Haematology Flashcards
Which one of the following is a correct description of erythropoeisis and thalassaemia?
A. Patients with thalassemia are more susceptible to malarial infection
B. Mutation of one beta-globin gene leads to beta-thalassaemia with severe anaemia
C. Beta-globin synthesis is normally controlled by four beta genes
D. Production of alpha-like and beta-like globins is normally balanced at each stage of development
E. In Beta-thalassaemia, beta chains precipitate in erythroid precursor cells, causing dyserythropoiesis
Answer D
Haemoglobin synthesis is controlled by two multigene clusters encoding alpha-like and beta-like globins. At each stage of development, the production of these chains are balanced.
Beta-globin synthesis is normally controlled by 2 genes (one on each copy of Ch11). The main pathophysiology of B-thalassaemia results from the insufficient synthesis of beta chains to partner the alpha-chains and generate adult Hb (a2B2). Excess alpha chains precipitate in erythroid precursors causing dyserythropoiesis, membrane damage and haemolysis.
If there is only 1 beta mutation, patients suffer from a mild microcytic anaemia. Homozygotes develop beta thalassemia major with severe anaemia, splenomegaly, severe bone deformities and early death <20yrs.
Treatment consists of periodic blood transfusion, splenectomy if splenomegaly and treatment of iron overload caused by transfusion. Cure can be achieved by bone marrow transplantation.
Heterozygotes are somewhat protected from falciparum malaria.
Granulocyte colony stimulating factor (G-CSF) causes an increase in the production of which one of the following cells in the bone marrow?
A. Dendritic cells B. Eosinophils C. Monocytes D. Neutrophils E. T lymphocytes
Answer D
Thrombopoietin (TPO):
A. Is synthesised by platelets
B. Activates the erythropoietin receptor
C. Promotes survival and differentiation of megakaryocytes
D. Promotes the formation of thrombin
E. Levels are inappropriately high in immune thrombocytopaenia
Answer C
TPO is the major regulator of megakaryocyte growth and differentiation, and therefore of platelet production.
It is synthesised mainly by the liver and most binds to TPO receptors on platelets, the remaining binds to bone marrow receptors (therefore rising and dropping platelet concentrations proportionately regulate the TPO effect on bone marrow)
Most patients with immune mediated thrombocytopaenia (ITP) have inappropriately low levels of TPO - the rationale for treatment with TPO receptor agonists. Romiplostim and Eltrombopag stimulate the TPO pathway and are used to treat thrombocytopaenia.
Prothrombin complex concentrate and fresh frozen plasma are used in warfarin reversal. Which one of the following coagulation factors is present in FFP, but only at low levels in Prothrombinex?
A. Factor II B. Factor V C. Factor VII D. Factor IX E. Factor X
Answer B - Factor V
FFP contains all the coagulation factors
Prothrombinex contains factors II, VIII, IX and X but only low levels of V.
Remember warfarin inhibits vitamin K-dependent synthesis of the four factors contained in Prothrombinex as well as protein C and protein S.
Protein C acts by:
A. Inactivating thrombin B. Inactivating factor V C. Activating endogenous heparin D. Activating anti-thrombin III E. Activating protein S
Answer B - Inactivating factor V
Protein C (in the presence of its cofactor protein S) inactivates factors V and VIII
Protein C is activated by the thrombin-thrombomodulin complex. Thrombomodulin is produced by all endothelial cells (except the cerebral microcirculation). As part of clotting homeostasis, thrombin which is usually procoagulant binds to thrombomodulin and develops anticoagulant activity, as well as activating further factors like protein C.
How does hepcidin regulate iron absorption through duodenal enterocytes?
A. Helps duodenal crypt cells to sense the body iron stores
B. Decreases iron transfer to the circulation by degrading ferroportin
C. Inhibits the haemochromatosis protein HFE
D. Inhibits B-2-microglobulin
E. Inhibits hepatic production of aminotransferases
Answer B - decreases iron transfer to the circulation by degrading ferroportin
Systemic iron regulation is mediated by hepcidin. It binds to and internalises the iron channel ferroportin, leading to its destruction in the intestinal epithelial cells. Absorbed iron is usually exported into the circulation at the basolateral gut surface by ferroportin.
Hepcidicin is produced in the liver and is an acute-phase reactant (reduces available iron for potential pathogens).
The body iron status is sensed by the body intestinal crypt cells through an interaction between circulating transferrin-bound iron and the transferrin receptor. This interaction is facilitated by a complex between the HFE protein and beta-2-microglobulin. When the iron stores are low, the body upregulates expression of divalent metal transporter 1 (DMT1) to increase luminal iron absorption.
Which of the following best describes the action of Imatinib mesylate?
A. Blocks the action of P-glycoprotein
B. Inhibits the BCR-ABL translocation
C. Inhibits c-kit kinase
D. Inhibits the kinase activity of BCR-ABL
E. Stimulates the platelet derived growth factor receptor (PDGFR)
Answer D - inhibits the kinase activity of BCR-ABL
Imatinib is an inhibitor of multiple tyrosine kinases including ABL, BCR-ABL, PDGFR and c-kit. Blockade of the BCR-ABL prevents downstream signalling and growth of BCR-ABL cells and induces apoptosis.
CML is a myeloproliferative disorder that is a consequence of an acquired mutation affecting haemopoietic stem cells. The classic mutation results in a balanced translocation between chromosomes 9 and 22 (t (9; 22)(q34; q11) = Philadelphia chromosome.
The result is the fusion of the ABL gene from Ch9 and the BCR (breakpoint cluster region) gene on Ch22, resulting in a fusion protein with tyrosine kinase activity, proliferative cell signalling and uncontrolled cell replication.
Further mutations in the BCR-ABL portein can affect the binding of Imatinib to kinase sites. Single nucelotide mutations can be detected in about 50 of patients resistant to Imatinib. Later generation TKIs have been developed e.g. Dasatinib and Nilotinib
Which of the following best describes the role of von Willebrand factor (vWF) in blood coagulation?
A. Activates thrombin by reducing its degradation
B. Activates factor VIII
C. Binds to factor VIII and reduces its degradation
D. Inactivates endogenous heparin
E. Activates factor V
Answer C - binds to factor VIII and reduces its degradation
VWF acts as a carrier for factor VIII in the circulation and increases its half-life five-fold.
It also performs the important task of helping normal platelets bind to exposed collagen in blood vessels. When the endothelium is disruption, platelets bind to the exposed collagen both directly by glycoprotein 1a (GP1a) membrane receptor and indirectly by binding to vWF by GP1b receptor - which in turn binds to collagen.
Following adhesion, platelets undergo shape change (disc to sphere) and release their granules containing ADP and serotonin, PDGF, fibrinogen etc. ADP release leads to a conformational change in the GPIIb-IIIa receptor on the platelet surface, allowing it to bind fibrinogen and form a stable clot.
EMQ
- Which of the following activates prothrombin?
- Which of the following inhibits platelet aggregation?
- Deficiency of which factor causes haemophilia A?
- Deficiency of which factor causes haemophilia B?
A. Factor XII B. Factor VIII C. Factor IX D. Factor X E. Fibrin F. Plasmin G. Prostacyclin H. Thrombin
- Answer D - Factor X
Factor 10 is the first member of the common pathway.
Coagulation cascade: F12 –> F11 –> F9 (with F8 cofactor)–> F10 –> prothrombin to thrombin –> fibrinogen to fibrin
Extrinsic pathway Tissue factor/F7 –> activate F10
- Answer G - Prostacyclin
Prostacyclin is produced by endothelial cells and chiefly prevents platelet plug formation. It inhibits platelet activation and also functions as an effective vasodilator.
- Answer B Factor VIII
- Answer C Factor IX
Haemophilia is an X-linked recessive bleeding disorder caused by deficient activity of factors VIII and IX. Haemophilia A and B are clinically indistinguishable and both cause prolonged APTT.
Haemophilia A has variable severity, depending of plasma activity of factor VIII. Classically bleeding after minor trauma, especially into joints and muscles (as opposed to platelet defects which are characterised by mucosal bleeds).
A previously health 68 year old woman presents with a spontaneous bleed into her psoas muscle. The results of the coagulation profile are shown below. which of the following best accounts for the results?
APTT 79s (26-38)
APTT correction (immediate mix) 38s (26-38)
APTT correction (2 hour incubation) 79 (26-38)
INR 1.1 (0.9 - 1.2)
Fibrinogen 3.2 (2.0-4.0)
A. Von Willebrand disease B. Disseminated intravascular coagulation (DIC) C. Acquired factor VIII inhibitor D. Chronic liver disease E. Haemophilia B
Answer C - Acquired factor VIII inhibitor
The sudden appearance of a large haemorrhage into muscle in an elderly person with elevated APTT should raise the suspicion for an acquired factor VIII inhibitor.
Patients often present with large haematomas, extensive ecchymoses or severe mucosal bleeding (epistaxis, GI bleeding and gross haematuria). Spontaneous haemarthroses, which are common in haemophilia are unusual. The cause is usually circulating autoantibodies directed against F8 , causing neutralisation +/- accelerated clearance from the plasma.
Associated with post-partum state, rheumatoid arthritis, SLE and underlying malignancy.
APTT is a reliable screening test and is typically prolonged once factor VIII activity decreases to 45% of normal. Mixing studies do not normally normalise the APTT HOWEVER weak autoantibodies can sometimes be corrected initially though prolonged APTT returns after 1-2 hours.
WVD can sometimes be diagnosed later in life and does cause a prolonged APTT with normal PT/INR - there is usually personal and family history of bleeding.
Coagulopathy due to liver disease will usually elevate INR and APTT.
DIC prolongs both APTT and IRN, while fibrinogen levels are lowered due to rapid consumption.
A 78 year old woman is incidentally found to have a lymphocyte count of 20.0 x10^9/L (0.5-3.5) on full blood count examination before her elective right knee replacement. On examination, there is no lymphadenopathy, splenomegaly or hepatomegaly. Her haemoglobin is 114 g/L (115-155) and platelet count is 220 x10^9/L (120-400). Lymphocyte surface markers show expression of CD5, CD19, CD 20 and CD28. What management should she receive?
A. Chlorambucil after bone marrow biopsy
B. Alemtuzumab after CT scan for staging
C. Observation without bone marrow biopsy
D. Fludarabine without bone marrow biopsy
E. Lenalidomide after molecular study
Answer C - observation without bone marrow biopsy
This patient has chronic lymphocytic leukaemia (CLL). CLL is characterised by progression accumulation of functionally incompetent lymphocytes of monoclonal origin. Blood smear shows small, mature appearing lymphocytes which are fragile when smeared onto glass (smudge cells). Flow cytometry characteristically shows atypical lymphocytes express CD19, dim CD20, dim CD5, CD23, CD 43 and CD79a. They usually weakly express surface IgM and IgD.
Treatment would not be required in this asymptomatic woman without cytopenias. Indications for therapy in CLL are symptomatic disease, bulky progressive lymphadenopathy, marrow failure of B-type symptoms (fever, night sweats, weight loss).
Bone marrow biopsy is not usually required at diagnosis. It is commonly performed at time of treatment or to evaluate cytopenias - helpful to determine if cytopenias are immune mediated or caused by marrow replacement.
Staging is by clinical examination and blood counts so CT is not required.
Molecular profile can provide predictors of progression, survival etc but is not used to select treatment.
A 32 year old woman presents to the emergency department with an 8-hour history of severe right upper quadrant pain. An abdominal ultrasound reveals several mobile gallstones and gallbladder wall thickening, consistent with acute cholecystitis. The liver is unremarkable but the spleen measures 14cm. The cholecystitis improves with conservative management.
On further questioning, she tells you that her father had his spleen removed. The results of her investigations are below. Which of the following test is the most appropriate?
Haemoglobin 111 (115 - 155) MCV 101 (80-98) White cell count 8.1 x10^9 ( 4 - 11) Platelet count 190 x10 ^9 ( 150 - 400) Reticulocyte count 7% (1-3%) Bilirubin 27 umol/L ( 2 - 24)
A. Autoimmune profile B. Bone marrow biopsy C. Coombs test D. Osmotic fragility test E. Haemoglobin electrophoresis
Answer D - Osmotic fragility test
The history is strongly suggestive of hereditary spherocytosis. Associated with increased haemolysis and therefore subsequent risk of gallstones (pigment stones).
Spherocytosis is causes by inherited defects in the red cell membrane, reducing deformability and increased removal from circulation by the spleen. This results in progressive splenic enlargement.
Disease is mild in 20-30% of patients, and can often present latera in life. However 60-70% of patients have more severe anaemia and splenomegaly presenting in childhood. Can necessitate splenectomy.
Hereditary spherocytosis most commonly follows autosomal dominant inheritance (75%). Common mutations are found in ankyrin, spectrin or Band 3 red cell proteins.
Diagnosis is usually made upon clinical picture and presence of spherocytes on blood film.
Severe tests are available for hereditary spherocytosis:
- Osmotic fragility test
- Ektacytometry
- Acidified glycerol lysis test (AGLT)
- Cryohaemolysis test
- Eosin-5-maleimide binding test (EMA binding test)
Which of the following is correct in a patient with severe aplastic anaemia?
A. Patients with severe aplastic anaemia usually present with severe infection at initial presentation
B. Megakaryocytes are not helpful in distinguishing myelodysplastic syndrome from severe aplastic anaemia
C. Aplastic anaemia and paroxysmal nocturnal haemoglobinuria rarely overlap (<1% cases)
D. The appearance of bone marrow in inherited and acquired aplastic anaemia is identical
E. Changes in leucocyte telomere length is not associated with severe aplastic anaemia
Answer D - the appearance of bone marrow is identical
Patients with aplastic anaemia (AA) usually present with symptomatic anaemia or haemorrhage. Infection at presentation is infrequent.
Megakaryocytes are the most reliable lineage to use in distinguishing myelodysplastic syndrome from severe AA:
- Small mononuclear or aberrant megakaryocytes are typical of MDS
- Markedly reduced or absent megakarocytes in AA
Aplastic anaemia and PNH overlap in 40-50% cases.
Reduced leucocyte telomere length is associated with a number of genetic abnormalities (DKC1, TERT, TERC)
A 60 year old man has recently been diagnosed with B-cell non Hodgkin lymphoma. He is waiting to commence chemotherapy in 2 days. He suddenly develops headache, confusion, visual deterioration and epistaxis. Fundoscopy reveals retinal haemorrhages. which of the following investigations should be included in the evaluation?
A. Complement levels B. C-reactive protein C. Plasma electrophoresis D. Serum free light chains E. Serum viscosity
Answer E - serum viscosity
This presentation should raise the suspicion of hyper viscosity syndrome in the setting of a lymphoproliferative disorder/possible cryoglobulinaemia.
B-cell lymphoproliferative disease are the major cause of cryoglobulinaemia associated with malignancy. Type 1 cryoglobulinaemia is predominatly in Waldenstrom’s, Multiple myeloma, or CLL. Mixed cryoglobulins are mainly in B-cell lymphomas.
Hyperviscosity syndrome develops mainly in patients with type I cryoglobulinaemia associated with haemotological malignancies. It is uncommon in mixed cryoglobulinaemia. The key symptoms neurological (headache, confusion), visual disturbance, ear/nose (epistaxis, hearing loss). Urgent treatment is required with plasma exchange.
Cryoglobulins are immunoglobulins which precipitate below 37 degrees and redissolve on rewarming
Several types:
- Type 1: MGUS/Myeloma/Waldenstroms macroglobulinaemia/CLL
- Usually few complement abnormalities
(prev MCQ)
- Type 2 & 3 are mixed cryoglobulinaemias:
-Type 2 (Monoclonal IgM plus polyclonal
IgG): chronic infections (Hepatitis C, HBV,
HIV), B-cell lymphoproliferative diseases - Type 3 (polyclonal): autoimmune diseases
(SLE, Sjogren’s syndrome), hepatitis C - Usually have reduced complement
proteins (Low C4 is a disease marker)
Which one of the following factors should be taken into account when determining the dose of an iron-chelating agent in a patient who is transfusion dependent because of myelodysplastic syndrome?
A. Presence of cardiac iron overload B. Presence of splenomegaly C. Haemoglobin level D. Mean corpuscular volume E. Pain at the site of subcutaneous infusion
Answer: A - presence of cardiac iron overload
Long-term red cell transfusion can sustain patients with chronic refractory anaemia, congenital or acquired. There is no effective means to eliminate excess iron, so long-term transfusion results in iron overload.
Iron chelating therapy should be considered in all patients with long-term red cell transfusions, and ideally started before iron overload develops.
Treatment should usually begin once received between 10 and 20 units of red cells. For individuals without iron deficiency, it is generally accepted that transfusion of more than 15 to 20 units of RBCs can cause clinically significant iron overload.
The dose is determined by 3 factors: 1. presence of cardiac iron overload (or liver), 2. the rate of transfusional iron loading, and 3. the body iron burden.
The best initial test for iron overload is the ferritin (elevated) transferrin saturation (unlikely if TSAT <45%, likely if >45%). If iron overload is likely then often requires MRI liver or heat to determine organ dysfunction/extent.
A 34yo primigravida is found to have a low platelet count (see below) on CBE performed at 34 weeks gestation. Her platelet count was 180 x 10^9/L at 12 weeks. She has no significant past medical history or medications. Her blood pressure is 105/70 mmHg. Her other investigation results are shown below; liver function tests are normal. Which of the following is the most likely cause of thrombocytopaenia?
Bloods: Hb 108 (115 - 160) WCC 4.3 (3.2 - 11) Platelet count 80 MCV 80 Reticulocyte count 1.8% Urinalysis protein 30 (negative) Serum creatinine 61 LDH 173 (70 - 250)
Options: A. Haemolysis, elevated liver enyzmes and low platelet (HELLP) syndrome B. Pre-eclampsia C. Evan syndrome D. Thrombotic thrombocytopaenia purpura E. Gestational thrombocytopaenia
Answer: E - gestational thrombocytopaenia
Asymptomatic mild gestational thrombocytopaenia is typically seen in late pregnancy, in up to 5% of pregnancies near term. It is typically mild with full resolution post partum and no neonatal thrombocytopaenia.
HELLP syndrome is seen after 20 weeks gestation and is associated with microangiopathic haemolytic anaemia, abnormal liver function tests and thrombocytopaenia.
Pre-eclampsia also occurs after 20 weeks gestation, usually accompanied by end-organ dysfunction, hypertension and proteinuria. Gestational hypertension is the most common cause of hypertension during pregnancy. It is defined as the new onset of hypertension (defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) after the 20th week of pregnancy in the absence of proteinuria or new signs of end-organ dysfunction.
Evan syndrome is an autoimmune haemolytic anaemia with idiopathic thrombocytopaenia.
TTP is characterised by thrombocytopaenic purpura, fever, fluctuating cerebral dysfunction, haemolytic anaemia with red cell fragmentation and often renal failure.
A 52 year old woman who had an ischaemic stroke 12 months ago but no residual neurological deficits was referred for evaluation of recurrent episodes of proximal DVT of the lower limbs in the last 10 months. Results are shown below. A bone marrow biopsy showed a mild hyperplasia or erythrocytic bone marrow. Urine dipstick for blood was 3+.
What is the most likely diagnosis?
Bloods: Hb 82 (115 - 155) MCV 98 (80 - 98) WCC 4.0 (4.0 - 11.0) Platelet count 93 (150 - 400) Reticulocytes 5.4% Total bilirubin 50 (2 - 24) LDH 944 (110 - 230) Coombs test negative
Options: A. Anti-thrombin III deficiency B. Haemolytic uraemic syndrome C. Paroxysmal nocturnal haemoglobinuria D. Homoscysteinaemia E. Protein C deficiency
Answer: C - paroxysmal nocturnal haemoglobinuria
PNH is a rare haematopoietic stem cell disorder caused by a somatic mutation in a gene known as phosphatidylinositol glycan class A (PIGA). It may arise de novo or in the setting of acquired aplastic anaemia.
The product of the PIGA gene is required for biosynthesis of a glycolipid anchor that attaches membrane proteins to the cell surface. Absence of anchored pretins leads to complement-mediated intravascular haemolysis because 2 important regulatory proteins are missing (CD55 and CD 59) from PNH cells.
Clinical presentations include acute intravascular haemolytic crisis, especially nocturnal , chronic haemolytic anaemia, haemoglobinuria, bone marrow failure and thrombosis.
Haemolysis in PNH occurs intravascularly, leading to free Hb and depletion of NO - causing fatigue, oesophageal spasm, thrombosis and erectile dysfunction.
Thrombosis is the leading cause of death.
Treatment options include bone marrow transplantation, and more recently biologic therapy with Eculizumab - binds C5 and blocks complement cascade.
Which of the following factors is the most important risk factor for acute graft-vs-host disease after allogeneic haemotopoietic stem cell transplantation?
A. Age of recipient B. CD4+ cell count of recipient at time of transplant C. CMV recipient status D. Donor and recipient mismatch in HLAs E. Total CD34+ cells transplanted
Answer: D - donor and recipient mismatch in HLAs
GVHD is one of the main complications of HSCT. An immunological disorder affecting multiple organ systems including the GIT, liver, skin and lung.
GVHD at onset usually affects skin (80%), GIT (50%), liver (50%).
It occurs due to donor T cells responding to proteins on host cells - the most important of which are the HLAs. The frequency of GVHD relates directly to the degree of mismatch between HLA proteins. Ideally donors and recipients are matched between HLA A, B, C and DRB1 loci (8/8 matches).
Prevalence of GVHD ranges from 35-45% in full matched sibling donor grafts, to 60^ in one mismatch unrelated donor grafts.
40% of full matched grafts develop GVHD requiring high dose steroids. This results from genetic differences outside the HLA loci.
Which one of the following best describes Rituximab use in the treatment of B cell lymphomas?
A. Rituximab is only used as a single agent
B. Rituximab is a chimeric monoclonal antibody that recognises CD38 antigen
C. Patients should be screened for Epstein-Barr virus prior to treatment
D. Rituximab when combined with chemotherapy improves progression-free survival of aggressive non-Hodgkin lymphoma
E. Rituximab-induced lymphopenia usually lasts more than 18 months
Answer: D - Rituximab when combined with chemotherapy improves progression-free survival of aggressive non-Hodgkin lymphoma
Rituximab is a chimeric monoclonal antibody directed against CD20. CD20 is a B-cell specific antigen expressed on mature B cells and most B-cell non-Hodgkin lymphomas.
CD38 is a marker of plasma cells.
Rituximab has been investigated in both aggressive and indolent NHL, including in combination with standard chemotherapy regimens for lymphoma - Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (CHOP). In aggressive NHL, 3yr survival was 85% with Rituximab compared to 68% with chemotherapy alone.
Lymphopenia occurs in most patients, typically lasting about 6 months with full lymphocyte recovery usually seen 9-12 months after cessation.
A 65 year old woman with headache, flushing and unexplained (anaphylactoid) shock was found to have a high serum tryptase level. Collateral history from her husband revealed previous allergic reactions to multiple medications including penicillin, cephalosporins and aspirin.
Which one of the following tests is the cornerstone of diagnosis in this patient’s condition?
A. Lymphocyte surface markers B. Radioallergosorbent test (RAST) C. Cytogenetic study D. Bone marrow biopsy E. Rechallenge the patient with the medications that she reports allergies to
Answer: D - bone marrow biopsy
History suggestive of systemic mastocytosis.
This is more commonly seen in adults and cutaenous mastocytosis in the paediatric population. Patients with systemic mastocytosis invariably have bone marrow involvement. Beyond bone marrow, abnormal growth and accumulation of neoplastic mast cells in various extracutaenous organs can cause pathology in the liver, spleen and bone. Careful histological with immunohistochemical study of the bone marrow is the cornerstone of establishing the diagnosis.
A 54
Other tests such as mast cell immunophenotyping, cytogenetic/molecular studies and serum tryptase levels are useful in confirming.
Mast cells express CD25 and/or CD2 - part of the WHO minor diagnostic criteria.
In normal bone marrow, the mast cell burden is very low <0.1%. A mast cell burden of more than 10% suggests a very high disease burden and may be associated with aggressive or advanced mast cell disorders. Cutaneous/low mast cell burden patients can be managed symptomatically; high mast cell burden patient may benefit from cytoreductive therapy.
A 54 year old obese woman presents with extensive DVT of her left leg. She has a family history of venous thromboembolism. She was started on low-molecular-weight heparin and warfarin 10mg daily for 2 days. Within 72hrs, she developed necrotic-looking skin lesions on her thighs without trauma.
What underlying condition is she most likely to have?
A. Anti-thrombin III deficiency B. Protein S deficiency C. Anti-phospholipid syndrome D. Protein C deficiency E. Homozygous factor V Leiden mutation
Answer: D - protein C deficiency
Protein C deficiency shows an autosomal dominant inheritance and is associated with recurrent familial thrombosis.
Patients are at high risk of warfarin-induced skin necrosis during initiation of therapy. This tends to occurr in the feet, buttocks, thighs, breasts, upper extremities and genitalia. The lesions usually begin as maculopapular lesions several days after initiation, which progress to bullous, haemorrhagic and necrotic lesions.
This is thought to occur due to an early imbalance of coagulation factors, with a rapid drop in protein C levels compared to other vitamin K dependent factors. This would lead to a relative hypercoagulable state with microvascular thrombotic occlusions and necrosis.
A 58 year old man presents with 3-month history of worsening breathlessness, confusion, headache and bleeding gums. His investigation results are shown below. Bone marrow biopsy reveals marrow infiltration by small lymphocytes showing plasma cell differentiation.
Bloods: Hb 95 (135 - 175) WCC 3.0 (4 - 11) Platelet count 135 x 10^9 (150 - 450) IgA 3.0 (0.9 - 3.4) IgG 6.0 (5.0 - 16) IgM 31 (0.5 - 3.0) Serum viscosity 4.2 (1.3 - 1.8)
What is the next appropriate treatment for this patient?
A. Chlorambucil B. Cyclophosphamide C. Plasma exchange D. Rituximab E. Thalidomide
Answer: C - Plasma exchange
Plasma exchange is indicated for the acute management of patients with hyperviscosity syndrome.
Waldenstrom macroglobulinaemia (WM) is a malignant lymphoplasmo-proliferative disorder with monoclonal pentameric IgM production. WM symptoms are attributable to:
- Tumour infiltration causing cytopaenias and progressive anaemia
- Circulating IgM leading to an increase in vascular resistance and viscosity
- Tissue deposition of IgM
- Autoantibody activity of IgM
Symptoms of hyperviscosity usually appear when greater than 4 (corresponds to serum IgM of >30g/L).
Epstein-Barr virus is associated with which of the following subtypes of non-Hodgkin lymphoma?
A. Gastric mucosa-associated lymphoid tissue lymphoma B. Follicular lymphoma C. Nasal natural killer cell lymphoma D. Chronic lymphocytic leukaemia E. Splenic marginal-zone lymphoma
Answer: C - nasal natural killer cell lymphoma
EBV has been recognised in association with nasal natural killer (NK) cell, Burkitt and T-cell lymphomas.
Hepatitis C is associated with splenic marginal-zone lymphoma.
H. pylori is implicated in the pathogenesis of gastric MALT lymphoma.
Nasal NK-cell and T-cell lymphoma associated with EBV are more frequent in East Asia, as is adult T-cell lymphoma associated with human T-cell lymphotropic virus type 1 (HTLV1)
Which one of the following is used to treat mild haemophilia A without the risk of transmitting infectious diseases?
A. Factor VIII concentrate B. Factor IX concentrate C. Prothrombin complex concentrate D. Tranexamic acid E. Desmopressin
Answer: E - desmopressin
In mild factor VIII deficiency (haemophilia A), vasopressin analogues (desmopressin) increase plasma concentrations of factor VIII and VWF 2-6 times through promoting endogenous release.
Desmopressin can be administered IV, intranasal or subcutaneously. There is no risk of infectious disease transmission either.
Not all patients achieve haemostatic activity levels with desmopressin, this depends on their baseline F8 activity.
Which one of the following is correct regarding atypical haemolytic uraemic syndrome (aHUS)?
A. It is only an acute disease
B. It is predominantly (>80%) a condition affecting children
C. It is associated with mutations in genes encoding complement regulatory proteins
D. It is due to mutations in the gene encoding ADAMTS13
E. Plasma exchange is the only effective treatment
Answer: C - It is associated with mutations in genes encoding complement regulatory proteins
aHUS is a genetic, chronic, systemic and potentially life-threatening disease in BOTH adults and children.
It results from chronic unregulated complement activation.
It is associated with mutations in genes encoding complement regulators (factor H, factor I, membrane cofactor protein and thrombomodulin) and activators (factors B and C3). Diagnosis does not require identification of mutations as 40% cannot be found.
Treatment: anti-C5 biologic therapy (Eculizumab)
o Terminal complement inhibition
o Remember to vaccinate against Neisseria
infections (increased susceptibility)
- TTP = TMA resulting from severe ADAMTS13 deficiency <5-10%
- aHUS/complement-mediated TMA > 10% ADAMTS13 activity
- Haemolytic uraemic syndrome = Shiga-toxin mediated TMA
A patient receiving chemotherpay for Burkitt lymphoma has the following biochemistry profile. He is transferred to ICU for cardiac monitoring and treatment. Which one of the following treatment options should be used to lower uric acid levels?
Potassium 6.8 (3.4 - 4.5) Phosphate 2.4 (0.70 - 0.95) Corrected calcium 1.60 (2.10 - 2.55) Urate 0.87 (0.45 - 0.60) creatinine 348 (60 - 120)
A. Aggressive IV diuretics B. Allopurinol C. Rasburicase D. Urinary alkalinisation E. Prednisolone
Answer: C - Rasburicase
This patient has tumour lysis syndrome as a result of chemotherapy for a highly aggressive mature B-cell lymphoma. They have developed an acute kidney injury, hyperkalaemia, hyperphosphatemia, secondary hypocalcaemia (from hyperphosphataemia) and hyperuricaemia.
Tumour lysis syndrome is seen in patients treated for bulky tumours and extensive metastasis, or with a high rate of proliferation of cancer cells, intensive cancer treatment regimen.
Supportive treatment, including IV fluids (not diuretics), cautious monitoring of electrolytes to prevent dysrhythmias and neuromuscular irritability, should be supplemented with treatment to lower uric acid.
Rasburicase removes uric acid by enzymatically degrading it into allantoin, a highly soluble product with no known adverse effects. The use of rasburicase can preserve or improve renal function and lower phosphorus as a secondary beneficial effect.
Allopurinol is a xanthine oxidase inhibitor which prevents conversion of hypoxanthine and xanthine into uric acid but does not remove existing uric acid. Allopurinol has been shown to worsen serum creatinine (by 12%) compared to rasburicase which improves creatinine (by 31%).
When rasburicase is available, it is recommended over allopurinol in high risk or clinically established TLS.
A 68 year old woman is recovering from elective knee replacement surgery for osteoarthritis. She has been receiving unfractionated heparined 5000 units BD. On day 10 she is breathless and CTPA shows bilateral pulmonary embolism. Laboratory investigations reveal a haemoglobin of 95 (115 - 155g/L) and platelet count of 45x10^9/L (150 -450). What additional diagnostic investigation should be undertaken?
A. Extractable nuclear antibodies B. Activated partial thromboplastin time C. Anti-phospholipid antibodies D. Anti-platelet factor 4/heparin antibodies E. Anti-thrombin III levels
Answer: D - anti-platelet factor 4 antibodies
Heparin induced thrombocytopaenia is caused by antibodies against complexes of platelet factor 4 and heparin.
Classically, patients present with low platelet counts or a decrease of 50% or more from baseline. Thrombotic complications develop in 20-50% and the risk of thrombosis remains high for days to weeks after discontinuation.
HITTS risk is 10x in UFH versus LMWH.
When HIT is suspected, initial testing is for anti-platelet factor 4/heparin antibodies. The major short-coming is limited specificity and false-positives are common, detecting non-pathogenic antibodies.
Functional assays measuring platelet activation and detecting antibodies capable of activity include the C14-serotonin release assay (SRA) and heparin-induced platelet activation assay (HIPA). Both are far more specific but they the technical requirements restrict their use and they commonly do not provide results in the real time necessary to guide initial management.
Treatment
o Discontinue heparin
o Alternative anticoagulation: Bivalirudin, Danaparoid, Fondaparinux, Rivaroxaban – usually continued for 2-3 months without thrombosis or 3-6mth if
Warfarin is not safe initially as takes 3-5 days to reach antithrombotic effect and rapidly declining protein C levels increase thrombotic risk
o Lifelong avoidance of heparin should be advised
EMQ: Anaemia
A. Haemolytic anaemia B. Pure red cell aplasia C. Iron deficiency anaemia D. Pernicious anaemia E. Beta-thalassaemia F. Sideroblastic anaemia G. Anaemia of chronic disease H. Sickle cell disease
- Which disorder predisposes to salmonella osteomyelitis?
- Answer H - sickle cell disease
Sickle cell disease patients are prone to bone infarcts and osteomyelitis, especially from salmonella.
This increased susceptibility of sickle cell disease has long been recognised with postulated mechanisms including hyposplenism, impaired complement acvitiy and presence of infarcted or necrotic bone.
The most common pathogens are salmonella followed by staph aureus and gram-negative enteric bacilli.
EMQ: Anaemia
A. Haemolytic anaemia B. Pure red cell aplasia C. Iron deficiency anaemia D. Pernicious anaemia E. Beta-thalassaemia F. Sideroblastic anaemia G. Anaemia of chronic disease H. Sickle cell disease
- 30year old woman with known hypoparathyroidism and Addison’s disease is found to have mutation in autoimmune regulator (AIRE) gene and has become progressively anaemic. What cause of anaemia should be considered?
Answer: D - pernicious anaemia
Mutations in AIRE are responsible for autoimmune polyendocrine syndrome type I.
Any 2 of the following in a patient would make the patient highly likely to have an AIRE mutation: mucocutaneous candidiasis, hypoparathyroidism, Addison’s disease.
There are associated risks in developing type 1 diabetes, hypothyroidism, pernicious anaemia, alopecia, vitiligo, hepatitis, ovarian atrophy.
EMQ: Anaemia
A. Haemolytic anaemia B. Pure red cell aplasia C. Iron deficiency anaemia D. Pernicious anaemia E. Beta-thalassaemia F. Sideroblastic anaemia G. Anaemia of chronic disease H. Sickle cell disease
- 70year old woman with 10 year history of myasthenia gravis adequately controlled with pyridostigmine, presents with general fatigue secondary to severe anaemia (Hb 62g/L). CT thorax shows an anterior mediastinal mass. Bone marrow aspirate shows severe erythroid hypoplasia associated with normal myeloid and megakaryocytic cell lines. What is the most likely diagnosis?
Answer: B - pure red cell aplasia
Myasthenia gravis and pure red cell aplasia can be associated with thymoma. MG appears in about 2-040% of patients with thymoma, and pure red cell aplasia in about 2-5% of those patients.
PRCA is found in 10-17% of MG patients.
PRCA causes an isolated anaemia in the presence of normal white cell and platelet counts. The bone marrow biopsy shows almost complete absence of erythroblasts but normal myeloid cells and megakaryocytes.
Evaluation for other possible causes should include history of drug use, toxins, infections, liver and kidney function, bone marrow examination including morphology, chromosome and rearrangement of T cell receptor analysis, peripheral blood flow cytometry, virologic examination (e.g. Parvovirus B19) and imaging to exclude malignancy or thymoma.
EMQ: Anaemia
A. Haemolytic anaemia B. Pure red cell aplasia C. Iron deficiency anaemia D. Pernicious anaemia E. Beta-thalassaemia F. Sideroblastic anaemia G. Anaemia of chronic disease H. Sickle cell disease
- 29year old man with 8 day history of fever, productive cough. Previously healthy and not using any drugs. Physical examination reveals an unwell mall with temperature of 39.8 degrees. His chest has bilateral basal crackles. Initial investigations are shown below.
Hb 93, MCV 94 WCC 18.1 Platelet 203 Reticulocytes 3.4% (0.5 - 1.5) LDH 758 (110 - 230)
Anti-mycoplasma antibody titre by complement fixation was high at 1: 10240. What is the most likely cause of his anaemia?
Answer: A - haemolytic anaemia
Cold antibody haemolytic anaemia can occur as a secondary disorder in association with multiple disorders including infections (e.g. mycoplasma and EBV/infectious mononucleosis), lymphoproliferative disorders (e.g. non-Hodgkin lymphoma and CLL).
An increase in cold agglutinin titres is frequently seen in myocplasma pneumoniae infection, in up to 50-60% of patients. They appear 1 week after illness onset and decline over 2-6 weeks. Severe haemolytic anaemia is rare and most patients recover completely/the haemolytic anaemia is self-limiting.
2011
A 74 year old man presents with bruising of his trunk and lower limbs. Clinical
examination reveals hepatosplenomegaly. His spleen is palpable 5 cm below the
costal margin. FBC: Hb 122 WCC 10 Plt 47
His liver function tests are normal as is his coagulation profile. His blood film (shown
below) demonstrates thrombocytopenia, poikilocytes and tear drop cells.
The likely cause of his clinical picture is: A. Chronic myelocytic leukaemia B. Myelofibrosis C. Myelodysplasia D. Thalassaemia E. Polycythaemia vera
Answer: B - myelofibrosis
Thrombocytopaenia secondary to myelodysplasia
Tear drops characteristic
Hepatosplenomegaly from extramedullary haematopoeisis
Myelofibrosis = worst prognosis of the MPNs
o 40-50% JAK2 positive
o Clinical features: anaemia with leucoerythroblastic blood smear, low platelets, hypercatabolic symptoms (fatigue, weight loss, fevers, bone pain)
Massive splenomegaly (extramedullary HP)
Bone marrow biopsy usually a dry tap with characteristic fibrosis, abnormal megakaryocytes
2011
A previously well, 33yo woman, with no significant past medical history, presented
with petechiae of the lower limbs with otherwise normal examination. Results of
bloods shown:
Hb 130 WCC 7 Plt 15
Blood film reveals decreased platelets only.
A diagnosis of idiopathic thrombocytopenia (ITP) is made. What is the most appropriate initial treatment?
A. Intravenous immunoglobulin B. Prednisone 1 mg/kg daily C. Plasmapheresis D. Romiplostin E. Platelet transfusion
Answer: B - Prednisolone 1mg/kg
Answer:
No emergency bleeding, first line treatment steroids and IVIG
Second line is splenectomy
Romiplostin (TPO antagonist) third line
