells stick to each other, which also causes the high ESR).
Beta 2 microglobulin levels (a component of MHC class 1 molecules) can also be measured, and are an important prognostic indicator. Along with albumin levels, the level of beta 2 microglobulin forms part of the International Staging System for myeloma.
Treatment of multiple myeloma includes high dose chemotherapy, with the possibility of stem cell transplantation in younger patients.
- Plasma cell disorders (2)
A 67-year-old woman presented with polyuria and polydipsia on a background of ongoing bone pain. Her blood tests revealed a high calcium, and a serum electrophoresis was sent. Her serum paraprotein was 25g/L and a BM biopsy revealed 6% clonal plasma cells. The most likely diagnosis is:
A Plasma cell dyscrasia
B Monoclonal gammopathy of undetermined significance
C Smouldering myeloma
D Multiple myeloma
E Hypercalcaemia with no evidence of underlying malignancy
D
This question tests your understanding of the diagnostic criteria for plasma cell disorders. Do not forget that:
1 Symptomatic myeloma (D):
Clonal plasma cells on bone marrow biopsy
Paraprotein in either serum or urine
Evidence of end-organ damage attributed to the plasma cell
disorder, commonly remembered using the acronym ‘CRAB’ (Calcium – high, Renal insufficiency, Anaemia and Bone lesions)
2 Asymptomatic (smouldering) myeloma (C):
Serum paraprotein >30 g/L AND/OR
Clonal plasma cells >10 per cent on bone marrow biopsy AND NO myeloma-related organ or tissue impairment
3 Monoclonal gammopathy of undetermined significance (MGUS) (B): Serum paraprotein <30g/L AND
Clonal plasma cells <10 per cent on bone marrow biopsy AND NO myeloma-related organ or tissue impairment
This woman has multiple myeloma because she has evidence of end organ damage in the form of hypercalcaemia. You can automatically exclude asymptomatic myeloma and MGUS on this basis!
MGUS itself is usually asymptomatic and does not normally require treatment. Patients will undergo regular blood tests to check their para- protein levels because of the small risk of transformation to multiple myeloma (approximately 1–2 per cent per year).
Plasma cell dyscrasia (A) is a more general term for cancers of the plasma cells, of which MGUS is the most common. This term also encompasses multiple myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, and Waldenström’s macroglobulinaemia amongst others. A plasmacytoma is a discrete neoplastic mass of plasma cells within the bone marrow or elsewhere (extra-medullary). There is no evidence of myeloma in this condition, but a serum paraprotein is sometimes present (usually IgM).
Waldenström’s macroglobulinaemia is a chronic, indolent disorder, also known as ‘lymphoplasmacytic lymphoma’. It is essentially a clonal dis- order of B cells, characterized by a high level of IgM. This leads to fea- tures of hyperviscosity and vascular complications. Because of the high IgM levels it used to be thought of as related to multiple myeloma, but is now classified as a lymphoproliferative disease (similar to a low grade non-Hodgkins lymphoma).
- Platelet count (1)
A 39-year-old motorcyclist is admitted following a road traffic accident com- plicated by severe burns. Several days later he is due to go home, when ooz- ing is noted from his cannula site and he has several nose bleeds. Repeat blood tests reveal an Hb of 12.2g/dL, WCC of 11.2×109/L, and platelets of 28×109/L. A coagulation screen shows a prolonged APTT and PT. He also has a reduced fibrinogen and raised D-dimers. The most likely diagnosis is:
A Liver failure B Disseminated intravascular coagulation C Thrombotic thrombocytopenic purpura D Aplastic anaemia E Heparin induced thrombocytopenia
B
This man has developed disseminated intravascular coagulation (DIC) (B) following his severe burns. DIC is widespread pathological activation of the clotting cascade in response to various insults. The cascade is activated in various ways: one mechanism is the release of a transmembrane glycoprotein called ‘tissue factor’ in response to cytokines or vascular damage. This results in fibrin formation, which can eventually cause occlusion of small and medium sized vessels and lead to organ failure. At the same time, depletion of platelets and coagulation proteins can result in bleeding (as in this case).
It can be caused by a wide range of factors, which can be remembered using the mnemonic ‘I’M STONeD!’: Immunological (e.g. severe allergic reactions, haemolytic transfusion reactions), Miscellaneous (e.g. aortic aneurysm, liver disease), Sepsis, Trauma (including serious tissue injury, burns, extensive surgery), Obstetric (e.g. amniotic fluid embolism, placental abruption), Neoplastic (myeloproliferative disorders as well as solid tumours such as pancreatic cancer), and Drugs and toxins.
Patients with DIC can present with rapid onset of shock, widespread bleeding, bruising and renal failure, or more insidiously (for example in the cases of malignancy). Blood tests will typically reveal a thrombocytopenia, raised PT and APTT, decreased fibrinogen and increased
D dimers. D dimers are fibrinogen degradation products, which form from intense fibrinolytic activity. The blood film may show the presence of schistocytes (broken red blood cells). The following table may help you to differentiate between the blood test results for various conditions.
Liver failure (A) is less likely to cause a thrombocytopenia, reduced fibrinogen and raised D dimers, and the history of burns points more towards DIC.
TTP (C) would not typically result in raised D dimers either, and the PT and APTT are not normally prolonged. This condition usually has other clinical features too, including a fever and fluctuating CNS signs.
Aplastic anaemia (D) does not typically cause abnormalities in clotting, and heparin induced thrombocytopenia (HIT) (E) is most likely to present paradoxically with throm- bosis rather than bleeding.
- Platelet count (2)
A 46yo woman is brought to A&E by her daughter, who reports that she had been feeling unwell for a few days with a fever and is now hallucinating.
O/E: temp 38.9°C, pale, widespread purpura over both arms. Blood tests: Hb of 9.1g/dL, platelet count: 60×109/L, creatinine: 226 and urea: 16.7. Blood film shows shistocytes. Most likely diagnosis:
A Weil’s disease
B Glandular fever
C Idiopathic thrombocytopenic purpura (ITP)
D Thrombotic thombocytopenic purpura (TTP)
E Haemolytic uraemic syndrome (HUS)
D
This woman has TTP, rare but potentially fatal haematological emergency. It consists of 6 key features:
1 MAHA 2 A fever 3 Renal failure 4 Fluctuating CNS signs, e.g. seizures, hallucinations, hemiparesis, decreased consciousness 5 Haematuria/proteinuria 6 Low platelet count
You can remember these as ‘MARCH with low platelets’.
TTP typically affects adults and is thought to occur due to a deficiency of a protease that is responsible for cleaving multimers of von Willebrand factor. The resulting formation of large vWF multimers stimulates platelet aggregation and fibrin deposition in small vessels. This in turn causes microthrombi to form in blood vessels, impeding the blood supply to major organs such as the kidneys, heart and brain. Haemolysis occurs and shistocytes form because of the sheer stress on rbcs as they pass through the microscopic clots.
Urgent plasma exchange can be lifesaving in patients with TTP, so it is important to consider this diagnosis early in patients who have unexplained thrombocytopenia and anaemia. The mortality rate is reported as >95% if untreated.
Idiopathic thrombocytopenic purpura (C) is an autoimmune disorder caused by IgG antibodies against platelets in most cases. Treatment depends on the platelet count and the presence of bleeding, but includes steroids, anti-D, immunosuppressants and splenectomy.
Haemolytic uraemic syndrome (D) typically affects young children infected with a specific strain of E. coli called O157, which produces a verotoxin that attacks endothelial cells and results in MAHA. The anaemia, thrombocytopenia, renal failure and presence of shistocytes could be caused by HUS in this question, but it is less likely given the patient’s age, the presence of neurological symptoms and the absence of preceding symptoms of gastroenteritis.
The presence of a fever may have led you to consider an infectious cause such as Weil’s disease (A) or glandular fever (B). Weil’s disease is caused by the spirochaete Leptospira interrogans, and is spread by infected rat urine. Although it can cause an abrupt onset of renal failure and a fever, it would not typically result in thrombocytopenia or features of MAHA. Glandular fever is also unlikely in this scenario: whilst it can cause palatal petechiae, it does not typically present with hallucinations or purpura, and a thrombocytopenia and anaemia are again less likely.
2. Blood transfusion (2) A 43-year-old woman is transfused three units of blood as an emergency fol- lowing prolonged haematemesis. A few minutes later she becomes restless, and complains of chest pain. On examination she is pyrexial and tachycardic with a blood pressure of 95/60. There is bleeding at the site where her cannula is inserted, and urinalysis reveals haemoglobinuria. The most likely diagnosis is: A Anaphylaxis B ABO incompatible blood transfusion C Myocardial infarction D Graft versus host disease E Bacterial contamination
B
An ABO incompatible blood transfusion (B) can occur immediately after a transfusion has been given. For example, if group A, B or AB blood is given to a group O patient, the patient’s anti-A and anti-B antibodies attack the blood cells in the donor blood. The most severe form of reaction is thought to occur if group A red cells are transfused to a group O patient. Even just a few millilitres of blood can trigger a severe reaction within a few minutes. These reactions can also occur with platelets or fresh frozen plasma because they also contain anti-red cell antibodies.
Symptoms can include chills, fever, pain in the back, chest or along
the IV line, hypotension, dark urine (intravascular haemolysis), and uncontrolled bleeding due to DIC. In this case, the management involves stopping the transfusion immediately and taking blood samples for
FBC, biochemistry, coagulation, repeat x-match, blood cultures and direct antiglobulin test, and contacting the haematology doctor as soon as possible. The blood bank should also be urgently informed because another patient may have also been given incompatible blood. These patients require fluid resuscitation and possibly inotropic support. They should be transferred to ICU if possible.
These reactions can be prevented through measures such as proper iden- tification of the patient from sample collection through to administering the blood product and careful labelling of the samples. If the patient is unconscious, then careful monitoring of observations before, during and after the transfusion can help to detect signs of a reaction as early as possible.
An anaphylactic reaction (A) can also present immediately following a blood transfusion, but look out for clues such as a rash, urticaria and a wheeze to point you towards this diagnosis. A myocardial infarction (C) is less likely in this setting, and would not cause intra- vascular haemolysis. Graft versus host disease (D) is a rare form of a delayed transfusion reaction which can occur in immunosuppressed patients, where lymphocytes from donor blood can attack the host. This can result in liver failure, diarrhoea, skin rashes and bone mar- row failure. Bacterial contamination (E) would also cause a fever and may lead to hypotension and tachycardia, so can be difficult to dif- ferentiate from ABO incompatibility. However, these reactions would not typically cause pain or haemoglobinuria. Usually a very high fever, rigors, and profound hypotension can be clues to this diagnosis in the question.
- Haemolytic anaemia
A Hereditary sherocytosis B Sickle cell anaemia C Beta-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
1 A 48-year-old woman diagnosed with chronic lymphocytic leukaemia devel- ops jaundice and on examination is found to have conjunctival pallor. Direct antiglobulin test is found to be positive at 37°C.
1) F
Autoimmune haemolytic anaemia (AIHA; F) is caused by autoantibodies that bind to red blood cells (RBCs) leading to splenic destruction. AIHA can be classified as either ‘warm’ or ‘cold’ depending on the tempera- ture at which antibodies bind to RBCs. Warm AIHA is IgG mediated, which binds to RBCs at 37°C; causes include lymphoproliferative dis- orders, drugs (penicillin) and autoimmune diseases (SLE). Cold AIHA is IgM mediated which binds to RBCs at temperatures less than 4°C; this phenomenon usually occurs after an infection by mycoplasma or EBV. Direct antiglobulin test (DAT) is positive in AIHA and spherocytes are seen on blood film.
Hereditary spherocytosis (A) and hereditary eliptocytosis are both auto- somal dominant disorders that result in RBC membrane defects and extravascular haemolysis.
Beta-Thalassaemia (C) results in defects of the globin chains of haemoglobin. As a consequence, there is damage to RBC membranes causing haemolysis within the bone marrow.
Pyruvate kinase deficiency (E) is an autosomal recessive genetic disorder that causes reduced ATP production within RBCs and therefore reduces survival.
Paroxysmal nocturnal haemoglobinuria (H; PNH) is a rare stem cell disorder which results in intravascular haemolysis, haemoglobinuria (especially at night) and thrombophilia. Ham’s test is positive.
- Haemolytic anaemia
A Hereditary sherocytosis B Sickle cell anaemia C Beta-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
2 An 18-year-old man presents to accident and emergency after eating a meal containing Fava beans. He is evidently jaundiced and has signs sug- gestive of anaemia. The patient’s blood film reveals the presence of Heinz bodies
2) D
Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency; D) is caused by an X-linked recessive enzyme defect. G6PD is an essential enzyme in the red blood cell pentose phosphate pathway; the pathway maintains NADPH levels which in turn supply glutathione to neutralize free radicals that may otherwise cause oxidative damage. Therefore, G6PD deficient patients are at risk of oxidative crises which may be precipitated by certain drugs (primaquine, sulphonamides and aspirin), fava beans and henna. Attacks result in rapid anaemia, jaundice and a blood film will demonstrate the presence of bite cells and Heinz bodies.
Hereditary spherocytosis (A) and hereditary eliptocytosis are both auto- somal dominant disorders that result in RBC membrane defects and extravascular haemolysis.
Beta-Thalassaemia (C) results in defects of the globin chains of haemoglobin. As a consequence, there is damage to RBC membranes causing haemolysis within the bone marrow.
Pyruvate kinase deficiency (E) is an autosomal recessive genetic disorder that causes reduced ATP production within RBCs and therefore reduces survival.
Paroxysmal nocturnal haemoglobinuria (H; PNH) is a rare stem cell disorder which results in intravascular haemolysis, haemoglobinuria (especially at night) and thrombophilia. Ham’s test is positive.
- Haemolytic anaemia
A Hereditary sherocytosis B Sickle cell anaemia C Beta-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
3 A 10-year-old girl presents to accident and emergency with jaundice. Blood tests reveal uraemia and thrombocytopenia. A peripheral blood film demon- strates the presence of schistocytes.
3) I
Microangiopathic haemolytic anaemia (I) is caused by the mechanical destruction of RBCs in circulation. Causes include thrombotic thrombocytopenic pupura (TTP), haemolytic uraemic syndrome (HUS; E. coli O157:57), disseminated intravascular coagulation (DIC) and systemic lupus erythematosus (SLE). In all underlying causes, the potentiation of coagulation pathways creates a mesh which leads to the intravascular destruction of RBCs and produces schistocytes (helmet cells). Schistocytes are broken down in the spleen, raising bilirubin levels and initiating jaundice.
Hereditary spherocytosis (A) and hereditary eliptocytosis are both auto- somal dominant disorders that result in RBC membrane defects and extravascular haemolysis.
Beta-Thalassaemia (C) results in defects of the globin chains of haemoglobin. As a consequence, there is damage to RBC membranes causing haemolysis within the bone marrow.
Pyruvate kinase deficiency (E) is an autosomal recessive genetic disorder that causes reduced ATP production within RBCs and therefore reduces survival.
Paroxysmal nocturnal haemoglobinuria (H; PNH) is a rare stem cell disorder which results in intravascular haemolysis, haemoglobinuria (especially at night) and thrombophilia. Ham’s test is positive.
- Haemolytic anaemia
A Hereditary sherocytosis B Sickle cell anaemia C Beta-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
4 A 9-year-old boy from sub-Saharan Africa presents to accident and emergency with abdominal pain. On examination the child is found to have dactylitis. Blood haemoglobin is found to be 6.2 g/dL and electrophoresis reveals the diagnosis.
4) B
Sickle cell anaemia (B) is an autosomal recessive genetic haematological condition due to a point mutation in the Beta-globin chain of haemoglobin (chromosome 11); this mutation causes glumatic acid at position six to be substituted by valine. Homozygotes for the mutation (HbSS) have sickle cell anaemia while heterozygotes (HbAS) have sickle cell trait. The mutation results in reduced RBC elasticity; RBCs therefore assume a sickle shape which leads to the numerous complications associated with a crisis. Blood tests will reveal an anaemia, reticulocytosis and raised bilirubin. Haemoglobin electrophoresis will distinguish between HbSS and HbAS.
Hereditary spherocytosis (A) and hereditary eliptocytosis are both auto- somal dominant disorders that result in RBC membrane defects and extravascular haemolysis.
Beta-Thalassaemia (C) results in defects of the globin chains of haemoglobin. As a consequence, there is damage to RBC membranes causing haemolysis within the bone marrow.
Pyruvate kinase deficiency (E) is an autosomal recessive genetic disorder that causes reduced ATP production within RBCs and therefore reduces survival.
Paroxysmal nocturnal haemoglobinuria (H; PNH) is a rare stem cell disorder which results in intravascular haemolysis, haemoglobinuria (especially at night) and thrombophilia. Ham’s test is positive.
- Haemolytic anaemia
A Hereditary sherocytosis B Sickle cell anaemia C Beta-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
5 A 1-day old baby has developed severe jaundice on the neonatal ward. The mother is rhesus negative and has had one previous pregnancy. Due to having her first baby abroad, she was not administered prophylactic anti-D.
5) G
Haemolytic disease of the newborn (G) occurs when the mother’s blood is rhesus negative and the fetus’ blood is rhesus positive. A first pregnancy or a sensitizing event such as an abortion, miscarriage or antepartum haemorrhage leads to fetal red blood cells entering the maternal circulation resulting in the formation of anti-D IgG. In a second pregnancy, maternal anti-D IgG will cross the placenta and coat fetal red blood cells which are subsequently haemolyzed in the spleen and liver. Therefore, anti-D prophylaxis is given to at-risk mothers; anti-D will coat any fetal red blood cells in the maternal circulation causing them to be removed by the spleen prior to potentially harmful IgG production.
Hereditary spherocytosis (A) and hereditary eliptocytosis are both auto- somal dominant disorders that result in RBC membrane defects and extravascular haemolysis.
Beta-Thalassaemia (C) results in defects of the globin chains of haemoglobin. As a consequence, there is damage to RBC membranes causing haemolysis within the bone marrow.
Pyruvate kinase deficiency (E) is an autosomal recessive genetic disorder that causes reduced ATP production within RBCs and therefore reduces survival.
Paroxysmal nocturnal haemoglobinuria (H; PNH) is a rare stem cell disorder which results in intravascular haemolysis, haemoglobinuria (especially at night) and thrombophilia. Ham’s test is positive.
- Obstetric haematology
A 28-year-old woman in her 29th week of pregnancy comes to accident and emergency with epigastric pain, nausea and vomiting. She also complains that her hands and feet have been swelling up. On examination her blood pressure is 165/96, HR 125bpm, and she is apyrexial. She is noted to have yellowing of her sclera and right upper quadrant tenderness. Blood tests reveal an Hb of 10.1, platelets 96, WCC 11.3, LDH 820 (N 70–250), AST 115 (N 5–35), and ALT 102 (N 5–35). Her coagulation screen is normal and a blood film is reported as showing the presence of schistocytes. The most likely diagnosis is
A Hepatitis B Thrombotic thrombocytopenic purpura C Pre-eclampsia D Acute fatty liver of pregnancy E HELLP syndrome
E
‘HELLP’ syndrome (E) is a potentially fatal occurrence in pregnancy, characterized by a triad of features:
1 H – haemolysis
2 EL – elevated liver enzymes
3 LP – low platelet count
In a similar way to DIC, generalized activation of the clotting cascade is triggered which can only be terminated with delivery. Platelet consumption and MAHA occurs, and liver ischaemia can lead to periportal necrosis and, in severe cases, formation of a subcapsular haematoma which can rupture.
It usually presents in the third trimester, but can happen even up to a week after delivery. Often patients with HELLP have had pregnancy-induced hypertension or pre-eclampsia prior to its development. Common symptoms are often vague, and can include nausea and vomiting, epigastric pain, peripheral swelling, paraesthesia, headaches and visual problems. On examination patients may be noted to have peripheral oedema, upper abdominal tenderness, jaundice and hepatomegaly. Complications can include liver and renal failure, pulmonary oedema, DIC and placental abruption. Clotting studies may be normal as in this case, unless DIC has occurred. The only effective treatment is delivery, but other supportive treatment includes control of the hypertension, seizure prophylaxis and corticosteroid use.
Hepatitis (A) can result in jaundice, right upper quadrant tenderness and abnormal LFTs, but is less likely to cause a marked thrombocytopenia and the presence of schistocytes (indicating haemolysis) in an apyrexial patient as in this case. A leukocytosis is also more likely.
TTP (B) is characterized by the classic sextet of symptoms as described previously, but deranged LFTs are not typical of this condition.
Haemolysis and abnormal LFTs are also rare in pre-eclampsia (C), and mild thrombocytopenia is present in only 10–15 per cent of cases.
Acute fatty liver of pregnancy (D) is a life-threatening rare complication of pregnancy that can also present non-specifically with deranged LFTs, but is often accompanied by abnormal coagulation, leukocytosis and hypoglycaemia.
- Vitamin K dependent clotting factors
A 56-year-old woman with known cirrhosis presents with falls. On examination she is clinically jaundiced and rectal examination reveals malaena. Blood tests reveal an INR of 2.2. She is diagnosed with decompensated chronic liver disease. Which of the following is not a vitamin K dependent clotting factor?
A Thrombin B Factor VII C Factor VIII D Protein C E Factor X
C
The vitamin K dependent clotting factors include II, VII, IX and X. Vitamin K is also required for the production for protein C, protein S and protein Z, although these are strictly not clotting factors, rather anticoagulant factors. Vitamin K is a fat soluble vitamin found in green leafy vegetables such as spinach, cabbage and cauliflower. It
is absorbed in the small bowel and is important in the production of functional clotting factors in the liver. This patient’s acute chronic liver failure has meant she is no longer producing functional clotting factors, represented as a raised INR.
Vitamin K is recycled in the liver and its oxidation is coupled with the post-translational modification of glutamate residues to form gamma-carboxyglutamate. Vitamin K is firstly reduced by vitamin K epoxide reductase to form vitamin K hydroquinone. This reduced form is oxi- dized by vitamin K dependent carboxylase to form vitamin K epoxide. This reaction is coupled with gamma-glutamyl carboxylase; the enzyme responsible for post-translational modification of the vitamin K depend- ent factors. Vitamin K epoxide is then reconverted to vitamin K by vitamin K epoxide reductase; thus completing the cycle. If the patient were to be given vitamin K metabolism antagonists, e.g. warfarin, the clotting factors produced would still be immunologically identical (these are also known as Proteins Induced by Vitamin K Absence/Antagonism – PIVKA) but would lack efficacy as they are unable to interact with calcium or platelet factor 3.
Factor VIII is not a vitamin K dependent clotting factor, it is synthe- sized by endothelium and sinusoidal cells of the liver and is found in the plasma as well as non-covalently bound to von Willebrand factor (vWF). It is classically described to be a part of the intrinsic pathway of the clotting cascade which is tested by the use of the prothrombin time. Factor VIII is a procofactor activated by thrombin during the amplification phase of the coagulation cascade. Once active, it binds to factor IXa on the platelet which together activate factor X with Va. Factors Va, Xa, phospholipids and calcium together form the prothrombinase complex which leads to a thrombin burst where thrombin production is rapidly amplified.
Thrombin (A) is the penultimate product of the coagulation cascade, its functions include cleaving fibrinogen to form fibrin, activating platelets, activating procofactors V and VIII and activating zymogens VII, XI and XIII. It also acts to control fibrinolysis by binding to endothelial-bound thrombospondin thus activating protein C (D) and protein S. This complex inhibits cofactors V and VIII and acts as a negative feedback control on the coagulation cascade.
Factor VII (B) is a vital part of the extrinsic clotting cascade which is activated by tissue factor, a factor expressed by damaged endothelial cells. Within this initiation phase, factor VIIa activates downstream factors IX and X. Factors Xa and Va bind to the damaged area provid- ing the base site of coagulation activity where the amplification phase begins. Here, the Xa/Va complex activates prothrombin to thrombin which then acts to activate XI, VIII and V. The end result is the pro-thrombinase complex; a structure consisting of factor Va heavy and light chains, Xa, phospholipids and calcium which explodes with throm- bin generating activity in order to produce fibrin rapidly and stabilize the platelet clot. This final phase is thus called the propagation phase.
- Deep vein thrombosis
A 46-year-old man presents with pain and swelling in the right calf 2 weeks after being fitted with a plaster cast to his leg after a fall. The calf is tender, erythematous and swollen. He is also a heavy smoker and slightly overweight. His admitting physician suspects a deep vein thrombosis (DVT) and books an ultrasound of the calf. A DVT is confirmed and 5mg warfarin is started the next day. Two days later, the same patient develops pain and swelling in the other calf, an ultrasound confirms a further DVT in the contralateral leg. What factor is least likely to contribute to the development of the second DVT?
A Smoking B Warfarin C Previous DVT D Being slightly overweight E Plaster cast
D
All of the factors except being slightly overweight probably directly contributed to this patient developing a second deep vein thrombosis. The risk factors for developing venous thrombosis may be categorized to mechanisms affecting the blood vessel wall, the blood flow and the blood itself, i.e. Virchow’s triad.
Smoking (A) increases thrombotic risk by inducing endothelial damage and increasing thromboxane A2 production, which stimulates platelet aggregation, and perhaps increasing platelet dependent thrombin generation. The link between smoking and venous thrombosis is well established although the risk reduction over time once someone quits is not fully understood.
Previous DVT (C) is probably one of the strongest risk factors for DVT with a five-fold increase over baseline risk. This, along with a recent fit- ting of a plaster cast (E) and associated immobility, represents the highest risk for this patient in developing a second DVT. Other important risk factors include major surgery, particularly involving the abdomen or lower limb, cancer, prothrombotic states, some chemotherapeutic agents, myocardial infarction and congestive heart failure, pregnancy and combined oral contraceptive pill.
Warfarin (B), a commonly used anticoagulant, probably contributed to
a second DVT in this situation. Warfarin antagonizes vitamin K epox-
ide reductase; a liver enzyme responsible for recycling vitamin K to its reduced state. Warfarin thus antagonizes the production of vitamin K dependent factors including factors II, VII, IX, X, protein C and protein S. The latter two are anticoagulant factors which provide a negative feedback on the coagulation cascade by inhibiting procofactor V and VIII activation. Protein C and S have a shorter half life than the other coagulant factors thus when their production is inhibited by warfarin, a state of transient hypercoagulability is formed in the first few days after starting warfarin. Normally, clinicians will cover this problem by the use of concomitant heparin until the therapeutic range is obtained. In this patient, the admitting physician unfortunately did not give any heparin, and thus transiently increased the thrombotic risk of this already high risk patient.
Although obesity is associated with risk of development of DVT, this man is described as slightly overweight (D). Thus, in comparison to the other risk factors presented, it probably represents the lowest attributable risk to the second DVT.
- Peripheral blood film
A 32-year-old woman presents with generalized fatigue. Full blood count shows a reduced haemoglobin level and reduced mean corpuscular volume. A peripheral blood film has revealed iron deficiency anaemia. What features are most likely to be seen on her peripheral blood film?
A Hypochromic and microcytic red blood cells with anisopoikilocytosis and acanthocytes
B Hypochromic and microcytic red blood cells with hypersegmented neutrophils
C Hypochromic and microcytic red blood cells with anisopoikilocytosis and no evidence of basophilic stippling
D Hypochromic and microcytic red blood cells with Howell–Jolly bodies and basophilic stippling
E Hypochromic and macrocytic red blood cells with target cells, acanthocytes and Howell–Jolly bodies
C
Features of iron deficiency anaemia are hypochromic (pale) and microcytic (small) red blood cells. Poikilocytes are red blood cells that are abnormally shaped. When there are variations in shape and size, it is known as anisopoikilocytosis. Basophilic stippling (aggregation of ribosomal material) is absent in iron deficiency and present in beta-thalassaemia trait and lead poisoning.
In megaloblastic anaemia, there is impaired DNA synthesis and this can be caused by B12 deficiency, folate deficiency and drugs. Here the features are the characteristic hypersegmented neutrophils and macrocytic red blood cells.
In hyposplenism, there is presence of target cells known as codocytes (red blood cells that have a high surface area:volume ratio).
Acanthocytes (spiculated blood cells/spur cells) and Howell–Jolly bodies (nuclear remnants visible in red cells) are also present in the hyposplenism picture.
- Thrombocytopenia
A 54-year-old man presents with haematemesis. He has known varices and is currently vomiting large amounts of bright red blood. The admitting doctor takes some blood for fast analysis and confirms a haemoglobin of 4g/dL. The patient’s haematemesis continues and he is transfused a total of 20 units of blood and 8 units of fresh frozen plasma in the next 24 hours. The patient underwent gastroscopy which revealed bleeding oesophageal varices which were successfully treated by endoscopic banding.
His post-transfusion bloods are the following:
Hb 9.2g/dL
White cells 8.0×109/L
Platelets 57×109/L
Prothrombin time normal
Activated partial thromboplastin time normal
Fibrinogen >1.0g/L
What is the most likely cause of his thrombocytopenia?
A Disseminated intravascular coagulopathy B Alcohol excess C Massive blood transfusion D Megaloblastic anaemia E Hypersplenism
C
Although all of the given options are causes of thrombocytopenia, the most likely cause in this patient is massive blood transfusion without replacement of platelets (C). Massive blood loss may be defined as losing one’s entire circulating blood volume in 24 hours. Other definitions include losing 50% of one’s blood volume in 3 hours or a rate of loss of greater than or equal to 150mL/min. This patient has been transfused 20 units of blood in the space of 24 hours, thus fulfilling the criteria for massive haemorrhage. Massive transfusion has its own par- ticular complications, including thrombocytopenia. This is because this patient was only given packed red cells and fresh frozen plasma. These two blood products contain very few platelets and in general, a platelet count of around 50×10/9L is to be expected when approximately 2 blood volumes have been replaced, as is the case in this patient. In this situation, the expert consensus is to keep the platelet level above 50×109/L, but there is marked interindividual variation therefore some consider using 75×109/L as the trigger value for platelet transfusion.
Disseminated intravascular coagulopathy (DIC) (A) is a feared complication of massive blood transfusion and carries with it a high mortality. It can be thought of as the loss of haemostatic control resulting in consumption of coagulant factors, platelets and fibrinogen. Widespread clotting ensues with microvascular structures becoming ischaemic, resulting in potential end organ failure. Once coagulation factors and platelets are depleted bleeding becomes apparent making this disorder a concomitant bleeding and clotting problem. Those at particular risk include patients with prolonged hypoxia or hypovolaemia with cerebral or extensive muscle damage, or those who become hypothermic from infusion of cold resuscitation fluids. It is biochemically detected by a rising prothrombin time, activated thromboplastin time in excess of that expected by dilution together with significant thrombocytopenia and low fibrinogen (<1.0g/L). This is not the case with this patient, although he should be monitored closely to look out for this complication.
Alcohol excess (B) can cause thrombocytopenia; it is a direct bone marrow suppressant thereby inhibiting megakaryocyte development and platelet production.
Cirrhosis, of any aetiology including alcohol, can cause portal hypertension thus causing splenomegaly and a potential hypersplenism (E). The normal human spleen contains about one-third of the circulating platelets, if it engorges in size due to portal hypertension it may sequester more platelets; this is the difference between hypersplenism (increased function) and splenomegaly (increased physical size). This is less likely in this case given the massive haemorrhage and the lack of clinical evidence of splenomegaly in the question, despite there being evidence of portal hypertension as there are oesophageal varices present. Megaloblastic anaemia (D) is caused by B12 or folate deficiency which is classically macrocytic in nature, although the mean cell volume will be difficult to interpret now given the patient has had a blood transfusion. It is most commonly caused by pernicious anaemia, an autoimmune condition where antibodies are directed against stomach parietal cells or intrinsic factor. The blood film classically shows meg- aloblasts – nucleated red blood cells along with polychromasia (where red cells have multiple colours due to premature release from bone marrow), basophilic stippling (peripheral dots which represent rRNA and is always pathological) and Howell–Jolly inclusion bodies (clus- ters of DNA within erythrocytes). This could potentially be true in this patient, but it is not the most likely answer given the circumstances of massive blood loss.
- Erythrocyte sedimentation rate
Which of the following is not often associated with a very high (>100mm/hour) erythrocyte sedimentation rate (ESR)?
A Myeloma B Anaemia C Leukaemia D Aortic aneurysm E Malignant prostatic cancer
B
ESR is a commonly used laboratory test to detect the presence of inflammation in general. It is performed by adding a sample of anticoagulant to a blood sample and adding this mixture to a calibrated vertical tube (Westergren tube). As the red cells fall with gravity and accumulate, they lie in the bottom of the tube, and are called sediment. The rate at which they accumulate is therefore the ESR.
Factors which influence the ESR include age, sex and pathological processes which increase plasma proteins or the number of red cells. Women generally have a higher ESR than men and it also increases with age. Depending on the exact reference range for your particular lab, women and men over 50 can have an ESR of up to 30 and 20mm/ hour, respectively, and still be normal. Conditions which increase plasma proteins such as fibrinogen, acute phase proteins and immunoglobulins can increase the ESR as these proteins reduce the ionic resist- ance between erythrocytes leading to an increased fall rate. They also promote rouleaux formation of erythrocytes which is the characteristic stacking of erythrocytes seen under the microscope. The most important protein to promote rouleaux formation is fibrinogen. The number of red cells in a given volume also influences ESR; in severe anaemia ESR is falsely raised as the reduced ionic repulsion between erythrocytes allow faster sedimentation. However, this rarely leads to an ESR of >100mm/ hour, making anaemia (B) the correct answer. The other conditions listed can all raise ESR above 100mm/hour.
Myeloma (A) and leukaemia (C) do this by the production of increased plasma proteins including immunoglobulins which promote rouleaux formation as well as reduce ionic erythrocyte repulsion.
Aortic aneurysms (D) can cause a very raised ESR, particularly when they are of the inflammatory type. Patients with chronic abdominal pain, weight loss, raised ESR with a known abdominal aneurysm should prompt the thought of an inflammatory aneurysm subtype. In these patients the inflammatory process sometimes encases the nearby ureters causing obstruction and eventually hydronephrosis.
Malignant prostate cancer (E) raises ESR by virtue of raising fibrinogen levels in the blood. Quantative in vitro studies have found a direct relationship between fibrinogen concentration and ESR.
Fibrinogen is an important part of the clotting cascade; its activation to fibrin is important in binding to platelets and stabilizing the platelet plug to maintain haemostasis. As mentioned, fibrinogen increases rouleaux formation as well as reducing ionic repulsion between erythrocytes, thus increasing ESR.
Sometimes patients present with a persistently raised ESR but a normal C reactive protein – another marker of inflammation which rises and falls more acutely. There are a few important conditions to note with this configuration of test results: systemic lupus erythematosus, multiple myeloma, lymphoma, anaemia and pregnancy.
- Polycythaemia
A 62-year-old man presents with shortness of breath. This has been gradually getting worse for the last few years and is associated with chronic productive cough. He is a heavy smoker. His chest X-ray reveals a hyperexpanded chest with no other abnormalities. His bloods tests are normal except for a raised haemoglobin and raised haematocrit. What is the most likely cause for this?
A Polycythaemia rubra vera B Idiopathic erythrocytosis C Secondary polycythaemia D Gaisbock’s disease E Combined polycythaemia
E Combined polycythaemia (E), also known as smoker’s polycythaemia, has multiple aetiological factors. Cigarettes contain high concentrations of carbon monoxide gas which bind avidly to haemoglobin, thus displacing oxygen. This leads to increased erythropoietin (EPO) secretion from the hypoxic renal interstitium. EPO promotes erythrocyte proliferation and differentiation and prevents their apoptosis in the bone marrow, thus increasing red cell mass. Smoking is also a significant risk factor for chronic obstructive pulmonary disease, which is what this man suffers from. The obstructed airways reduce oxygen delivery to the alveoli and pulmonary vessels they supply thus causing a reduction of oxygen supply furthering the hypoxia. Finally, smokers also have an associated reduced plasma volume, thus increasing the relative concentration of haemoglobin. This is therefore ‘combined’ because of the presence of both increased red cell mass and reduced plasma volume.
Polycythaemia rubra vera (PRV) (A) is a chronic myeloproliferative dis- order characterized by a V617F point mutation in exon 14 of the JAK2 gene (E). It is present in 95–97% of patients with PRV, but the finding of this mutation is not specific to this condition (it also occurs in a substantial proportion of patients with essential thrombocythaemia and myelofibrosis). Crucially, these patients will have an increased red cell mass. It is important to realize that a raised haemoglobin, raised haematocrit or raised red blood cell count alone is not the same as a raised red cell mass. Haemoglobin may be raised with relative deficiency of plasma (i.e. relative or apparent polycythaemia, historically known as Gaisbock’s disease (D)). This is also the same with haematocrit, which is a measurement of the proportion of a centrifuged test tube red cells occupy compared with the entire sample. If there is a relative deficiency of plasma, e.g. secondary to dehydration, there is a relative increase in the haematocrit. The red cell mass is an absolute measure and is assessed by isotope dilution studies. This is sometimes used to differentiate between true and apparent polycythaemia.
Idiopathic erythrocytosis (B) is the label given to those with polycythaemia secondary to JAK2 mutation, but not with the V617F exon 14 mutation, e.g. exon 12 mutations.
Secondary polycythaemia (C) is where there are circulating plasma factors stimulating erythropoeisis, usually EPO but sometimes anabolic steroids (e.g. testosterone). It can also be secondary to an EPO secreting tumour – the 5 most common of which include hepatocellular carcinoma, renal cell carcinoma, haemangioblastoma, phaechromocytoma and uterine myomata. Oxygen sensitive EPO response may be appropriate, for example in chronic hypoxia when living at altitude or inappropriate, e.g. post transplant erythrocytosis where other hormones act to increases erythropoiesis and the EPO concentration is not elevated.
