Haem SBAs

Question 1

A 22-year-old motorcyclist is involved in a road traffic accident, and is transfusedtwo units of blood. Four hours later he develops acute shortness of breathand hypoxia, and despite attempts at ventilation deteriorates rapidly and goesinto respiratory arrest. An autopsy shows evidence of massive pulmonary oedemawith granulocyte aggregation within the pulmonary microvasculature. Themost likely diagnosis is:A AnaphylaxisB ABO incompatible blood transfusionC Fluid overloadD Transfusion related acute lung injuryE Air embolism

Answer 1

D Transfusion related acute lung injuryTransfusion related acute lung injury (TRALI) (D) is rare but is one ofthe leading causes of transfusion related mortality. It can present withacute shortness of break and hypoxia, as in this case, typically within6 hours of receiving the transfusion. The classic presentation to lookout for is that of non-cardiogenic pulmonary oedema, i.e. pulmonaryoedema that is not due to fluid overload.The underlying mechanism is not fully understood, but it is thought toinvolve HLA antibodies in the blood donor reacting with correspondingHLA antigens on the patient’s white blood cells. This leads to the formationof aggregates of white blood cells which become stuck in smallpulmonary capillaries. The release of proteolytic enzymes from neutrophilsand toxic oxygen metabolites causes lung damage, and subsequentnon-cardiogenic pulmonary oedema which can be fatal. Treatment isessentially supportive, and includes stopping the transfusion, givingIV fluids and ventilation if needed. TRALI can occur with platelets andFFP, as well as with packed red cells as in this case. You might find ithelpful to remember the mechanism by rearranging ‘TRALI’ to form theword ‘TRAIL’, and think of the blood donor leaving a ‘trail’ of antibodiesin the recipient.

Question 2

A 43-year-old woman is transfused three units of blood as an emergency followingprolonged haematemesis. A few minutes later she becomes restless, andcomplains of chest pain. On examination she is pyrexial and tachycardic witha blood pressure of 95/60. There is bleeding at the site where her cannula isinserted,and urinalysis reveals haemoglobinuria. The most likely diagnosis is:A AnaphylaxisB ABO incompatible blood transfusionC Myocardial infarctionD Graft versus host diseaseE Bacterial contamination

Answer 2

B ABO incompatible blood transfusionAn ABO incompatible blood transfusion (B) can occur immediatelyafter a transfusion has been given. For example, if group A, B or ABblood is given to a group O patient, the patient’s anti-A and anti-Bantibodies attack the blood cells in the donor blood. The most severeform of reaction is thought to occur if group A red cells are transfusedto a group O patient. Even just a few millilitres of blood can trigger asevere reaction within a few minutes. These reactions can also occurwith platelets or fresh frozen plasma because they also contain anti-redcell antibodies.Symptoms can include chills, fever, pain in the back, chest or alongthe IV line, hypotension, dark urine (intravascular haemolysis), anduncontrolled bleeding due to DIC. In this case, the management involvesstopping the transfusion immediately and taking blood samples forFBC, biochemistry, coagulation, repeat x-match, blood cultures anddirect antiglobulin test, and contacting the haematology doctor as soonas possible. The blood bank should also be urgently informed becauseanother patient may have also been given incompatible blood. Thesepatients require fluid resuscitation and possibly inotropic support. Theyshould be transferred to ICU if possible.

Question 3

An 83-year-old woman with myelodysplasia is found to have a haemoglobin of6.2 on admission. She is transfused two units of blood, and is discharged 2 dayslater. Six days after her admission her carer calls the GP with concerns that sheis feverish and her skin looks slightly yellow. She is readmitted to hospital whereblood tests reveal the following: bilirubin 35, ALT 15 (N 5–35), ALP 82(N 20–140), Hb 7.3 g/dL, platelets 264 × 109/L. The most likely diagnosis is:A Febrile haemolytic transfusion reactionB Hepatitis BC Graft versus host diseaseD Post-transfusion purpuraE Delayed haemolytic transfusion reaction

Answer 3

E Delayed haemolytic transfusion reactionDelayed haemolytic transfusion reactions (E) can occur more than 24hours after a transfusion is given. They occur when patients are sensitizedfrom previous transfusions or pregnancies, and therefore haveantibodies against red cell antigens which are not picked up by routineblood bank screening if they are below the detectable limits. The mostfrequent causes are the antibodies of the Kidd (Jk) and Rh systems.Clinical features might include falling haemoglobin concentration, asmaller rise in haemoglobin than expected following a transfusion as inthis case, fever, jaundice and rarely haemoglobinuria or renal failure. Ablood film may show a raised reticulocyte count. Management of thesereactions includes monitoring renal function, sending a repeat groupand antibody screen and cross-match and further transfusion if needed.The blood bank should be notified too, and further specific treatmentmight not be needed unless renal failure develops.

Question 4

An 8-year-old boy is brought to his GP by his father, who reports that he hasbeen feeling progressively more tired over the past few months. On examinationthe GP notices a slight yellowing of his sclera, and the presence of splenomegaly.His father recollects that he himself was told he had a problem with his bloodcells as a child, but has never been affected by it. A peripheral blood film showsa raised reticulocyte count and spherocytes. He is likely to have a positive:A Coombs testB Osmotic fragility testC G6PD testD Sickle cell screenE Schilling test

Answer 4

B Osmotic fragility testHereditary spherocytosis is a type of autosomal dominant inheritedhaemolytic anaemia. It occurs due to an increase in the fragility ofthe red blood cell membrane due to dysfunctional skeletal proteins inthe membrane, such as spectrin, ankyrin and band 4.2. Most patientsdevelopa haemolytic state that is partially compensated. Clinicalfeaturescan include tiredness from anaemia, as in this case, and thepresence of jaundice and splenomegaly on examination. They can alsodevelop pigment gallstones from the haemolysis. As with this child,there is often a positive family history. A blood film can show the presence of spherocytes and reticulocytes,and a Coombs test is negative. They may have a positive osmotic fragilitytest (B), but remember that this is just used to confirm that there arespherocytes present, not that the cause is hereditary spherocytosis. Withthis test, because the membrane is more permeable to salt and water,the spherocytes rupture in a mildly hypotonic solution. Do not forgetthat spherocytes may also be found in autoimmune haemolytic anaemia.

Question 5

A 33-year-old Turkish man presents with extreme tiredness and shortness ofbreath after being started on a course of anti-malarial tablets. A full blood countreveals an Hb of 6.8. His Coombs test is negative. The cell type most likely to befound on his blood film is:A Heinz bodiesB Pencil cellsC Target cellsD SpherocytesE Sickle cells

Answer 5

A Heinz bodiesThis man is suffering from glucose-6-phosphate dehydrogenase (G6PD)deficiency, an X-linked recessive disorder that is common in peoplefrom the Mediterranean, South East Asia, Middle East and West Africa. This enzyme is responsible for maintaining levels of glutathionefrom the pentose phosphate pathway, which protects against oxidantfree radicals. Oxidative stress, for example in the form of chemicals,food or infection, can put people with this condition at risk of severehaemolyticanaemia. Drugs to be avoided in these patients includeanti-malarials,such as primaquine, and others such as sulphonamides,vitamin K and dapsone. The exam favourite of broad beans can lead toa reaction called favism in these patients.

Question 6

A 25-year-old student is treated for infectious mononucleosis following a positivePaul Bunnell test. A blood film reveals target cells, Howell–Jolly bodies andatypical lymphocytes. Together, these suggest that he has features of:A Bone marrow suppressionB HyposplenismC Disseminated intravascular coagulationD Haemolytic anaemiaE Liver failure

Answer 6

B HyposplenismUp to half of all patients might develop splenomegaly in infectiousmononucleosis. This does not often cause symptoms but can lead tosplenic rupture, either spontaneously or following minor trauma, andmay necessitate treatment with splenectomy. Postoperatively a combinationof features on a blood film might suggest hyposplenism:• Howell–Jolly bodies: these are small fragments of non-functionalnuclei that are normally removed by the spleen, so might be seen ona blood film in hyposplenism. They may also be seen in megaloblasticand iron-deficiency anaemias• Target cells: these have a central dense area with a ring of pallor,and can occur in the three Hs: hepatic pathology, hyposplenism andhaemoglobinopathies• Occasional nucleated red blood cells• Lymphocytosis• Macrocytosis• Acanthocytes: spiculated red cells that are found in hyposplenism,α-β-lipoproteinaemia, chronic liver disease and α-thalassaemia trait

Question 7

A 4-year-old Afro-Caribbean boy has chest and abdominal pain. His blood testsreveal an Hb of 6.1 g/dL, with an MCV of 65. A blood film shows the presence ofsickle cells. The most likely diagnosis is:A Sickle cell traitB Sickle cell anaemiaC Sickle cell/b-thalassaemiaD Sickle cell/haemoglobin CE b-Thalassaemia

Answer 7

B Sickle cell anaemiaThis boy is suffering from sickle cell anaemia (B), an autosomal recessivehaemoglobinopathy. The term sickle cell disease actually comprisesseveral different states: sickle cell anaemia, but also compoundheterozygous states including sickle cell/haemoglobin C (D) and sicklecell/b-thalassaemia (C).Do not forget that the haemoglobin molecule consists of four chains,and there are three different forms: haemaglobin A (α2β2), haemoglobinA2 (α2d2) and haemoglobin F (α2ϒ2). The proportions of the differentforms vary with age – haemoglobin F predominates before birth,but concentrations of haemaglobin A and A2 increase after birth, withhaemoglobin A predominating. In sickle-cell anaemia a point mutationin the β-globin chain of haemoglobin (found on chromosome 11)results in the hydrophilic amino acid glutamic acid being replaced bythe hydrophobic amino acid valine at the sixth position. This promotesaggregation of the haemoglobin chains in conditions of low oxygen,distorting the red blood cells so they adopt a sickle shape. These cellsbecome adherent to the endothelieum of post capillary venules, causingretrograde capillary obstruction which can lead to painful crises.

Question 8

A 7-year-old child has known sickle cell disease. He presents with a 5-day historyof fever, shortness of breath and extreme fatigue. His mother reports thathis younger brother, who also has sickle cell disease, has been feeling unwell toorecently. A blood test for the patient reveals a severe anaemia and low reticulocytecount. He has most likely developed:A Splenic sequestrationB Pneumococcal infectionC Vaso-occlusive crisisD Folic acid deficiencyE Parvovirus B19 infection

Answer 8

E Parvovirus B19 infectionAplastic crises caused by parvovirus B19 infection (E) can occur inpatients with sickle cell disease. They can present with acute worseningof the patient’s baseline anaemia, which might manifest as shortness ofbreath and fatigue as in this case. The fever points to an infectious cause.The virus affects erythropoiesis by invading erythrocyte precursors anddestroying them. Infants and children with sickle cell disease initiallyhave no immunity to parvovirus B19, and their first exposure can leadto pure red cell aplasia. In a normal individual the virus blocks redcell production for 2 or 3 days with little consequence, but it can belife threatening in sickle cell patients in whom the red cell life span isalready shortened. This can lead to profound anaemia over the courseof just a few days, and a dramatic drop in the reticulocyte count. SerumIgM antibodies to parvovirus B19 can confirm the diagnosis, and bloodtransfusion may be required.

Question 9

A 26-year-old pregnant woman is found to have an Hb of 9.5 g/dL on a routineblood test, with an MCV of 70. Serum electrophoresis reveals an Hb A2 of3.9 per cent and Hb A of 96.1 per cent. Her ferritin levels are normal. The mostlikely diagnosis is:A Iron deficiency anaemiaB Cooley’s anaemiaC b-Thalassaemia intermediaD b-Thalassaemia minorE a-Thalassaemia

Answer 9

D b-Thalassaemia minorIn b-thalassaemia minor (D) only one of the b-globulin alleles is mutated,so these individuals usually only have a well-tolerated microcytic anaemia(Hb >9 g/dL) which is clinically asymptomatic. They might be pickedup on a routine blood test, with a low MCH and significantly low MCV(3.5–4 percent to compensate for the reduced amount of normal haemoglobin, andthey might have a slight increase in Hb F. It can worsen in pregnancy, asin this case.

Question 10

A 24-year-old unemployed man presents to his GP with a 4-week history offlu-like symptoms and a persistent dry cough. On examination he has a maculopapularrash. A blood film reveals a haemolytic anaemia, and he is positive forcold agglutinins. The most likely organism implicated is:A Streptococcus pneumoniaeB Mycoplasma pneumoniaeC Legionella pneumophiliaD Chlamydophila psittaciE Borrelia burgdorferi

Answer 10

B Mycoplasma pneumoniaeAutoimmune haemolytic anaemia is a form of mainly extravascularhaemolysis, which is mediated by autoantibodies. It is classified intowarm and cold autoimmune haemolytic anaemia, according to the optimaltemperature at which the antibodies bind to red blood cells. Thisactivates the classical pathway in the complement system, resultingin haemolysis. Cold AIHA is mediated by IgM antibodies, and as thename suggests these antibodies bind optimally at lower temperatures(28–31°C), resulting in anaemia that is aggravated in cold conditions. Insevere cases, patients may suffer from Raynaud’s or acrocyanosis (purplishdiscolouration of peripheries). Most cases are idiopathic, but thereare 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 protractedhistory of flu-like symptoms (such as myalgia, arthralgia, headache)and a non-productive cough. Treatment includes avoiding cold conditions,use of chlorambucil, and treating the underlying cause. The other infectiousagents listed here do not typically cause a cold haemolytic anaemia.

Question 11

A 7-year-old boy is taken ill from school on a cold December day, with a presumedviral infection. On returning home that day, he beings to feel even moreunwell with a very high fever, headache and abdominal pain. His father begins toworry that his skin has taken on a yellow tinge, and the boy says his urine is nowa dark reddy-brown colour. He is taken to the GP and after several tests the presenceof ‘Donath–Landsteiner antibodies’ is reported. This child is suffering from:A Paroxysmal cold haemoglobinuriaB Paroxysmal nocturnal haemoglobinuriaC Sickle cell diseaseD Acute intermittent porphyriaE Epstein–Barr virus

Answer 11

A Paroxysmal cold haemoglobinuriaParoxysmal cold haemoglobinuria (A) is a rare form of autoimmunehaemolytic anaemia. It usually affects children in the acute setting afteran infection, and the key in this case is the presence of sudden haemoglobinuriaand jaundice after exposure to a cold temperatures. IgGautoantibodies usually form after an infection, and bind to red blood cellsurface antigens, inducing variable degrees of intravascular haemolysis inthe cold. The antibodies are known as ‘Donath–Landsteiner antibodies’. Analysis of the urine will confirm the presence of haemaglobinuria, andblood tests often reveal a normocytic or macrocytic anaemia. It is possibleto test indirectly for the IgG antiglobulins at a low temperature, asin this case. Blood transfusion may be required if the anaemia is severe,but in children who have an acute onset with an antecedent infection, itis usually a transient and self limiting condition.

Question 12

A 21-year-old student has recently been diagnosed with coeliac disease. Shepresents to her GP complaining of increased tiredness and shortness of breathon climbing stairs. Which of the following are most likely to be raised in thispatient?A Serum ironB HaematocritC TransferrinD FerritinE Mean cell haemoglobin

Answer 12

C TransferrinThis patient is suffering from iron deficiency anaemia, a common complicationin coeliac disease. The tiredness and shortness of breath arecommon symptoms. Causes can include blood loss (e.g. upper or lowerGI bleeding, menstruation), malabsorption (as in this case), dietary deficiency(rare in adults but can be seen in children) or infestation withparasitic worms (the most common cause worldwide). Blood tests characteristicallyreveal a low mean cell volume, mean cell haemoglobin(E) and mean cell haemoglobin concentration. A blood film may revealhypochromic red blood cells with anisocytosis (variation in cell size)and poikilocytosis (variation in cell shape). The red blood cell distributionwidth (RDW) (a measure of the variation of the width of red bloodcells) may be increased initially.

Question 13

A 34-year-old woman with known Addison’s disease is brought to the GP by herhusband, as he is concerned that she keeps falling over at night. On examinationthe GP notes that she has conjunctival pallor. A thorough neurological examinationreveals absent knee jerks, absent ankle jerks and extensor plantars bilaterally. Whichof the following is the most sensitive test for the condition she has developed?A Anti-intrinsic factor antibodiesB Anti-endomysial cell antibodiesC Anti-smooth muscle antibodiesD Anti-parietal cell antibodiesE Anti-voltage gated calcium channel antibodies

Answer 13

D Anti-parietal cell antibodiesThis woman has developed pernicious anaemia leading to vitamin B12deficiency. It can be associated with other autoimmune conditions, suchas Addison’s disease or thyroid disease. Specifically, she has developeda condition called subacute combined degeneration of the cord (SACD)which has led to symmetrical loss of dorsal columns (resulting in lossof touch and proprioception leading to ataxia, and LMN signs) and corticospinaltract loss (leading to UMN signs), with sparing of pain andtemperature sensation (which is carried by spinothalamic tracts). Theataxia and loss of joint position sense have resulted in her falling atnight, which may be exacerbated by optic atrophy – another manifestationof 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 ileumafter binding to intrinsic factor produced by the parietal cells in thestomach. 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).

Question 14

A 58-year-old woman is referred to a haematology clinic following repeated chest infections and epistaxis. On examination the doctor notes that 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 drughistory includes omeprazole, carbamazepine, gliclazide, metformin, paracetamol,and simvastatin. A bone marrow biopsy reveals a hypocellular marrow. The mostlikely diagnosis is:A Aplastic anaemiaB MyelodysplasiaC HypothyroidismD Chronic myeloid leukaemiaE Myeloma

Answer 14

A Aplastic anaemia14 A Causes of macrocytosis can be divided into:1 Megaloblastic, e.g. folate and B12 deficiency2 Non-megalobastic, causes of which can be remembered as RALPH =reticulocytosis (e.g. in haemolysis), alcohol, liver disease, pregnancyand hypothyroidism)3 Other haematological disorders, e.g. myelodysplasia, aplastic anaemia,myeloma, myeloproliferative disordersThis woman is suffering from aplastic anaemia (A), where the bonemarrow stops producing cells leading to a pancytopenia. Bone marrowexamination is needed to confirm the diagnosis, and shows a hypocellularbone marrow. Causes of aplastic anaemia can be primary or secondary.Primary causes can be congenital (e.g. Fanconi’s anaemia) or idiopathicacquired aplastic anaemia. Secondary causes include drugs (allthe 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 carbamazepinetherapy for hypothyroidism

Question 15

A 50-year-old diabetic man sees his GP complaining of generalized tiredness anda painful right knee. He is found on examination to have five finger breadths ofhepatomegaly. An X-ray of his right knee is reported as showing chondrocalcinosis.His blood tests are likely to reveal:A Raised MCVB Raised total iron binding capacityC Reduced serum ferritinD Reduced iron levelE Raised transferrin saturation

Answer 15

E Raised transferrin saturationThis man has hereditary haemachromatosis, an inherited disorder ofiron metabolism. It is particularly common in those of Celtic descent,and the gene responsible for the majority of cases is the HFE gene onchromosome 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 raisedserum ferritin, raised serum iron, reduced or normal total iron bindingcapacity and raised transferrin saturation (E) (>80 per cent).

Question 16

A 64-year-old woman is seen in the haematology clinic with generalized bonepain and recurrent infections. Following a set of blood tests, a skeletal surveyreveals multiple lytic lesions and a bone marrow biopsy reports the presence of>10 per cent plasma cells. Her blood tests are most likely to have shown:A Raised calcium, normal alkaline phosphatase, raised ESRB Normal calcium, raised alkaline phosphatase, normal ESRC Raised calcium, raised alkaline phosphatase, raised ESRD Raised calcium, normal alkaline phosphatase, raised CRPE Normal calcium, normal alkaline phosphatase, raised CRP

Answer 16

A Raised calcium, normal alkaline phosphatase, raised ESRThis woman has multiple myeloma, a cancer of plasma cells. The symptomscan be remembered using the mnemonic BRAIN: Bone pain (due toosteoclast activation leading to hypercalcaemia and the presence of lyticlesions on a skeletal survey, characteristically with a ‘pepperpot skull’appearance), Renal failure (which can be secondary to one or a combinationof: hypercalcaemia, tubular damage from light chain secretion,or secondary amyloidosis), Anaemia (typically normocytic), Infections(particularly pneumonias and pyelonephritis), and Neurological symptoms(such as a headache and visual changes from hyperviscosity, orconfusion and weakness from the hypercalcaemia).The diagnostic criteria for symptomatic myeloma are as follows:• Clonal plasma cells >10 per cent 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 compressionfactors)Blood tests may reveal a high calcium but the alkaline phosphataseis often normal (A) (in contrast to other malignancies, with osteolyticmetastases and raised alkaline phosphatase).

Question 17

A 67-year-old woman presented with polyuria and polydipsia on a backgroundof ongoing bone pain. Her blood tests revealed a high calcium, and a serumelectrophoresis was sent. Her serum paraprotein was 25 g/L and a bone marrowbiopsy revealed 6 per cent clonal plasma cells. The most likely diagnosis is:A Plasma cell dyscrasiaB Monoclonal gammopathy of undetermined significanceC Smouldering myelomaD Multiple myelomaE Hypercalcaemia with no evidence of underlying malignancy

Answer 17

D Multiple myelomaThis question tests your understanding of the diagnostic criteria forplasma 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 celldisorder, 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 impairment3 Monoclonal gammopathy of undetermined significance (MGUS) (B):• Serum paraprotein

Question 18

A 39-year-old motorcyclist is admitted following a road traffic accident complicatedby severe burns. Several days later he is due to go home, when oozingis noted from his cannula site and he has several nose bleeds. Repeat bloodtests reveal an Hb of 12.2 g/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 reducedfibrinogen and raised D-dimers. The most likely diagnosis is:A Liver failureB Disseminated intravascular coagulationC Thrombotic thrombocytopenic purpuraD Aplastic anaemiaE Heparin induced thrombocytopenia

Answer 18

B Disseminated intravascular coagulationThis man has developed disseminated intravascular coagulation (DIC)(B) following his severe burns. DIC is widespread pathological activationof the clotting cascade in response to various insults. The cascadeis activated in various ways: one mechanism is the release of a transmembraneglycoprotein called ‘tissue factor’ in response to cytokines orvascular damage. This results in fibrin formation, which can eventuallycause occlusion of small and medium sized vessels and lead to organfailure. At the same time, depletion of platelets and coagulation proteinscan result in bleeding (as in this case).It can be caused by a wide range of factors, which can be rememberedusing the mnemonic ‘I’M STONeD!’: Immunological (e.g. severe allergicreactions, haemolytic transfusion reactions), Miscellaneous (e.g. aorticaneurysm, liver disease), Sepsis, Trauma (including serious tissue injury,burns, extensive surgery), Obstetric (e.g. amniotic fluid embolism, placentalabruption), Neoplastic (myeloproliferative disorders as well assolid tumours such as pancreatic cancer), and Drugs and toxins.

Question 19

A 46-year-old woman is brought to accident and emergency by her daughter,who reports that she had been feeling unwell for a few days with a fever and isnow hallucinating. On examination she has a temperature of 38.9°C, is noted tobe pale and has widespread purpura over both arms. Blood tests reveal an Hb of9.1 g/dL, platelet count of 60 × 109/L, creatinine of 226 and urea 16.7. A blood filmis reported as showing the presence of shistocytes. The most likely diagnosis is:A Weil’s diseaseB Glandular feverC Idiopathic thrombocytopenic purpuraD Thrombotic thombocytopenic purpuraE Haemolytic uraemic syndrome

Answer 19

D Thrombotic thombocytopenic purpuraThis woman has thrombotic thrombocytopenic purpura (TTP) (D), a rarebut potentially fatal haematological emergency. It consists of six keyfeatures:1 MAHA2 A fever3 Renal failure4 Fluctuating CNS signs, e.g. seizures, hallucinations, hemiparesis,decreased consciousness5 Haematuria/proteinuria6 Low platelet countYou can remember these as ‘MARCH with low platelets’.TTP typically affects adults and is thought to occur due to a deficiencyof a protease that is responsible for cleaving multimers of vonWillebrand factor. The resulting formation of large vWF multimersstimulates platelet aggregation and fibrin deposition in small vessels.This in turn causes microthrombi to form in blood vessels, impedingthe blood supply to major organs such as the kidneys, heart and brain.Haemolysis occurs and shistocytes form because of the sheer stress onred blood cells as they pass through the microscopic clots.

Question 20

A 28-year-old woman in her 29th week of pregnancy comes to accident andemergency with epigastric pain, nausea and vomiting. She also complains thather hands and feet have been swelling up. On examination her blood pressureis 165/96, HR 125 bpm, and she is apyrexial. She is noted to have yellowing ofher 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 asshowingthe presence of schistocytes. The most likely diagnosis is:A HepatitisB Thrombotic thrombocytopenic purpuraC Pre-eclampsiaD Acute fatty liver of pregnancyE HELLP syndrome

Answer 20

E HELLP syndrome‘HELLP’ syndrome (E) is a potentially fatal occurrence in pregnancy,characterized by a triad of features:1 H – haemolysis2 EL – elevated liver enzymes3 LP – low platelet countIn a similar way to DIC, generalized activation of the clotting cascadeis triggered which can only be terminated with delivery. Platelet consumptionand MAHA occurs, and liver ischaemia can lead to periportalnecrosis and, in severe cases, formation of a subcapsular haematomawhich can rupture.It usually presents in the third trimester, but can happen even up to aweek after delivery. Often patients with HELLP have had pregnancy-inducedhypertension or pre-eclampsia prior to its development.Common symptoms are often vague, and can include nausea and vomiting,epigastric pain, peripheral swelling, paraesthesia, headaches andvisual problems. On examination patients may be noted to have peripheraloedema, 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 thiscase, unless DIC has occurred. The only effective treatment is delivery,but other supportive treatment includes control of the hypertension,seizureprophylaxis and corticosteroid use.

Question 21

A 56-year-old woman with known cirrhosis presents with falls. On examinationshe is clinically jaundiced and rectal examination reveals malaena. Blood testsreveal 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 ThrombinB Factor VIIC Factor VIIID Protein CE Factor X

Answer 21

C Factor VIIIThe vitamin K dependent clotting factors include II, VII, IX and X.Vitamin K is also required for the production for protein C, protein Sand protein Z, although these are strictly not clotting factors, ratheranticoagulant factors. Vitamin K is a fat soluble vitamin found ingreen leafy vegetables such as spinach, cabbage and cauliflower. Itis absorbed in the small bowel and is important in the production offunctional clotting factors in the liver. This patient’s acute chronic liverfailure has meant she is no longer producing functional clotting factors,representedas a raised INR.Vitamin K is recycled in the liver and its oxidation is coupled with thepost-translational modification of glutamate residues to form gammacarboxyglutamate.Vitamin K is firstly reduced by vitamin K epoxidereductase to form vitamin K hydroquinone. This reduced form is oxidizedby vitamin K dependent carboxylase to form vitamin K epoxide.This reaction is coupled with gamma-glutamyl carboxylase; the enzymeresponsible for post-translational modification of the vitamin K dependentfactors. Vitamin K epoxide is then reconverted to vitamin K byvitamin K epoxide reductase; thus completing the cycle. If the patientwere to be given vitamin K metabolism antagonists, e.g. warfarin, theclotting factors produced would still be immunologically identical (theseare also known as Proteins Induced by Vitamin K Absence/Antagonism– PIVKA) but would lack efficacy as they are unable to interact withcalcium or platelet factor 3.

Question 22

A 46-year-old man presents with pain and swelling in the right calf 2 weeksafter 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 anultrasound of the calf. A deep vein thrombosis is confirmed and 5 mg warfarin isstarted the next day. Two days later, the same patient develops pain and swellingin the other calf, an ultrasound confirms a further deep vein thrombosis in thecontralateral leg. What factor is least likely to contribute to the development ofthe second DVT?A SmokingB WarfarinC Previous DVTD Being slightly overweightE Plaster cast

Answer 22

D Being slightly overweightAlthough obesity is associated with risk of development of DVT, thisman is described as slightly overweight (D). Thus, in comparison to theother risk factors presented, it probably represents the lowest attributablerisk to the second DVT.

Question 23

A 54-year-old man presents with haematemesis. He has known varices and iscurrently vomiting large amounts of bright red blood. The admitting doctor takessome blood for fast analysis and confirms a haemoglobin of 4 g/dL. The patient’shaematemesis continues and he is transfused a total of 20 units of blood andeight units of fresh frozen plasma in the next 24 hours. The patient underwentgastroscopy which revealed bleeding oesophageal varices which were successfullytreated by endoscopic banding. His post-transfusion bloods are the following:Hb 9.2 g/dLWhite cells 8.0 × 109/LPlatelets 57 × 109/LProthrombin time normalActivated partial thromboplastin time normalFibrinogen >1.0 g/LWhat is the most likely cause of his thrombocytopenia?A Disseminated intravascular coagulopathyB Alcohol excessC Massive blood transfusionD Megaloblastic anaemiaE Hypersplenism

Answer 23

C Massive blood transfusionAlthough all of the given options are causes of thrombocytopenia, themost likely cause in this patient is massive blood transfusion withoutreplacement of platelets (C). Massive blood loss may be defined as losingone’s entire circulating blood volume in 24 hours. Other definitionsinclude losing 50 per cent of one’s blood volume in 3 hours or a rateof loss of greater than or equal to 150 mL/min. This patient has beentransfused 20 units of blood in the space of 24 hours, thus fulfilling thecriteria for massive haemorrhage. Massive transfusion has its own particularcomplications, including thrombocytopenia. This is because thispatient was only given packed red cells and fresh frozen plasma. Thesetwo blood products contain very few platelets and in general, a plateletcount of around 50 × 109/L is to be expected when approximatelytwo blood volumes have been replaced, as is the case in this patient. Inthis situation, the expert consensus is to keep the platelet level above50 × 109/L, but there is marked interindividual variation therefore someconsider using 75 × 109/L as the trigger value for platelet transfusion.

Question 24

Which of the following is not often associated with a very high (>100 mm/hour)erythrocyte sedimentation rate (ESR)?A MyelomaB AnaemiaC LeukaemiaD Aortic aneurysmE Malignant prostatic cancer

Answer 24

B AnaemiaESR is a commonly used laboratory test to detect the presence of inflammationin general. It is performed by adding a sample of anticoagulantto a blood sample and adding this mixture to a calibrated vertical tube(Westergren tube). As the red cells fall with gravity and accumulate, theylie in the bottom of the tube, and are called sediment. The rate at whichthey accumulate is therefore the erythrocyte sedimentation rate. Factors which influence the ESR include age, sex and pathologicalprocesses which increase plasma proteins or the number of red cells.Women generally have a higher ESR than men and it also increaseswith age. Depending on the exact reference range for your particularlab, women and men over 50 can have an ESR of up to 30 and 20 mm/hour, respectively, and still be normal. Conditions which increaseplasma proteins such as fibrinogen, acute phase proteins and immunoglobulinscan increase the ESR as these proteins reduce the ionic resistancebetween erythrocytes leading to an increased fall rate. They alsopromote rouleaux formation of erythrocytes which is the characteristicstacking of erythrocytes seen under the microscope. The most importantprotein to promote rouleaux formation is fibrinogen. The number of redcells in a given volume also influences ESR; in severe anaemia ESR isfalsely raised as the reduced ionic repulsion between erythrocytes allowfaster sedimentation. However, this rarely leads to an ESR of >100 mm/hour, making anaemia (B) the correct answer.

Question 25

A 62-year-old man presents with shortness of breath. This has been graduallygetting worse for the last few years and is associated with chronic productivecough. He is a heavy smoker. His chest X-ray reveals a hyperexpanded chestwith no other abnormalities. His bloods tests are normal except for a raised haemoglobinand raised haematocrit. What is the most likely cause for this?A Polycythaemia rubra veraB Idiopathic erythrocytosisC Secondary polycythaemiaD Gaisbock’s diseaseE Combined polycythaemia

Answer 25

E Combined polycythaemiaCombined polycythaemia (E), also known as smoker’s polycythaemia,has multiple aetiological factors. Cigarettes contain high concentrationsof carbon monoxide gas which bind avidly to haemoglobin, thusdisplacing oxygen. This leads to increased erythropoietin (EPO) secretionfrom the hypoxic renal interstitium. EPO promotes erythrocyte proliferationand differentiation and prevents their apoptosis in the bonemarrow, thus increasing red cell mass. Smoking is also a significant riskfactor for chronic obstructive pulmonary disease, which is what thisman suffers from. The obstructed airways reduce oxygen delivery tothe alveoli and pulmonary vessels they supply thus causing a reductionof oxygen supply furthering the hypoxia. Finally, smokers also havean associated reduced plasma volume, thus increasing the relative concentrationof haemoglobin. This is therefore ‘combined’ because of thepresence of both increased red cell mass and reduced plasma volume.

Question 26

A 25-year-old black man develops jaundice and dark red urine 2 days afterstarting primaquine, an anti-malarial. His blood tests reveal a macrocytic anaemiawith raised bilirubin and urine dipstick is positive for blood. A peripheralblood film reveals ‘bite cells’ and Heinz bodies. The most likely diagnosis is:A Hereditary spherocytosisB Glucose-6-phosphate dehydrogenase deficiencyC Paroxysmal nocturnal haemoglobinuriaD Microangiopathic haemolytic anaemiaE Autoimmune haemolytic anaemia

Answer 26

B Glucose-6-phosphate dehydrogenase deficiencyG6PD deficiency (B) (also known as favism) is an X-linked conditionwhere the lack of this enzyme increases the oxidative damage sustainedby red blood cells. It is part of the pentose phosphate pathway whichmaintains levels of reduced glutathione – an important erythrocyte antioxidant.People with this condition have erythrocytes with less reduced glutathione and are thus more sensitive to oxidative stress resulting inhaemolysis. There are many variants of G6PD of differing severity. It isunlike some X-linked conditions where women can also be affected ifthey are homozygous. Precipitating factors include anti-malarials, primaquine,nitrofurantoin, dapsone, sulphonylureas and sulphonamides.Its alternate name, favism, relates to the fact that fava beans (broadbeans) can trigger a haemolytic attack. The haemolysis released intracellularhaemoglobin causing jaundice in this patient and haemoglobinuria,which caused a positive dipstick result. It is important to note thatthe differential for a positive dipstick for blood includes haemoglobinuriaand myoglobinuria. Macrocytosis occurs from the raised reticulocyteproduction from increased bone marrow activity. Heinz bodies are seendue to the denatured haemoglobin which gets removed by macrophagesin the spleen leaving ‘bite’ cells. A G6PD assay is useful in this patientbut less so in the acute setting as the new reticulocytes can containnormal G6PD levels, thus giving a false negative result.

Question 27

What are the likely laboratory findings for a patient with renal cell carcinomawith secondary polycythaemia who is not dehydrated?A Normal red cell count, normal red cell mass, increased erythropoietin concentrationB Increased red cell count, increased red cell mass, increased erythropoietinconcentrationC Decreased red cell count, decreased red cell mass, normal erythropoietinconcentrationD Increased red cell count, decreased red cell mass, increased erythropoietinconcentrationE Decreased red cell count, increased red cell mass, decreased erythropoietinconcentration

Answer 27

B Increased red cell count, increased red cell mass, increased erythropoietinconcentrationThis question tests your understanding of erythropoeisis physiologyand your understanding of laboratory measurements in a standardfull blood count analysis. Red cell count is measured as the number oferythrocytes in a quantum of plasma, whereas red cell mass is determinedby isotope studies quoted as mL/kg. It is a measure of absolutered cell mass and is therefore not affected if someone is dehydrated, forexample, where the relative plasma volume is reduced giving a falselyhigh red cell concentration. There are many situations where the red cellconcentration and red cell mass do not parallel each other, e.g. vomiting,diarrhoea or overuse of diuretics. If a patient has increased red cellconcentration this may therefore be absolute or relative – the latterbeing secondary to reduced plasma volume thus making the polycythaemiasecondary to haemoconcentration. Absolute polycythaemia maybe primary or secondary. In this case there is secondary polycythaemiawhere the renal cell carcinoma is inappropriately producing too muchEPO, thus overstimulating bone marrow erythropoeisis. Secondary polycythaemiais not always inappropriate – people with cyanotic heartdisease, lung disease, haemoglobinopathies with high oxygen affinity orthose living at altitude can get appropriate secondary polycythaemia asa physiological response to chronic hypoxaemia.

Question 28

von Willebrand’s disease is characterized by abnormal platelet aggregation whenthey are exposed to:A StreptomycinB AspirinC FibrinogenD CollagenE Ristocetin

Answer 28

E Ristocetinvon Willebrand’s disease (vWD) is characterized by a quantitive orqualititative defect in von Willebrand factor (vWF). Ristocetin, an antibioticno longer used clinically, causes vWF to bind the platelet receptorglycoprotein Ib (GlpIb) through an unknown mechanism. If ristocetinis added to platelets with defective vWF or defective GlpIb (calledBernard–Soulier syndrome) then platelet aggregation does not occur. Itwill occur, however, with other pro-aggregative factors including collagen(D) and fibrinogen (C). If vWF or GlpIb is absent, aggregation doesnot occur with collagen as there is no molecular link between collagenand the platelet. However, this is the case with all patients with vWF. Furthermore, cryoprecipitate which contains vWF will correct defects invWD but not in Bernard–Soulier syndrome.

Question 29

An 18-month-old child with Down syndrome presents with recurrent infectionsand petechial bleeding. A blood film was analyzed showing a particular distinctivefeature of haematological malignancy. What is the most likely diagnosticallyhelpful finding seen in this patient?A Smudge cellB Reed Sternberg cellC Auer rodD Pelger Huet anomalyE Hairy cell

Answer 29

C Auer rodThe Auer rod (C) is pathognomonic of acute myeloblastic leukaemia(AML). Children with Down syndrome are at higher risk of this diseasedue to chromosome 21 duplication where a ‘dosage’ effect istheorized to increase the expression of proto-oncogenes. This mayalso explain the increased risk of AML in Warkany syndrome type 2(trisomy 8). Another dosage effect example, also in Down syndrome,is the increased risk of Alzheimer’s disease with beta amyloid, whichaccumulates in Alzheimer’s disease and is coded for on chromosome21. Epidemiologically, children with Down syndrome are more likelyto get AML than ALL in the first 3 years of their life, but thereafter aremore likely to get ALL, similar to those without Down syndrome. Auerrod’s are pathognomonic for AML and are found in the cytoplasm. Theyrepresent stacked granules in myeloblasts and are azurophilic. Theyare particularly common in the M3 subtype of AML (according to theFrench American British classification).

Question 30

An 8-year-old African boy presents with a large jaw mass which has been growingrapidly over the last few weeks. A histological sample was taken and a classical‘starry sky’ appearance was observed. The most likely diagnosis is:A Follicular lymphomaB Marginal zone lymphomaC Burkitt’s lymphomaD Diffuse large B cell lymphomaE Mantle cell lymphoma

Answer 30

C Burkitt’s lymphomaBurkitt’s lymphoma (C) is one of the most aggressive malignanciesknown to man. It is a type of non-Hodgkin’s lymphoma (NHL)which arises from lymph node germinal centres. It is associated withEpstein–Barr virus and there are three subtypes – endemic, sporadicand immunodeficiencyrelated. It is associated with translocation anddysregulation of the c-myc gene on chromosome 8 including t(8;14),t(2;8) and t(8;22). Histologically, there is profound proliferation. Thestarry sky appearance reflects islands of macrophages ingesting necrotictumour cells as they have outgrown their own blood supply. Clinically,the endemic form affects younger men and classically presents with ajaw mass which spreads to extranodal sites including mesentery, ovary,testis, bone marrow and meninges.

Question 31

A 35-year-old Afro-American man presents with painless lymphadenopathywhich he noticed after shaving. He denies any recent infections, fevers, weightloss or night sweats. A biopsy is performed which shows lymphocytic and histiocyticcells. A haematologist calls to confirm the diagnosis of non-classicalHodgkin’s lymphoma. Which subtype is this?A Nodular sclerosisB Mixed cellularityC Nodular lymphocyticD Lymphocytic richE Lymphocytic depleted

Answer 31

C Nodular lymphocyticNodular lymphocytic (C) Hodgkin’s lymphoma is often called the nonclassicalsubtype of Hodgkin’s lymphoma. It is so called due to the atypicalnature of the Reed–Sternberg cell which characterizes all Hodgkin’slymphomas. This cell is known as the lymphocytic and histiocytic cellor L&H variant. Sometimes these cells are referred to as ‘popcorn’ cellsbecause their nucleus resembles an exploded popcorn kernel. This subtypeof HL accounts for 5 per cent of cases and has a bimodal age distribution– children and adults between the ages of 30 and 40. Unlike commonHL, this type is more common in African American men compared withCaucasians in the US. Clinically, patients often present with peripherallymphadenopathy without B symptoms (namely fever, night sweats andweight loss). It is generally thought of as a more indolent form of HL.

Question 32

A 17-year-old boy with glucose-6-phosphate dehydrogenase (G6PD) deficiencypresents with tiredness and is noticed to be jaundiced. These features have developedsince he was diagnosed with a chest infection 1 week ago. What is the mostlikely haematological finding?A Positive direct antiglobulin testB Low mean cell volumeC Reduced reticulocyte countD HaemoglobinuriaE Increased haptoglobin concentration

Answer 32

D HaemoglobinuriaThis patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency;a common X-linked condition where the reduction of G6PD functionleads to haemolysis when erythrocytes are exposed to oxidative stress.Less commonly there is a chronic haemolysis when enzymatic activity isless than 10 per cent of normal. Unlike some other X-linked conditions,women can be affected due to the random nature of X chromosomeinactivation (lyonization) which leads to some cells being vulnerableto oxidative stress. G6PD is important in the pentose phosphate shuntwhich critically regenerates NADPH, a cofactor important in glutathionemetabolism. Reduced glutathione is the primary buffer against oxidativestress. Haemoglobinuria (D) occurs due to intravascular haemolysis inthe face of oxidative stress in a susceptible patient. Red cells undergointravascular and extravascular haemolysis leading to haemoglobinaemiaand haemoglobinuria. Common precipitants include intercurrentinfection but also drugs, the most notorious of which are dapsone, primaquineand nitrofurantoin. Classically, haemolysis can be triggered byfava beans (hence its alternate name ‘Favism’) as well as naphthalene(found in moth balls and henna).

Question 33

A 35-year-old Asian woman presents with tiredness. The full blood count shows:Haemoglobin: 10.1 g/dL (11.5–16.5)Platelet count: 160 × 109 (150–400 × 109)White cell count: 6.6 × 109 (4–11 × 109)Mean cell volume: 62 fL (80–96 fL)Hb A2: 6.3 per cent (2–3 per cent)Which of the following is the most likely diagnosis?A Sickle cell diseaseB Acute myeloid leukaemiaC b-Thalassaemia majorD b-Thalassaemia traitE Hereditary spherocytosis

Answer 33

D b-Thalassaemia traitThis woman presents with microcytic anaemia, the most common causeof which is iron deficiency. However, the mean cell volume is disproportionallyreduced compared with the degree of anaemia indicating theremight be a haemoglobinopathy present. The presence of increased Hb A2confirms the diagnosis of b-thalassaemia trait. Unfortunately the nomenclaturesurrounding b-thalassaemia is relatively confusing but an attemptto clarify it will be made here. Firstly, thalassaemia is the reduction orabsence of a type of globin gene. Normal haemoglobin is a tetramer oftwo alpha and two beta globin proteins. The ratio of alpha to non-alphaglobin production is tightly controlled. There are two alpha genes locatedon chromosome 16, whereas only one beta gene on chromosome 11.b-Thalassaemia implies a reduction or absence of the beta chain. Beta (0)thalassaemia refers to an absence of beta globin production. This encompassesover 40 genetic mutations. Patients with this are often describedas having b-thalassaemia major (C), however, confusingly some patientscan produce beta globin genes but to such a poor extent they behavevery similar clinically, as if they had no production. Within the first yearof life they have profound life-long transfusion dependent anaemia. Thisis therefore not compatible in this patient’s case.

Question 34

A 62-year-old man presents with bruising and tiredness. Examination revealsmoderate splenomegly and his a reveal a normocytic anaemia with blood testsplatelet count of 900 × 109/L, neutrophilia, basophilia, numerous myelocytes and4 per cent myeloblasts. The neutrophils have low leukocyte alkaline phosphataselevels. Which of the following is likely to be present in this patient?A t(9;22)B t (8;14)C BCR-Abl fusion gene onlyD V617F point mutation in JAK2E 5q-Syndrome

Answer 34

A t(9;22)This patient exhibits features of chronic myeloid leukaemia as evidencedby raised myeloid lineage cells including neutrophils, myelocytesand basophils. The neutrophils are morphologically normal butcytochemically different – a laboratory test sometimes used to differentiatebetween reactive or leukaemoid neutrophilia and CML is theleukocyte alkaline phosphatase. It is normal or high in the former, butcharacteristically low in CML. Absolute basophilia is a universal findingin CML, with absolute eosinophilia found in 90 per cent of cases.A raised platelet count is also common in CML; a low platelet count,however, should make one reconsider the diagnosis, e.g. myelodysplasticsyndromes.Up to 95 per cent of patients with chronic myeloid leukaemia have thePhiladelphia chromosome – a fusion chromosome between the longarms of chromosomes 9 and 22 (A). The formation of the BCR-Ablfusion gene acts as a constitutively active tyrosine kinase, but the induction of leukaemogenesis is complicated and mediated throughboth tyrosine dependent and independent pathways. It is known, however,that the tyrosine kinase activity of the BCR-Abl gene is absolutelyrequired for transformation. BCR-Abl fusion genes alone (C) can occurwithout the t(9;22) translocation but this is much less common. ThisRobertsonian translocation is worth remembering as it is frequentlyasked about in examinations.The t(8;14) translocation occurs in Burkitt’s lymphoma: a highly aggressivelymphoma where cmyc, an oncogene, is under the influence ofan immunoglobulin promoter, which is highly expressed. The V617Fpoint mutation in JAK2 (D) is found in up to 99 per cent of cases ofpolycythaemia rubra vera. JAK2 is involved in downstream processingof the erythropoietin receptor signalling

Question 35

Which of the following patients has the worse prognosis?A 25-year-old man with inguinal lymphadenopathyB 25-year-old woman with mediastinal and inguinal lymphadenopathyC 25-year-old woman with mediastinal and inguinal lymphadenopathy andnight sweatsD 25-year-old woman with mediastinal and inguinal lymphadenopathy with5 per cent weight loss in last 6 monthsE 25-year-old man with cervical and mediastinal lymphadenopathy

Answer 35

C 25-year-old woman with mediastinal and inguinal lymphadenopathy andnight sweatsThis question relies on the candidate’s knowledge and understanding ofthe Ann Arbor staging system. This clinical staging system is relativelyintuitive – stages are between I and IV either in the absence or presenceof ‘B symptoms’. A simplified version of the classification is as follows:• Stage I: involvement of a single lymph node region• Stage II: involvement of two or more lymph node regions on thesame side of the diaphragm• Stage III: involvement of lymph nodes on both sides of thediaphragm• Stage IV: extranodal spread (not spleen however, this is taken as alymph node)The definition of B symptoms includes significant unexplained fever,night sweats or unexplained weight loss of over 10 per cent during6 months prior to diagnosis. The presence of B symptoms is denotedby a B subscript after the stage number, the absence is denoted by anA subscript. Patient A would therefore be classified as Ia, patient B asIIa, patient C as IIIb, patient D as IIIa, technically as she does not quitefulfil the 10 per cent loss in 6 months and finally patient E as stageIIa. Note that in Hodgkin’s lymphoma, the disease always spreads contiguouslywhereas in non-Hodgkin’s lymphoma this is not always thecase. Further investigations for clinical staging include an upright chest X-ray, integrated positron emission tomography/computer tomographyof the chest/abdomen/pelvis and sometimes a unilateral bone marrowaspirate and biopsy for those with stage III or IV with B symptoms.

Question 36

A patient presents with acute promyelocytic leukaemia. What is the most likelymechanism of underlying leukaemogenesis?A Telomere shorteningB Aberrant fusion of two genesC Impaired protein degredationD Over-expression of cellular oncogeneE Post-translational modification

Answer 36

B Aberrant fusion of two genesAcute promyelocytic leukaemia is interesting for a number of reasons.There is a reciprocal translocation between the long arms of chromosomes15 and 17 giving the PML-RARA fusion gene (B). This links theretinoic acid receptor alpha (RARA) gene on chromosome 17 with thepromyelocytic leukaemia (PML) gene on chromosome 15. RARA is amember of a family of retinoin-binding transcription factors that regulategene expression. It heterodimerizes with retinoid X receptor (RXR)and binds to retinoic acid response elements to influence gene transcription.In the absence of retinoic acid, the RARA/RXR dimer interactswith another protein (nuclear corepressor) to repress gene transcription.Therefore, addition of retinoic acid stimulates gene transcription. Inthe setting of promyelocytic leukaemia, retinoic acid induces myeloiddifferentiationwhich is abnormally halted thus providing remissionby encouraging cell differentiation rather than cell death. The secondreasonthis type of leukaemia is interesting is its association with disseminatedintravascular coagulopathy. The pathogenesis is not completelyunderstood but recognizing it early is important as treatmentwith retinoic acid plus supportive therapy can lead to rapid improvementin the coagulopathy.

Question 37

A 64-year-old man presents with lethargy, weight loss and abdominal fullness.He is found to have chronic myeloid leukaemia. He is started on imatinib as partof the initial treatment to control his disease. What is the mechanism of actionof imatinib?A Proteosome inhibitorB Tyrosine kinase inhibitorC IL-6 inhibitorD p53 inhibitorE Human epidermal growth factor receptor 2 protein inhibitor

Answer 37

B Tyrosine kinase inhibitorImatinib is a tyrosine kinase inhibitor (B) and is used in the treatment ofchronic myeloid leukaemia. It is a rational therapy which acts to inhibitthe BCR-Abl tyrosine kinase thus blocking proliferation and inducingapoptosis in BCR-Abl positive cell lines. The BCR-Abl fusion is mostcommonly secondary to a balanced Robertsonian translocation betweenchromosomes 9 and 22. Imatinib is also used for gastrointestinal stromaltumour (GIST). Other tyrosine kinase inbitors include dasatinib andnilotinib. They do not cure CML but provide long-term control in themajority of patients, thus they are the initial treatment of choice foralmost all newly diagnosed patients with CML.

Question 38

A 16-year-old girl with mild von Willebrand’s disease is scheduled for a dentalextraction. She has had one previously where she required two units of bloodtransfused. What is the most appropriate treatment for this patient prior tosurgery?A CryoprecipitateB DesmopressinC Fresh frozen plasmaD Vitamin KE Recombinant factor VIII concentrate

Answer 38

B DesmopressinThis woman has mild von Willebrand’s disease (vWD) which can betreated with desmopressin (B). There are three types of vWD – type I isa quantitative deficiency of von Willebrand Factor (vWF), type II is aqualitative defect in vWF whereas type III results in profound deficiencyin vWF. There are four subtypes of type II vWF (2A, 2B, 2M and 2N).vWF is important in two ways; first it acts as a bridge between plateletsand between platelets and subendothelial structures at the site ofinjury; and second it carries factor VIII which is a key molecule in theclotting cascade. Desmopressin acts to increase vWF and factor VIIIconcentration by encouraging its release from endothelial cell storagesites. Desmopressin is efficacious in type I and most type II disease but not in type III. This woman is known to have ‘mild’ disease thus makingdesmopressin a viable option. Interestingly, desmopressin in patientswith type 2B will lead to a transient worsening of their thrombocytopenia.Patients with type 2B vWD have increased binding of the abnormalvWF to platelets causing sequestration and clearance of platelets.This is worsened for desmopressin, if only for a few hours. Despite this,there have been reports of patients benefiting from desmopressin.

Question 39

An 80-year-old man presents with tiredness and lethargy. After initial work-up,a diagnosis of myelodysplastic syndrome is suspected. Which of the following istrue about this condition?A A blood film will typically show neutrophil toxic granulationB If there are 1 per cent blasts of the total white cell count, this representsleukaemic transformationC Cytotoxic chemotherapy is first line treatmentD Mortality is more likely to be from infection than leukaemic transformationE Absence of the short arm of chromosome 5 is a subtype

Answer 39

D Mortality is more likely to be from infection than leukaemic transformationThe myelodysplastic syndromes are a heterogeneous group of conditionscharacterized by an abnormal clone of stem cells with impaired proliferationand differentiation. The result is a peripheral cytopenia, qualitativeabnormalities in erythroid, myeloid and megakaryocyte maturation,as well as increased risk of leukaemic transformation. The abnormalities,both quantitative and qualitative, in neutrophils mean susceptibility tobacterial infection is high and thus a corresponding increased likelihoodof mortality (D). Skin infections are particularly common and resistantto treatment.

Question 40

A middle-aged woman comes to the dermatology clinic with a suspicious moleon her back. You decide excision is required and during the history she says ‘Ihave Factor V Leiden’. Which of the following best describes the pathophysiologyof Factor V Leiden mutation?A Prothrombin mutationB Activated protein C resistanceC Antithrombin III deficiencyD Protein C deficiencyE Protein S deficiency

Answer 40

B Activated protein C resistanceFactor V Leiden is an autosomal dominantly inherited point mutationwhere arginine is replaced by glutamine in the 506th position. Factor Vnormally circulates in plasma as an inactivated factor and is activatedby thrombin which then acts as a co-factor, with factor Xa, to convertprothrombin to thrombin. Factor Va is inactivated by cleavage of itsheavy chain; firstly at position Arg506, which causes conformationalchange to reveal a further two cleavage sites (Arg306 and Arg 679).This inactivation is performed by the activated protein C complex, andthus the Leiden mutation confers resistance (B). The prothromboticconsequence of Factor V Leiden is actually two-fold – first Factor V isdegraded more slowly thus there is more generation of thrombin in theprothrombinase complex and second, once factor V is cleaved at thefirst Arg506 site, it is thought to play a role, with protein S, to supportactivated protein C in Factor VIIIa degradation too.