Haematology Flashcards
1
Q
Name three genes that are associated with myeloproliferative disorders
A
JAK2 (V617F)
Calreticulin
MPL
2
Q
Outline the treatment options for essential thrombocythaemia.
A
Aspirin
Hydroxycarbamide
Anagrelide (specifically inhibits platelet function but rarely used because of side-effects)
NOTE: hydroxycarbamide is an antimetabolite that suppresses cell turnover)
3
Q
What might you expect to see in the blood film of a patient with primary myelofibrosis?
A
Leucoerythroblastic picture
Tear drop poikilocytes (dacrocytes)
Giant platelets
Circulating megakaryocytes
NOTE: can cause Budd-Chiari syndrome
4
Q
What might you see on histological analysis of a trephine biopsy in primary myelofibrosis?
A
Increased reticulin and collagen fibrosis
Prominent megakaryocyte hyperplasia and clustering
New bone formation
5
Q
Outline the treatment options for primary myelofibrosis.
A
Supportive – RBC and platelet transfusions (usually ineffective because of splenomegaly)
Hydroxycarbamide (may worsen anaemia)
Ruxolitinib – JAK2 inhibitor
Allogeneic stem cell transplantation
Splenectomy – dangerous operation but may provide symptomatic relief
6
Q
List some diagnostic techniques used to identify the disease (CML) and monitor response to treatment.
A
FBC and leucocyte count
Cytogenetics and detection of Philadelphia chromosome (FISH)
RT-PCR to detect and quantify the number of copies of Bcr-Abl1 fusion transcript
NOTE: RT-PCR transcript % is the most sensitive
Bcr = breakpoint cluster region; Abl = ableson tyrosine kinase
7
Q
What are the next steps in treatment if the first-line treatment of CML fails?
A
1st line fails (no complete cytogenetic response at 1 year or initial response is followed by resistance) switch to 2nd or 3rd generation
2nd line fails (inadequate response or disease progresses to accelerated or blast phase) allogeneic stem cell transplantation
8
Q
How much more folate is needed in pregnancy than when non-pregnant?
A
200 µg/day more
9
Q
What proportion of pre-eclampsia patients will develop thrombocytopaenia?
A
50% - probably due to increased activation and consumption
NOTE: also associated with coagulation activation
10
Q
How is ITP in pregnancy treated?
A
IVIG
Steroids
Anti-D (if RhD-negative)
11
Q
List the main changes in coagulation factors that occurs in pregnancy.
A
Factor 8 and vWF – increase 3-5 fold Fibrinogen – increase 2 fold Factor 7 – increase 0.5 fold Protein S – falls by 0.5 PAI-1 – increase 5 fold PAI-2 – produced by the placenta NOTE: all of these changes lead to a procoagulant state
12
Q
List some other conditions in pregnancy that can increase the risk of thromboembolic disease.
A
Hyperemesis/dehydration Pre-eclampsia Obesity Thrombophilia Age (> 35 years) Parity Multiple pregnancy Ovarian hyperstimulation (IVF)
13
Q
In women receiving anticoagulant therapy because of high VTE risk, when should it be stopped?
A
When labour begins or at the time of a planned delivery
14
Q
Which type of haemoglobin variant cannot be identified using HPLC?
A
Alpha thalassemia
15
Q
What are the possible complications that a mother with sickle cell disease may encounter during pregnancy?
A
More frequent vaso-occlusive crises Foetal growth restriction Miscarriage Preterm labour Pre-eclampsia Venous thrombosis
16
Q
Which antigens do myeloma cells test positive for on immunohistochemistry?
A
CD138 CD38 CD56/CD58 Monotypic cytoplasmic immunoglobulin Light chain restriction
NOTE: CD38, CD138 and cytoplasmic Ig are present on normal plasma cells
17
Q
Which antigens do myeloma cells test negative for on immunohistochemistry?
A
CD19
CD20 (unlike B cell lymphomas and CLL)
Surface immunoglobulin
18
Q
Describe how the antibody screen of a patient’s plasma works.
A
Conducted using the indirect antiglobulin test (IAT)
2 or 3 reagent red blood cells are used which contain all the important red cell antigens
The patient’s serum is incubated with these screening cells
Anti-human immunoglobulin is added to the solution which allows bridging of red cells that are coated with IgG
This results in the formation of a visible clump
This is a group and screen
19
Q
What is a full crossmatch?
A
Uses indirect antiglobulin test
Patients plasma is incubated with DONOR red cells at 37 degrees for 30-40 mins
Anti-human immunoglobulin is added to allow cross-linking of antibodies
Formation of a clump would suggest that antibodies against donor red cell antigens are present in the patient’s plasma
20
Q
What is the adult dose of FFP?
A
15 mL/kg
21
Q
List some causes of delayed transfusion reactions.
A
Delayed haemolytic transfusion reaction Infection (viral, malaria, vCJD) TA-GvHD Post-transfusion purpura Iron overload
22
Q
Outline the mechanism of TRALI.
A
Anti-WBC antibodies in donor blood interact with WBC in the patient
Aggregates of WBCs get stuck to pulmonary capillaries resulting in the release of neutrophil proteolytic enzymes and toxic oxygen metabolites
This leads to lung damage
23
Q
Which patient group tends to be affected by post-transfusion purpura?
A
HPA-1a negative patients who have previously been immunised by pregnancy or transfusion
24
Q
How is post-transfusion purpura treated?
A
IVIG
25
If anti-D antibodies are detected in a pregnant women, what further steps should be taken?
Check if the father has the antigen
Monitor the level of antibody
Check cffDNA
Monitor foetus for signs of anaemia (MCA Doppler ultrasound)
Deliver the baby early because it gets a lot worse around term
26
What factor (related to stem cell harvesting) does the success of a bone marrow transplant depend on?
Number of CD34 cells per kg of weight of the recipient
27
List some clinical features of poorly controlled beta thalassemia major.
Anaemia heart failure, growth retardation
Erythropoietic drive bone expansion, hepatomegaly, splenomegaly
Iron overload heart failure, gonadal failure
28
How is a diagnosis of acute promyelocytic leukaemia confirmed?
Cytogenetic/FISH/molecular genetic analysis
| 15;17 translocation forming the PML: RARA fusion gene
29
How is acute promyelocytic leukaemia treated?
Platelets
Chemotherapy
All-trans-retinoic acid (ATRA)
NOTE: 90% 5-year survival
30
Outline the mechanisms by which anaemia of chronic disease causes anaemia.
Reduced red cell lifespan
Cytokine release (IFN-gamma, IL1, TNF) leads to reduced EPO receptor production and EPO synthesis
IL6 and LPS stimulate hepcidin production in the liver, which decreases intestinal iron absorption
Accumulation of iron in macrophages
31
Which HLA genotype is associated with Hodgkin lymphoma?
HLA-DPB1
32
List some investigations for thrombocytopaenia.
Coagulation screen
Blood film
Bone marrow aspirate
ANA/RAPA/anti-platelet antibodies (check for rheumatoid arthritis, SLE)
HIV (common cause of isolated platelet destruction worldwide)
33
List some investigations for suspected DIC.
```
Blood film
D-dimer
Fibrinogen
Septic screen
LFTs
```
34
What is paroxysmal nocturnal haemoglobinuria caused by?
An acquired defect in the GPI anchor which is one of two mechanisms by which cells attach proteins to their surface
Leads to increased risk of VTE and haemolysis
35
List some proteins that link the lipid bilayer to the cytoskeleton.
Band 3
Ankyrin-1
GPI
36
What is the difference between vertical interaction and horizontal interaction with regards to the red cell membrane?
Vertical – between proteins that link the lipid bilayer to the cytoskeleton (band 3, protein 4.2, Ankyrin, beta spectrin)
Horizontal – mainly involving alpha and beta spectrin (also protein 4.1)
37
What is the hall mark of red cells in hereditary spherocytosis?
Osmotic fragility – red cells show increases sensitivity to lysis in hypotonic saline
38
What is another test for hereditary spherocytosis?
Positive eosin 5-maleimide (dye) test (most sensitive)
| This is shown by flow cytometry
39
Describe the appearance of the blood film in hereditary pyropoikilocytosis.
Fragmentation of red cells and a lot of variation in the shape of red cells (poikilocytosis)
It can cause severe haemolytic anaemia
40
Outline the importance of G6PD in the red cell.
G6PD catalyses the first step in the pentose phosphate pathway
This reaction generates NADPH which is required to maintain intracellular glutathione
Glutathione protects red cells against oxidative stress
A lack of G6PD, means that red cells are at increased risk of oxidative damage
41
Describe the appearance of the blood film in G6PD deficiency during acute haemolysis.
Contracted cells
Nucleated red cells
Bite cells
Hemighosts (Hb retracted to one side of the cell)
NOTE: high bilirubin, low haptoglobins and haemoglobinuria will be seen with all intravascular haemolysis
42
Which stain is used to look for Heinz bodies?
Methylviolet
43
What is a characteristic blood film feature of pyruvate kinase deficiency?
Echinocytes (aka Burr cells) – red cells with a lot of short projections
NOTE: as the cells decrease in size due to dehydration, the cells will resemble spherocytes. The number of echinocytes usually increases post-splenectomy
44
Describe how pyrimidine 5-nucleotidase deficiency leads to haemolytic anaemia.
Defect in nucleotide metabolism
Pyrimidine nucleotides are toxic to the cell but the cell must recycle purines
This means that red cells have a mechanism for selectively eliminating pyrimidines – this is dependent on pyrimidine 5-nucleotidase
Deficiency of pyrimidine 5-nucleotidase leads to an accumulation of toxic pyrimidines
45
What is a characteristic blood film feature of pyrimidine 5-nucleotidase deficiency?
Basophilic stippling
| NOTE: this is also seen in lead poisoning because lead inhibits pyrimidine 5-nucleotidase
46
What are Ham’s test and flow cytometry for GPI-linked proteins used for?
Paroxysmal nocturnal haemoglobinuria
| NOTE: Ham’s test looks at the sensitivity of red cells to lysis by acidified serum
47
List some specific criteria for splenectomy.
```
Transfusion dependence
Growth delay
Physical limitation
Hypersplenism (where it causes pooling and physical symptoms)
Age > 3 years and < 10 years
```
48
Which chromosomal duplications are most commonly associated with AML?
8 and 21 (there is a predisposition seen in Down syndrome)
49
Give an example of how disruption of a transcription factor can lead to leukaemogenesis.
Core binding factor (CBF) is the master controller of haemopoiesis
Translocation 8;21 fuses RUNX1 with RUNX1T1 leading to the formation of a fusion gene that drives leukaemia
The fusion transcription factor binds to co-repressors leading to a differentiation block
Inversion of chromosome 16 also affects CBF in a similar way
50
Which chromosomal aberration causes APML?
Translocation 15;17
| PML-RARA fusion gene
51
What is a characteristic feature of APML? Why does this occur?
Haemorrhage – this is because APML is associated with DIC and hyperactive fibrinolysis
52
Give a type 1 and type 2 mutation for APML.
Type 1: FLT3-ITD
| Type 2: PML-RARA
53
Outline the tests that may be used to diagnose AML.
Blood film
Bone marrow aspirate
Cytogenetic studies (done in EVERY patient)
Molecular studies and FISH
54
What do dense granules contain?
Energy stores (ATP and ADP)
55
Outline the initiation phase of the clotting cascade.
Damage to the endothelium results in exposure of tissue factor which binds to factor 7 and activates it to factor 7a
The tissue factor-factor 7a complex then activates factors 9 and 10
Factor 10a binds to factor 5a resulting in the first step of the coagulation cascade
56
Outline the amplification phase of the clotting cascade.
Activated factors 5 and 10 will result in the production of a small amount of thrombin
This thrombin will activate platelets
Thrombin will also activate factor 11 which activates factor 9
Thrombin also activates factor 8 and recruits more factor 5a
Factors 5a, 8a and 9a will bind to the activated platelet
57
Outline the propagation phase of the clotting cascade.
Activated factors 5, 8 and 9 will recruit factor 10a
This results in the generation of a large amount of thrombin (thrombin burst)
This enables the formation of a stable fibrin clot
58
Name two factors that convert plasminogen to plasmin.
Tissue plasminogen activator
| Urokinase
59
Name two factors that directly inhibit plasmin.
Alpha-2 antiplasmin
| Alpha-2 macroglobulin
60
What is the role of thrombin-activatable fibrinolysis inhibitor (TAFI)?
Inhibitor of fibrin breakdown
61
Outline the role of protein C and protein S.
Trace amounts of thrombin generated at the start of the clotting cascade activate thrombomodulin
This allows protein C to bind to thrombomodulin through the endothelial protein C receptor
Protein C is then fully activated in the presence of protein S
Fully activated protein C will inactivate factors 5a and 8a
62
When is treatment for platelet disorders required?
Platelet count < 30 x 109/L (this is associated with spontaneous haemorrhage)
63
What can cause immune-mediated thrombocytopaenia?
```
Idiopathic
Drug-induced (e.g. quinine, rifampicin)
Connective tissue disorder (e.g. SLE)
Lymphoproliferative disease
Sarcoidosis
```
64
List two non-immune mediated conditions that cause thrombocytopaenia.
DIC
| MAHA
65
What is a typical lesion seen in coagulation factor disorders?
Ecchymoses
66
Outline the classification of von Willebrand disease.
Type 1 – partial quantitative deficiency
Type 2 – qualitative deficiency
Type 3 – complete quantitative deficiency
NOTE: encoded on chromosome 12
67
Describe the expected laboratory test results for the three types of von Willebrand disease.
Type 1 – low antigen, low activity, normal multimer
Type 2 – normal antigen, low activity, normal multimer
Type 3 – very low antigen, very low activity, absent multimer
68
List some causes of DIC.
Sepsis (MOST COMMON)
Trauma (e.g. fat embolism)
Obstetric complications (e.g. amniotic fluid embolism)
Malignancy
Vascular disorders
Reaction to toxin
Immunological (e.g. transplant rejection)
69
Describe the typical clotting study results in DIC.
```
Prolonged APTT and PT
Prolonged TT
Decreased fibrinogen
Increased FDP
Decreased platelets
Schistocytes (due to shearing of red blood cells as it passes through a fibrin mesh)
```
70
Describe how liver disease leads to bleeding disorders.
Decreased synthesis of clotting factors 2, 7, 9, 10, 11 and fibrinogen
Dietary vitamin K deficiency
Dysfibrogenaemia
Enhanced haemolysis (decreased alpha-2 antiplasmin)
DIC
Thrombocytopaenia due to hypersplenism
71
Outline the treatment of:
a. Prolonged PT/APTT
b. Low fibrinogen
c. DIC
```
a. Prolonged PT/APTT
Oral vitamin K
FFP infusion
b. Low fibrinogen
Cryoprecipitate
c. DIC
Replacement therapy
```
72
In which conditions are acanthocytes/spur cells seen?
Abetalipoproteinaemia
Liver disease
Hyposplenism
73
In which conditions are echinocytes seen?
Pyruvate kinase deficiency
Uraemia
Gastric cancer
74
Which membrane proteins are defective in many cases of hereditary spherocytosis?
Spectrin (most common)
| Also ankyrin, band 2 and band 3
75
Which proteins are defective in hereditary eliptocytosis?
Spectrin
Band 4.1
NOTE: all are autosomal dominant except hereditary pyropoikilocytosis which is autosomal recessive
76
Which substance accumulates in pyruvate kinase deficiency?
2,3-bisphosphoglyceric acid (2,3-BPG)
This shifts the oxygen dissociation curve to the right thereby releasing oxygen more readily
NOTE: PK normally converts phosphoenolpyruvate to pyruvate, but its absence means that an intermediate (2,3-BPG) collects instead
77
Which types of gallstones form in patients with hereditary spherocytosis?
Calcium bilirubinate
78
Where do the start and end steps of haem synthesis take place within the cell?
Mitrochondrion
79
What is the inheritance pattern of hereditary spherocytosis?
```
Autosomal dominant (75%)
De novo mutations (25%)
```
80
What is the inheritance pattern of pyruvate kinase deficiency?
Autosomal recessive
81
What causes hyponatraemia in acute intermittent porphyria?
SIADH
82
Describe the clinical presentation of polycythaemia vera.
Incidental finding
Symptoms of hyperviscosity (headaches, visual disturbances, fatigue, dyspnoea)
Increased histamine release (Aquagenic pruritus, peptic ulceration)
Splenomegaly
Plethora
Erythromelalgia (red painful extremities)
Thrombosis
Retinal vein engorgement
Gout
83
Describe the appearance of a bone marrow biopsy in polycythaemia vera.
```
Increased cellularity (mainly erythroid cells)
Slight reticulin fibrosis and megakaryocyte abnormalities
```
84
What investigation finding is considered diagnostic of polycythaemia vera?
Presence of JAK 2 V617F mutation
On chromosome 9
85
How is red cell mass and plasma volume measured?
Isotope dilution
Red cells are incubated with radioactive chromium
Plasma is incubated with radioactive iodine
86
On which exon is the JAK2 V617F mutation found?
Exon 14
87
Which other JAK mutation is a significant finding and which condition is it associated with?
Exon 12 mutation
| It is associated with idiopathic erythrocytosis
88
What is idiopathic erythrocytosis?
Isolated erythrocytosis with low EPO
Treated with venesection only
NO JAK 2 V617F mutation, but some cases will have an exon 12 mutation
89
Define chronic idiopathic myelofibrosis.
A clonal myeloproliferative disease with proliferation mainly of megakaryocytes and granulocytic cells, associated with reactive bone marrow fibrosis and extramedullary haemopoiesis
90
Describe the structure of janus kinases.
They have a kinase domain and a catalytically inactive pseudokinase domain with regulatory function
91
What effect does the JAK 2 V617F mutation have on janus kinases?
It inactivates the pseudokinase domain thereby removing inhibition of activation so it becomes constitutively activated
92
What are the morphological features of leucoerythroblastic anaemia seen on blood film?
Tear drop red blood cells (aniso- and poikilocytosis)
Nucleated RBCs
Immature myeloid cells
93
What are the two main groups of haemolytic anaemia? List some examples.
Inherited (defects with the cell)
• Hereditary spherocytosis (membrane problem)
• G6PD deficiency (enzyme problem)
• Sickle cell disease, thalassemia (haemoglobin problem)
Acquired (defects with the environment)
• Immune-mediated
• Non-immune mediated
94
List some systemic diseases that can cause autoimmune haemolytic anaemia.
Cancer involving the immune system (e.g. lymphoma)
Disease of the immune system (e.g. SLE)
Infections (disturbs the immune system)
95
List some key features of MAHA.
Usually caused by underlying adenocarcinoma
Red cell fragments
Low platelets
DIC/bleeding
96
List some causes of neutrophilia.
```
Corticosteroids (due to demargination)
Underlying neoplasia
Tissue inflammation (e.g. colitis, pancreatitis)
Myeloproliferative/leukaemia disorder
Infection
```
97
List some infections that characteristically do not cause neutrophilia.
Brucella
Typhoid
Many viral diseases
98
List some key features of a reactive neutrophilia on a blood film.
Band cells (presence of immature neutrophils (band cells) show that the bone marrow has been signalled to release more WBCs)
Toxic granulation
Clinical signs of infection/inflammation
99
List some causes of monocytosis.
Bacteria: TB, Brucella, typhoid
Viral: CMV, VZV
Sarcoidosis
Chronic myelomonocytic leukaemia
100
Which gene mutation causes chronic eosinophilic leukaemia?
FIP1L1-PDGFRa fusion gene
101
Which type of virus typically causes basophilia?
Pox viruses
102
List some anticoagulant molecules produced by the endothelium.
```
Thrombomodulin
Endothelial protein C receptor
Tissue factor pathway inhibitor
Heparans
NOTE: it does not normally produce tissue factor
```
103
List some disadvantages of heparin.
Administered by injection
Risk of osteoporosis
Variable renal dependence
Risk of heparin-induced thrombocytopaenia
104
How is unfractionated heparin monitored?
It has variable pharmacokinetics and a variable dose-response
Must be monitored with APTT or anti-Xa levels
105
List some properties of DOACs.
```
Oral administration
Immediate action (peak = 3-4 hours)
Useful in long-term
Short half-life
No monitoring needed
```
106
How can the action of warfarin be reversed?
Administering vitamin K – takes 12 hours
| Giving factors 2, 7, 9 and 10 – immediate
107
Outline the treatment of DVT/PE.
Start LMWH (e.g. tinzaparin 175 u/kg) + warfarin
Stop LMWH when INR > 2 for 2 days
ALTERNATIVE: start a doac
These should be continued for:
- Known cause: 3 months
- unknown cause or cancer VTE: 3-6 months
- thrombophilic/recurrent: lifelong
108
What should all patients > 60 years old with idiopathic thromboembolic disease be offered?
CT scan to check for an underlying cause
109
What are the key characteristics of myelodysplastic syndromes?
Development of a clone of marrow stem cell with abnormal maturation resulting in functionally defective blood cells and a reduction in cell counts
This leads to cytopaenia, functional abnormalities of cell maturation and an increased risk of transformation to leukaemia
110
Which staging systems are used for multiple myeloma?
Durie-Salmon Staging
| International Staging System
111
What type of anaemia are all haemolytic anaemias?
Normocytic
112
How is severe hereditary spherocytosis treated?
Splenectomy
| Vaccination
113
What bone abnormality may result from hereditary spherocytosis?
Osteoporosis
114
What is the pentad of thrombotic thrombocytopaenic purpura?
```
Fever
Change in mental status
Thrombocytopaenia
Reduced renal function
Haemolytic anaemia
```
NOTE: may require plasma exchange
115
List and describe some blood and bone marrow features of myelodysplastic syndromes.
Pelger-Huet anomaly (bilobed neutrophils)
Dysgranulopoiesis of neutrophils (failure of granulation)
Dyserythropoiesis of red blood cells (lack of separation between red cell precursors, presence of abnormal ring of cytoplasm around the nucleus of precursor red cells)
Dysplastic megakaryocytes (micro-megakaryocytes)
Increased proportion of blast cells in the bone marrow (normally < 5%)
116
What might you see if you stained for iron in the bone marrow of a patient with a myelodysplastic syndrome?
Ringed sideroblasts (accumulation of iron around the nuclei of red blood cell precursors)
117
List some factors that are taken into account when classifying types of myelodysplastic syndrome.
```
Cell lineage affected
Blast cell proportions
Cytogenetics
Presence of ringed sideroblasts
Cytopaenias
```
118
What are the five prognostic variables that are used to calculate prognostic risk using the Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes?
```
Bone marrow blast percentage
Karyotype
Haemoglobin
Platelets
Neutrophils
NOTE: high risk is considered a score > 6, low risk < 1.5
```
119
List some causes of primary bone marrow failure.
Fanconi anaemia (multipotent stem cell)
Diamond-Blackfan syndrome (red cell aplasia)
Kostmann syndrome (neutrophil progenitor)
Acquired: idiopathic aplastic anaemia (multipotent stem cell)
120
List some drugs that can cause bone marrow failure.
Cytotoxic drugs (predictable, dose-dependent)
Phenylbutazone, Gold salts (idiosyncratic, rare)
Antibiotics – chloramphenicol, sulphonamides
Diuretics – thiazide
Antithyroid drugs – carbimazole
121
List some inherited causes of aplastic anaemia.
```
Fanconi anaemia (pancytopaenia)
Schwachman-Diamond syndrome (primarily neutropaenia)
Dyskeratosis Congenita (BM failure)
```
122
List some differential diagnosis for pancytopaenia and hypocellular marrow.
```
Hypoplastic MDS/AML
Hypocellular ALL
Hairy cell leukaemia
Atypical mycobacterial infection
Anorexia nervosa
ITP (although Hb and RBC will be normal)
```
123
What is the Camitta criteria for severe aplastic anaemia?
```
2 out of 3 peripheral blood features:
• Reticulocytes < 1% (< 20 x 109/L)
• Neutrophils < 0.5 x 109/L
• Platelets < 20 x 109/L
Bone marrow cellularity < 25%
```
124
Outline the management approaches used for bone marrow failure.
Seek and remove cause
Supportive (blood products, antibiotics, iron chelation)
Immunosuppressive therapy (anti-thymocyte globulin, steroids, ciclosporin A)
Drugs that promote bone marrow recovery (oxymetholone (androgen), thrombopoietin receptor agonist (eltrombopag))
Stem cell transplantation
Alemtuzumab (T cell depletion) – for refractory cases
125
What is the inheritance pattern of Fanconi anaemia?
Autosomal Recessive or X-linked Recessive
126
What do the gene mutations implicated in Fanconi anaemia tend to result in?
```
Abnormalities in DNA repair
Chromosomal fragility (breakage in the presence of in vitro mitomycin and diepoxybutane)
```
127
List some somatic abnormalities that are seen in Fanconi anaemia.
```
Short stature
Hypopigmented spots/café-au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hypogonadism
Developmental delay
NOTE: these are only present in 70% of patients
```
128
What are the three main somatic features of dyskeratosis congenita?
Abnormal skin pigmentation
Nail dystrophy
Leukoplakia
Main Features: bone marrow failure, cancer predisposition
129
Which genes are involved in dyskeratosis congenita and what are the inheritance patterns?
X-linked recessive (MOST COMMON) – DKC1 gene (defective telomere functioning)
Autosomal dominant – TERC (RNA components of telomerase)
Autosomal recessive – no mutation identified
NOTE: abnormal telomeric structure and function is heavily implicated in dyskeratosis congenita
130
List some oncogenes that are implicated in lymphoma/leukaemia.
Bcl2
Bcl6
Cyclin D1
c-Myc
131
List two examples of viral infections that can lead to lymphoma.
Direct viral integration: HTLV1
• HTLV1 infects T cells by vertical transmission
• May cause adult T cell leukaemia/lymphoma (very aggressive) - shows 'flower cells'
• Caused by viral genome integrating into T cell genome and driving proliferation
EBV infection and immunosuppression
• EBV established latent infection in B cells which is kept in check by cytotoxic T cell (kill EBV antigen-expressing B cells)
• Loss of T cell function (e.g. HIV, post-transplant immunosuppression) can lead to EBV-driven lymphoma
132
Describe the normal histological appearance of a lymph node.
There are rounded areas full of B cells (B cell follicles)
The mantle zone is a crescent-shaped region where naïve unstimulated B cells are found
These naïve B cells will eventually migrate into the germinal centre, and mature B cells will end up in the medulla
T cells are found in T cell areas surrounding the B cell follicles
133
Describe the composition of T cell areas in lymph nodes.
Consists of lots of T cells, antigen-presenting cells and high-endothelial vessels
This is the site where T cells bind to antigens and are selected/activated
134
What are the main markers used for B and T cells?
T cell = CD3, CD5
| B cell = CD20
135
Outline the WHO classification of lymphoma.
```
Hodgkin lymphoma
• Classical
• Lymphocyte predominant
Non-Hodgkin lymphoma
• B cell (MOST COMMON)
o Precursor B cell neoplasm
o Peripheral B cell neoplasm (low and high grade)
• T cell
o Precursor T cell neoplasm
o Peripheral T cell neoplasm
```
136
Give an example of a chromosomal translocation that is prognostic in lymphoma.
2;5 = anaplastic large cell lymphoma
137
List some types of low grade lymphoma.
Follicular lymphoma
Small lymphocytic lymphoma (CLL)
Marginal zone lymphoma
Mantle zone lymphoma
138
Name a type of intermediate grade lymphoma.
Burkitt’s lymphoma
139
Name a type of high grade lymphoma.
Diffuse large B cell lymphoma
140
Describe the histological features of follicular lymphoma.
Follicular pattern – the follicles are neoplastic and spread from the node into adjacent tissues
Cells have a germinal centre cell origin (positive staining for CD10 and Bcl6)
141
Which molecular feature is associated with follicular lymphoma?
14;18 translocation involving Bcl2 gene
142
Outline the histological features of small lymphocytic lymphoma.
Small lymphocytes
Arise form naïve B cells or post-germinal centre memory B cells
Cells are CD5 and CD23 positive
They replace the entire lymph node so that you can no longer identify follicles or T cell areas
143
What is marginal zone lymphoma?
Arise mainly in extra-nodal sites (e.g. gut, spleen)
Thought to arise due to chronic antigenic stimulation
Arise from post-germinal centre memory B cells
Low-grade disease can be treated by non-chemotherapeutic methods (e.g. H. pylori eradication)
144
Outline the key histological features of mantle cell lymphoma.
Located in the mantle zone of the lymph node
Arise from pre-germinal centre cells
Show aberrant expression of cyclin D1 and CD5
145
Which molecular features are characteristic of mantle cell lymphoma?
11;14 translocation
| Cyclin D1 overexpression
146
Outline the histological features of Burkitt’s lymphoma.
Arises from germinal centre cells
| Starry sky appearance
147
Which molecular feature is associated with Burkitt’s lymphoma.
c-Myc tranlocation (8;14, 2;8 or 8;22)
148
Outline the histological features of diffuse large B cell lymphoma.
Arise from germinal centre or pre-germinal centre B cells
Large lymphoid cells
Lymph node is effaced so follicles and germinal centres cannot be identified
149
List some prognostic association of diffuse large B cell lymphoma.
Good prognosis – germinal centre phenotype
| Poor prognosis – p53-positive and high proliferation fraction
150
List some types of T cell lymphoma and their associations.
Adult T cell leukaemia/lymphoma – HTLV1
Enteropathy-associated T cell lymphoma – Coeliac disease
Cutaneous T cell lymphoma (mycosis fungoides)
Anaplastic large cell lymphoma
151
Outline the key histological features of anaplastic large cell lymphoma.
Large epithelioid lymphocytes
T cell or null phenotype (anaplastic)
NOTE: this tends to mainly affect children and young people
152
Which molecular features are associated with anaplastic large cell lymphoma?
2;5 translocation
| Alk-1 protein expression – BETTER prognosis
153
Outline some histological features of classical Hodgkin lymphoma.
Nodular sclerosis
Mixed cell population of Reed-Sternberg cells
Lymphoma cells are few in number and are scattered around
Eosinophils
Arise from germinal centre or post-germinal centre cells
154
What are the diagnostic markers for Hodgkin lymphoma?
CD15
| CD30
155
Outline the key histological features of lymphocyte predominant Hodgkin lymphoma.
B cell rich nodules
Scattered around L&H cells
Reactive population in the background consisting of small lymphocytes
NO eosinophils and macrophages
156
Which markers are key in the diagnosis of lymphocyte predominant Hodgkin lymphoma?
```
Positive = CD20
Negative = CD15, CD30 (unlike classical Hodgkin lymphoma)
```
157
Which chemotherapy regimen is usually used for Hodgkin lymphoma?
ABVD: Adriamycin, Bleomycin, Vincristine, Dacarbazine
NOTE: this is usually given at 4-weekly intervals for 2-6 cycles and it preserves fertility
Consequences: cardiomyopathy, pulmonary fibrosis
158
What are some important tests to perform in non-Hodgkin lymphoma and why are they important?
LDH – marker of cell turnover
HIV serology – HIV can predispose to NHL (HTLV1 serology may also be important)
Hepatitis B serology – NHL treatment may deplete B cells resulting in fulminant liver failure due to reactivation of hepatitis B in chronic carriers
159
What are the two most common types of non-Hodking lymphoma?
Diffuse large B cell lymphoma (DLBCL)
| Follicular lymphoma
160
List some types of non-Hodgkin lymphoma that are:
a. Very aggressive
b. Aggressive
c. Indolent
```
a. Very aggressive
Burkitt’s lymphoma
T or B cell lymphoblastic lymphoma/leukaemia
b. Aggressive
Diffuse large B cell lymphoma
Mantle cell lymphoma
c. Indolent
Follicular lymphoma
Small lymphocytic lymphoma (CLL)
MALToma
```
161
Which factors are taken into account by the international prognostic index (IPI) for lymphoma?
```
Age > 60
High LDH
Performance status 2-4
Stage III or IV
More than one extranodal site
```
162
Which chemotherapy treatment is usually used for diffuse large B cell lymphoma?
```
R-CHOP
Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisolone
Usually 6-8 cycles
NOTE: achieves a 50% cure rate
Also used for Mantle cell lymphoma
```
163
What is the usual first-line treatment approach to follicular lymphoma?
Watch and wait
| Only treat it clinically indicated (e.g. compression symptoms, massive nodes, recurrent infection)
164
Which chemotherapy regimen may be used in the treatment of follicular lymphoma?
```
R-CVP
Rituximab
Cyclophosphamide
Vincristine
Prednisolone
```
165
List some diseases that can lead to marginal zone lymphoma.
H. pylori infection – gastric MALToma
Sjogren’s syndrome – parotid lymphoma
Hashimoto’s thyroiditis – thyroid lymphoma
Psittaci infection – lacrimal gland
166
How might gastric MALToma stage I-II disease be treated?
Triple therapy to eradicate H. pylori (2 antibiotics + 1 PPI)
Repeat breath test at 2 months
Repeat endoscopy every 6 months for 1-2 years then annually
NOTE: failure may require chemotherapy
167
What are the main features of enteropathy-associated T cell lymphoma?
Mature T cells
Involves small intestines
Aggressive
Caused by chronic antigenic stimulation by gliadin/gluten
168
What distinctive antigen phenotype (presence and absence) is suggestive of:
a. Mature B cells
b. Mature T cells
```
a. Mature B cells
CD19 positive
CD5 negative
b. Mature T cells
CD19 negative
CD5 positive
CD3 positive
CD4 or CD8 positive
```
169
Which antigen phenotype is suggestive of CLL?
CD5+ B cells (i.e. CD19+ and CD5+)
| NOTE: this could potentially also be mantle cell lymphoma
170
Which staging system is used for CLL?
Rai and Binet
Binet: stages A-C depending on number of lymphoid areas A - no cytopaenia, < 3 areas (watch and wait)
B - no cytopaenia, > 3 areas (consider referral)
C - cytopaenia (treat)
171
Which laboratory tests are used in CLL to help gauge prognosis?
BAD: CD38, high LDH, 11q23 deletion
GOOD: hypermutated Ig gene, low ZAP-70, 13q14 deletion
172
What is the difference between the VH genes of pre- and post-germinal centre B cells?
Pre-germinal centre: VDJ section is unmutated and looks identical to germline
Post-germinal centre: undergone somatic hypermutation so VDJ is mutated and looks different to germline
173
What is an important chromosomal abnormality in CLL that is tested for using FISH?
Deletion of 17p (Tp53)
This is part of the p53 tumour suppressor gene
This deletion is associated with a poor prognosis
174
Which cells are in excess in CLL?
B cells
175
How would a Richter transformation be treated?
R-CHOP
176
What are some indications for treatment of CLL?
Progressive lymphocytosis (more than doubling in < 6 months)
Progressive bone marrow failure
Massive or progressive lymphadenopathy/splenomegaly
Systemic symptoms (B symptoms)
Autoimmune cytopaenias (1st line: steroids, 2nd line: rituximab)
177
What is the first line treatment for TP53 intact CLL?
FCR – Fludarabine, Cyclophosphamide, Rituximab
NOTE: less intensive options may include, rituximab and bendamustine or obinutuzumab (anti-CD20) and chlorambucil (alkylating agent)
NOTE: if TP53 mutated --> ibrutinib or idelalisib (alemtuzumab used to be used in the past)
178
What are some newer treatment options for high risk CLL?
Bruton Tyrosine Kinase Inhibitors – ibrutinib, idelalisib
Bcl2 Inhibitors – venetoclax
CAR-T therapy
179
Describe how CAR-T therapy for CLL works.
CAR-T are autologous T cells that are modified to contain chimeric antigen receptors
The internal part of the receptor is responsible for cell signalling
The external part is designed to target CD19 (on B cells) thereby enabling B cell depletion
180
Which chemotherapy agents may be used in the management of multiple myeloma?
```
Melphalan
Bortezomib
Lenalidomide
Thalidomide
NOTE: stem cell transplant is used for younger patients
```
181
Outline the typical presentation of a fat embolus.
Neurological abnormality
Respiratory compromise
Purpuric rash
182
What can cause the appearance of stomatocytes on a peripheral blood film?
Alcoholics
Liver disease
Hereditary stomatocytosis
183
List some causes of sideroblastic anaemia.
```
Myelodysplastic disorders
Following chemotherapy
Irradiation
Alcohol excess
Lead poisoning
Myeloproliferative disease
NOTE: iron levels increase, TIB is normal and ferritin increases in sideroblastic anaemia
```
184
Describe some skeletal changes that occur in long-standing beta-thalassemia.
Skull bossing
Maxillary hypertrophy
Hairs on end skull X-ray
185
What is the difference between warm and cold agglutinins?
Warm: occur at 37 degrees, IgG antibodies, extravascular haemolysis
Cold: occur < 37 degrees, IgM antibodies, intravascular haemolysis
186
List some causes of warm and cold agglutinins.
Warm: CLL, SLE, methyldopa, lymphoma
Cold: infections (EBV, mycoplasma, hepatitis C), lymphoma
187
What is paroxysmal cold haemoglobinuria? Which antibody is implicated?
Haemoglobin in the urine usually after a viral infection (e.g. measles)
Donath-Landsteiner antibodies stick to RBCs in the cold and cause complement-mediated haemolysis on rewarming
NOTE: self-limiting
188
Outline the pathophysiology of TTP.
Most TTP is caused by autoimmune inhibition of ADAMTS13 which leads to decreased breakdown of large multimers of vWF
This leads to long strands of vWF in blood vessels breaking up the RBCs
189
How does the target INR when receiving warfarin therapy depend on the indication?
2. 5 = 1st episode DVT/PE, atrial fibrillation, cardiomyopathy, cardioversion, inherited thrombophilia
3. 5 = recurrent DVT/PE, mechanical prosthetic valve, coronary artery graft thrombosis, antiphospholipid syndrome
190
How can the effects of warfarin be reversed in cases of major bleeding?
Stop warfarin
Give prothrombinase complex concentrate (use FFP if this is unavailable)
IV vitamin K
NOTE: IV vit K is used if INR > 5
191
What are the stages of chemotherapy used for acute leukaemia?
Remission induction: chemotherapy usually with steroids
Consolidation: high-dose multi-drug chemotherapy
Maintenance
192
What type of fever is sometimes seen in lymphoma?
Pel-Ebstein fever (cyclical 1-2 weeks)
193
What's the difference between MGUS and multiple myeloma?
MGUS:
- IgG/IgA < 30 g/L
- < 10% clonal plasma cells in BM
- No CRAB
- No organ damage
- do annual blood test
Smouldering Multiple Myeloma
- IgG/IgA > 30 g/L
- > 10% clonal plasma cell inBP
- NO CRAB or end organ damage
Multiple Myeloma
- IgG/IgA > 30 g/L
- high clonal plasma cells in BM
- end organ damage
194
What is Waldenstrom's macroglobinaemia?
Low-grade NHL with lymphoplasmacytoid cells that produce monoclonal serum IgM that infiltrates the lymph nodes and bone marrow
aka lymphoplasmacytoid lymphoma
Presents with weakness, purpura, arthralgia and cold-sensitivity symptoms
195
Describe how the variant version of APML is different from the original version.
The variant form has granules that are below the resolution of a light microscope
They also tend to have bilobed nuclei
196
What are the effects of thrombin?
Activates fibrinogen
Activates platelets
Activates profactors (factor 5 and 8)
Activates zymogens (factor 7, 11 and 13)
197
Outline the process by which B cells become plasma cells.
Centroblasts mature in lymph nodes where they are stimulated by antigens and turn into memory B cells or immature plasmablasts
Various transcription factors regulate the conversion of plasmablasts into plasma cells
198
Describe the histological appearance of mature plasmacytic cells.
Nucleus is pushed to one side of the cell
Clumped chromatin
Large cytoplasm (low nuclear-to-cytoplasmic ratio)
199
Describe the histological appearance of immature plasmablastic cells.
Prominent nucleoli
Reticular chromatin
Less abundant cytoplasm
NOTE: the presence of these cells is associated with a poor prognosis
200
How does multiple myeloma lead to lytic bone disease?
The myeloma cells release osteoclast activating factors and osteoblast inhibiting factors
201
Outline the mechanisms by which multiple myeloma causes kidney injury.
Immunoglobulin light chains activate inflammatory mediators in the proximal tubule epithelium
Proximal tubule necrosis
Fanconi syndrome (renal tubule acidosis with failure of reabsorption in the proximal tubule) with light chain crystal deposition
Cast nephropathy
202
What are the four main domains of treatment of multiple myeloma?
Classical cytostatic drugs (e.g. melphalan)
Steroids (very cytotoxic to lymphocytes)
Immunomodulators (IMIDs e.g. thalidomide)
Proteasome inhibitors
203
What is melphalan?
An alkylating agent that acts as a cytostatic drug
| Usually given with thalidomide and dexamethasone in people who cannot have an autologous stem cell transplant
204
Describe the physiological role of proteasomes.
All proteins produced by a cell are folded in the endoplasmic reticulum
If this process goes wrong, misfolded proteins would accumulate in the ER
These misfolded proteins are insoluble and non-functional and lead to fatal ER stress and cell death
So, we have proteasomes in the cytoplasm which targets misfolded proteins and degrades them into amino acids (a process called ER-associated degradation (ERAD))
Inhibition of proteasomes leads to an accumulation of misfolded proteins in myeloma cells leading to cell death
NOTE: proteasome inhibitors only work in multiple myeloma and not other cancers
205
The presence of which cell type on a blood film is associated with a poor prognosis in CML?
Basophils
206
Describe the presenting features of Budd-Chiari syndrome.
Abdominal pain
Nausea
Tender hepatomegaly
Ascites
207
Describe the presentation of digoxin toxicity.
Arrhythmia and chest pain
Anorexia, nausea, diarrhoea
Confusion amongst the elderly
Blurred vision and photophobia
208
Which serine protease assists the breakdown of clots by binding to the clot and localising agents that break it down?
Tissue plasminogen activator
209
How can bacterial contamination be distinguished from febrile non-haemolytic transfusion reaction?
Both of them develop quite quickly (FNHTR can develop over days)
Bacterial contamination causes a more profound fever and hypotension
210
Which protein deficiency is associated with anaphylactic reactions to blood transfusions?
IgA deficiency
211
Which type of myelodysplasia is treated with lenalidomide?
5q minus syndrome
Characterised by anaemia, normal/high platelets and < 5% blasts
212
List some causes of relative polycythaemia.
Alcoholism
Diuretics
Obesity
213
What is the recommended daily iron intake in pregnancy?
30 mg/day
NOTE: iron absorption in pregnancy increases from 1-2 mg/day to 6 mg/day
214
What are the WHO recommendations for daily supplementation in pregnancy?
60 mg iron
| 400 µg folic acid
215
Why is epidural anaesthesia a risk in patients with thrombocytopaenia and at what platelet count would this be considered dangerous?
Can cause spinal haematoma
| A platelet count > 70 x 109/L is required
216
What is RDW a measure of?
RDW = red cell distribution width
Looks at the variation in red cell volume
```
High RDW = iron deficiency, folate/B12 deficiency
Normal RDW (but low Hb) = thalassemia
```
217
What is the difference between a full cross match and an immediate spin?
Full X-match will detect all incompatible haemolytic reactions (takes 40-50 mins)
Immediate spin will detect only ABO incompatibility (takes 5 mins)
218
How long do red cells survive in storage?
35 days in 4 degrees
They need to be transfused within 4 hours of leaving the fridge (but can be returned within 30 mins)
219
Which antigens need to be taken into account for platelet and plasma transfusions?
Platelets: no X-match needed because antigens are weakly expressed
Plasma: only ABO
220
Which patients require irradiated blood and why?
Highly immunosuppressed patients
These patients cannot destroy donor lymphocytes and the presence of lymphocytes in donated blood can cause graft-versus-host disease
221
Which patients require washed blood?
Patients who have severe allergic reactions to donors’ plasma proteins
This takes 4 hours so must be requested in advance
NOTE: IgA deficient patients are more likely to need washed blood
222
List some contraindications for platelet transfusion.
Heparin-induced thrombocytopaenia
| TTP
223
List some indications for FFP transfusion.
Massive transfusion
DIC
Liver disease
224
List some causes of acute transfusion reactions.
```
Acute haemolytic (ABO incompatibility)
Allergic/anaphylaxis
Infection (bacterial)
Febrile non-haemolytic
Respiratory (TACO and TRALI)
```
225
What is the most common transfusion reaction?
Transplant-associated circulatory overload (TACO)
226
What causes febrile non-haemolytic transfusion reactions?
Release of cytokines from white cell during storage
Also caused by antibodies against donor lymphocytes and HLA
Treated by slowing down/stopping the transfusion and giving paracetamol
227
How is an allergic transfusion reaction managed?
Stop or slow the transfusion
| IV antihistamines
228
List some symptoms of an acute haemolytic transfusion reaction.
```
Chest/loin pain
Fever
Vomiting
Flushing
Collapse
Haemoglobinuria
Low BP
High HR
High Temp
```
229
Describe the storage and shelf-life of platelets.
Stored at 22 degrees for 7 days
| NOTE: they are screened for bacterial before release
230
What are the typical blood test results you expect to see during a haemolytic episode?
High bilirubin
Low haemoglobin
High reticulocytes
Haemoglobinuria (for a few days until haemolysis stops)
NOTE: U&E should be tested to check for renal failure. Also group and screen should be repeated to check for the development of new antibodies
231
What are the clinical manifestations of transfusion-associated Graft-versus-Host Disease?
```
Diarrhoea
Liver failure
Skin desquamation
Bone marrow failure
Death (weeks to months)
```
232
At what point after transfusion does post-transfusion purpura happen?
7-10 days after transfusion of platelets or red blood cells
| NOTE: it usually resolves in 1-4 weeks but can cause life-threatening bleeding
233
How much iron is there in a unit of blood?
200-250 mg
234
When should all women have a group and screen done in pregnancy?
12 weeks
| 28 weeks
235
When should anti-D be given routinely to RhD-negative women?
500 iU at 28 weeks and 34 weeks
Or 1500 iU at 28-30 weeks
NOTE: anti-c and anti-Kell can also cause severe haemolytic disease
236
State an equation that relates the probability of having a sibling with a matching tissue type to the number of siblings a patient has.
Probability of match = 1 – (3/4)number of siblings
| NOTE: there is a 25% chance that your sibling has the same tissue type as you
237
Name three ways of harvesting stem cells.
Bone marrow sampling
Peripheral blood sampling
Umbilical cord stem cells
238
List some treatment options for GvHD.
```
Corticosteroids
Ciclosporin A
FK506
Mycophenolate mofetil
Monoclonal antibodies
Photophoresis
Total lymphoid irradiation
```
239
What are the main differences between the blood count of neonate and an adult?
Higher WCC (neutrophils, lymphocytes)
Higher Hb
Higher MCV
50% less G6PD
240
What is another term to describe congenital leukaemia?
Transient abnormal myelopoiesis (TAM)
Usually remits spontaneously within the first 2 months of life
Some will relapse after 1-2 years
NOTE: the leukaemia is mainly MYELOID with major involvement of the megakaryocyte lineage
241
On which chromomes are the different globin genes expressed?
```
Chromosome 11
• Beta
• Delta
• Gamma
• Epsilon
Chromosome 16
• 2 x alpha
• Zeta
```
242
Which globin chains make up HbA2 and what level is considered normal in a health adult?
2 x alpha
2 x delta
< 3.5%
243
Aside from the haemolysis, what else contributes to anaemia in sickle cell anaemia?
HbS has a low affinity for oxygen meaning that it releases oxygen readily to tissues
This reduces EPO-drive
244
List some differential diagnoses for bruising in a young child.
```
ITP
HSP
Leukaemia
NAI
Haemophilia
```
245
Which clotting factor has the shortest half life?
Factor 7
| i.e. this is inhibited first by warfarin
246
Describe how TRALI manifests.
```
Hypotension
Tachycardia
SOB and low O2 saturations
Fever
Usually started within 6 hours of transfusion
```
247
How does the sickle solubility test work?
Blood is mixed with sodium dithionite which lyses the cells
HbA will dissolve
HbSS will appear cloudy
HbS will appear less cloudy
This is a screening test and is usually followed up with haemoglobin electrophoresis
248
What level of HbF and HbA would you expect to see in sickle cell anaemia?
No HbA
| High HbF
249
What is cryoglobulinaemia?
A medical condition in which the blood contains large amounts of pathological cold-sensitive antibodies (cryoglobulins) that become insoluble at reduced temperatures
250
How long should warfarin therapy for a DVT go on for?
Unprovoked: 3 months
Provoked: 6 months
251
Describe the inheritance pattern of von Willebrand disease.
Type 1 and 2: autosomal dominant
| Type 3: autosomal recessive
252
What does bleeding time represent?
Integrity of primary haemostasis
Prolonged bleeding time suggest issue with primary platelet plug (e.g. von Willebrand disease)
253
What are the laboratory and clinical criteria for tumour lysis syndrome?
```
Positive laboratory TLS requires 2 or more of the below within 7 days of chemotherapy or 3 days before:
Uric acid - HIGH
Potassium - HIGH
Phosphate - HIGH
Calcium - LOW
```
Positive clinical TLS requires any one of:
Serum creatinine - HIGH
Cardiac arrhythmia or sudden death
Seizure
254
What are the main features of Chediak-Higashi syndrome?
It is a microtubule polymerisation defect leading to reduced phagocytosis
Causes partial albinism and peripheral neuropathy
Recurrent bacterial infections
Giant granules in neutrophils and platelets
255
What are the main features of ataxia telangiectasia?
Autosomal recessive defect in DNA repair
Cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia
256
Which chemotherapy induction regimen has the best evidence pre-autologous stem cell transplantation in multiple myeloma?
Lenalidomide + low dose dexamethasone
257
Which protein, if elevated, is associated with a poor prognosis in multiple myeloma?
Beta-2 microglobulin
258
What is an important growth factor in the development of multiple myeloma?
IL-6
259
Which stain is used for hairy cell leukaemia?
Tartrate-resistant acid phosphatase
260
Which drug is given prophylactically with methotrexate?
Folic acid
261
Which drug is used as rescue therapy to ameliorate the toxic effects of high-dose methotrexate therapy?
Folinic acid
NOTE: this is a form of folic acid that does NOT need activation in the body
262
Outline the treatment of Stage I/II Hogkin Lymphoma and advanced Hodgkin lymphoma.
Stage I/II - ABVD combination chemotherapy + radiotherapy if required
Advanced - combination chemotherapy
NOTE: Hodgkin lymphoma is very sensitive to radiotherapy (but it risks damaging surrounding structures)
263
Why might G6PD levels appear normal in G6PD deficiency?
During acute haemolysis, the body responds by producing a reticulocytosis
Reticulocytes are high in G6PD which can mask an underlying G6PD deficiency
Reticulocytosis will cause polychromasia and high MCV
264
How is non-diarrhoeal haemolytic uraemic syndrome treated?
Eculizumab (anti-C5 complement)
265
The detection of which blood cell antigen is suggestive of acute lymphoblastic leukaemia?
TdT+
266
The detection of which enzyme by immunohistochemistry is used to diagnose AML?
Myeloperoxidase
267
Define the following type of myelodysplastic syndromes:
MDS with ringed sideroblasts
MDS with multilineage dysplasia
MDS with excess blasts
MDS with ringed sideroblasts: > 15% ringed sideroblasts, anaemia, multilineage dysplasia
MDS with multilineage dysplasia: 2-3 lineages affected, <5% blasts
MDS with excess blasts: > 5% blasts, 10-19% blasts = MDS with excess blasts 2
268
What stage is a lymphoma with bone marrow or spleen involvement?
Spleen: stage 3 (only if on both sides of the diaphragm)
| Bone marrow: stage 4
269
What is the normal range for haemoglobin in men and women?
Men: 135-180 g/l
Women: 115-160 g/l
270
List some causes of macrocytic anaemia.
Megaloblastic anaemia (B12 and folate deficiency)
Alcohol
Hypothyroidism
Pregnancy
271
What is elevated in the serum of a patient with B12 deficiency?
Serum methylmalonic acid
272
How can AIHA be treated?
Treat underlying cause
| Rituximab
273
What causes haemolytic uraemic syndrome?
E. coli O157:H7 (shiga-like toxin)
Triad of MAHA, thrombocytopaenia and acute renal failure
274
State two differentials for von Willebrand disease.
Bernard-Soulier disease (large platelets)
Glanzmann's thrombasthenia (normal ristocetin)
NOTE: ristocetin is an assay looking at platelet function with the help of vWF (result is abnormal in von Willebrand disease)
275
Which inherited thrombophilia carries the highest risk of thrombosis?
Anti-thrombin deficiency
NOTE: this is autosomal dominant, differentials include protein C/S deficiency, they will need long-term anticoagulation with warfarin
276
What are the consequences of protein C/S deficiency?
VTE
Warfarin-induced skin necrosis
NOTE: it is autosomal dominant
277
Outline the changes in blood cell parameters that occur during pregnancy.
```
Plasma volume: increase
Hb: decrease
Red cell mass: increase
MCV: increase
Haematocrit: decrease
Platelets: decrease
WCC: increase
Factors 7, 8, 9, 10 and 12: increase
Factor 11: decrease
Protein S: decrease
```
278
Outline the guidelines for warfarin reversal based on INR.
< 5 = lower or omit next dose
5-9 = omit next dose or oral vitamin K
> 9 = omit next dose AND oral vitamin K
279
Which type of classical Hodgkin lymphoma has the best prognosis?
Lymphocyte predominant
Good Prognosis: nodular sclerosing (most common 70%), mixed cellularity (20%)
Worst Prognosis: lymphocyte depleted
280
List some types of lymphoma that arise from germinal centre cells.
Follicular lymphoma
Burkitt's lymphoma
Hodgkin lymphoma
Diffuse large B cell lymphoma (can be post-germinal centre)
NOTE: mantle cell lymphoma is pre-germinal centre
281
List some types of lymphoma that arise from post-germinal centre cells.
Marginal zone lymphoma
Small lymphocytic lymphoma
Diffuse large B cell lymphoma (can have a germinal centre phenotype)
282
Which type of cell seen on histological analysis of a lymph node in lymphoma is suggestive of high grade lymphoma?
Large cells (centroblasts, immunoblasts, plasmablasts)
283
What are the subtypes of classical Hodgkin lymphoma?
Nodular sclerosing (70%)
Mixed cellularity (20%)
Lymphocyte rich
Lymphocyte depleted
284
List some examples of specific T cell lymphomas.
Enteropathy associated T-cell lymphoma (EATL)
Mycosis fungoides (cutaneous T cell lymphoma)
Adult T-cell leukaemia/lymphoma
Anaplastic large cell lymphoma
285
Which chromosomal translocation is associated with gastric MALToma?
t(11;18)
286
List some causes of true polycythaemia.
```
High altitude
Hypoxic lung disease (COPD)
Cyanotic heart disease
High affinity haemoglobin
Renal disease (cysts, tumours)
Uterine myoma
```
287
Outline the treatment of polycythaemia vera.
Aim to reduce HCT (< 45%) using venesection and cytoreductive therapy (hydroxycarbamide)
Aim to reduce risk of thrombosis (control HCT, aspirin, keep platelets < 400)
288
List some examples of Bcr-Abl tyrosine kinase inhibitors.
1st Gen - Imatinib
2nd Gen - Dasatinib, Nilotinib
3rd Gen - Bosutinib
289
What counts as a complete cytogenetic response in the treatment of CML?
```
Complete = 0% Ph positive
Partial = 1-35% Ph positive
```
Other measures of response include haematological (looking at WCC) and molecular (looking at BCR-ABL transcripts (most sensitive))
290
What is the finding of cabot rings in a blood film suggestive of?
Vitamin B12 deficiency
291
Which prothrombin mutation predisposes to VTE?
Prothrombin G20210A
292
Outline the clinical features of adult T-cell leukaemia/lymphoma.
```
More common in Japan and the Caribbean
Cloverleaf nuclei
Lymphadenopathy
Hepatosplenomegaly
Skin lesions
Hypercalcaemia
```
293
List some components of the alternative pathway of complement activation.
B, I and P
294
Name some drugs that cause aplastic anaemia.
Chloramphenicol
Carbamazepine
Cytotoxics
Anti-epileptics (e.g. phenytoin)
295
In which conditions might a splenectomy be therapeutically beneficial?
```
Thalassemia
Pyruvate kinase deficiency
ITP
AIHA
Elliptocytosis
Spherocytosis
```
296
Which type of cancer is pernicious anaemia associated with?
Gastric cancer
297
What do alpha granules in platelets contain?
Growth factors
Fibrinogen
Factor V
vWF
298
What is the only DOAC that has an antidote available?
Dabigatran
299
What treatment regimen is considered for patients with multiple myeloma who are not suitable for stem cell transplantation?
Melphalan and prednisolone (bortezomib may be added)
300
What are the haemoglobin transfusion thresholds for red cell transfusions?
< 70 g/L
If acute coronary syndrome or post-chemo: < 80 g/L
Or if > 30% blood loss
301
What are the transfusion thresholds for platelet transfusions?
Most of the time: < 30
If severe bleeding: < 100
Prevent bleeding (post chemo): < 10
Prevent bleeding (surgery): < 50
