Haem Flashcards
1
Q
Define haemolytic anaemia
A
Anaemia caused by shortened RBC survival
2
Q
List some e.g.s of extravascular haemolysis
A
AI haemolytic anaemia
Hereditary spherocytosis
3
Q
List some e.g.s of intravascular haemolysis
A
Malaria (most common worldwide) G6PD deficiency Pyruvate kinase deficiency Mismatched blood transfusion MAHA Paroxysmal nocturnal haemoglobinuria
4
Q
What is paroxysmal nocturnal haemoglobinuria caused by>
A
Acquired defect in GPI anchor which is 1 of 2 mechanisms by which cells attach proteins to their surface
5
Q
List some consequences of haemolytic anaemia
A
Anaemia Erythroid hyperplasia Increased folate demand Susceptibility to parvovirus B19 infection Propensity to gallstones Increased risk of Fe overload Increased risk of osteoporosis
6
Q
Why is parvovirus B19 infection dangerous in patients with haemolytic anaemia?
A
Infects erythroid cells in bone marrow & arrests their maturation
If this happens in someone with shortened RBC survival, can cause dramatic drop in Hb (aplastic crisis)
N.B: Can be identified by observing low reticulocyte count
7
Q
Why do people with haemolytic anaemia have increased risk of developing gallstones?
A
Increased generation of bilirubin
8
Q
Co-inheritance of which condition with haemolytic anaemia could further increase risk of gallstones?
A
Gilbert’s syndrome
9
Q
Describe genetic cause of Gilbert’s syndrome
A
Caused by UGT TA7/TA7 genotype
Instead of usual 6TA repeats, extra dinucleotide on each allele - associated with reduced transcription of UGT 1A1
Reduced production of enzyme in liver
Less efficient bilirubin conjugation
10
Q
Why is there an increased risk of Fe overload with haemolytic anaemia?
A
Increased intestinal Fe absorption (also due to transfusions)
11
Q
List some clinical features of haemolytic anaemia
A
Pallor Jaundice Splenomegaly Family history Pigmenturia
12
Q
List some lab features of haemolytic anaemia
A
Anaemia Increased reticulocytes Polychromasia Increased LDH (intracellular enzyme released when RBCs destroyed) Increased bilirubin Reduced/absent haptoglobins Haemoglobinuria Hemosiderinuria
13
Q
What is polychromasia?
A
RBC take up both eosinophilic & basophilic dye giving them bluish appearance - due to presence of reticulocytes
14
Q
What is increased LDH a marker of?
A
Increased LDH suggests intravascular haemolysis
15
Q
What are haptoglobins? What is the significance of reduced haptoglobins?
A
Haptoglobins are proteins in bloodstream that bind to & remove free Hb from bloodstream
Low haptoglobins suggests lots of free Hb in bloodstream
16
Q
Which stains used for haemosiderinaemia?
A
Perl’s stain
Prussian blue stain
17
Q
What does presence of haemoglobinuria & haemosiderinuria imply?
A
Intravascular haemolysis
18
Q
RBC lipid membrane rests on a cytoskeleton made of what?
A
Spectrin
19
Q
Describe the inheritance of hereditary spherocytosis
A
75% family history (autosomal dominant)
25% de novo mutations
N.B: Most common defect of RBC cytoskeleton
20
Q
What is the hallmark feature of RBC in hereditary spherocytosis?
A
Osmotic fragility - RBC show increased sensitivity to lysis in hypotonic saline
21
Q
What is another test for hereditary spherocytosis?
A
Reduced binding to eosin 5-maleimide (dye)
Shown by flow cytometry
22
Q
Describe appearance of blood film in hereditary spherocytosis
A
Cells lack central area of pallor because have lost biconcave shape
Cells are small & more densely stained
May be polychromatic cells (due to presence of young RBC population)
23
Q
Outline the blood film & FBC features of hereditary elliptocytosis
A
RBC elliptical but no polychromasia & blood count likely to be normal because there is little haemolysis
24
Q
What is the homozygous form of elliptocytosis called?
A
Hereditary pyropoikilocytosis
25
Describe appearance of blood film in hereditary pyropoikilocytosis
Fragmentation of RBC & lot of variation in shape of RBC (poikilocytosis)
Can cause severe haemolytic anaemia
26
Describe the inheritance pattern of G6PD deficiency
X-linked recessive
27
Outline the importance of G6PD in RBCs
G6PD catalyses 1st step in pentose phosphate pathway
This reaction generates NADPH which is required to maintain intracellular glutathione
Glutathione protects RBCs against oxidative stress
Lack of G6PD means RBCs at increased risk of oxidative damage
28
List possible clinical effects of G6PD deficiency
Neonatal jaundice
Acute haemolysis
Chronic haemolytic anaemia (rare)
29
List some triggers for haemolysis in G6PD deficiency
Drugs (antimalarials, abx, dapsone, Vit K)
Infections
Fava beans
Naphthalene mothballs
30
Describe appearance of blood film in G6PD deficiency during acute haemolysis
Contracted cells
Nucleated RBCs
Bite cells
Hemighosts (Hb retracted to one side of cell)
31
What is a Heinz body? What is it suggestive of?
| What stain is used to look for them?
Denatured Hb
Suggestive of oxidative haemolysis
Methylviolet
32
What is a characteristic blood film feature of pyruvate kinase pathway?
Echinocytes - RBCs with lots of short projections
N.B: As cells decrease in size due to dehydration, RBCs will resemble spherocytes. Number of echinocytes usually increases post-splenectomy
33
Describe how pyrimidine 5-nucleotidase deficiency leads to haemolytic anaemia
Defect in nucleotide metabolism
Normal:
- Pyrimidine nucleotides are toxic to the cell but the cell must recycle purines
- RBCs have mechanism for selectively eliminating pyrimidines
- This mechanism dependent on pyrimidine 5-nucleotidase
Deficiency of pyrimidine 5-nucleotidase leads to accumulation of toxic pyrimidines
34
What is a characteristic blood film feature of pyrimidine 5-nucleotidase deficiency?
Basophilic stippling
| N.B: Also seen in lead poisoning because lead inhibits pyrimidine 5-nucleotidase
35
What are Ham's test & flow cytometry for GPI-linked proteins used for?
Paroxysmal nocturnal haemoglobinuria
| N.B: Ham's test looks at sensitivity of RBCs to lysis by acidified serum
36
What investigations are used for malaria?
Thick & thin blood film
37
Outline the principles of management of haemolytic anaemia
Folic acid supplementation
Avoidance of triggers in G6PD deficiency
Blood transfusions/exchange
Immunisations against blood-borne viruses
Monitor for chronic complications (e.g. gallstones)
Splenectomy if needed
38
List some indications for splenectomy
```
Pyruvate kinase deficiency
Hereditary spherocytosis
Severe eliptocytosis/pyropoikilocytosis
Thalassaemia symptoms
AI haemolytic anaemia
```
39
What is the main risk of splenectomy?
Overwhelming sepsis due to susceptibility to encapsulated bacteria (e.g. pneumococcus)
N.B: Risk can be reduced by using penicillin prophylaxis & immunisations
40
List some specific criteria for splenectomy
```
Transfusion dependence
Growth delay
Physical limitation
Hypersplenism (where causes pooling & physical symptoms)
3< Age <10
```
41
What is Hb Hammersmith (HH)?
Severe unstable Hb variant that produces a Heinz body haemolytic anaemia
42
Which chromosomal duplications are most commonly associated with AML?
8 & 21 (hence Down's syndrome predisposition)
43
List some RFs for AML
```
Familial
Constitutional (e.g. Down's syndrome)
Anticancer drugs
Irradiation
Smoking
```
44
What are type 1 & type 2 abnormalites with regards to leukaemogenesis?
Type 1: Promotes proliferation & survival (anti-apoptosis)
Type 2: Blocks differentiation
N.B: Leukaemogenesis in AML requires multiple genetic hits
45
Give an e.g. of how disruption of a transcription factor can lead to leukaemogenesis
Core binding factor (CBF) = master controller of haemopoiesis
Translocation 8;21 fuses RUNX1 with RUNX1T1 leading to formation of fusion gene that drives leukaemia
Fusion transcription factor binds to co-repressors leading to differentiation block
Inversion of Chr16 also affcts CBF in a similar way
46
Which chromosomal aberration causes APML?
| What fusion gene does this produce?
Translocation 15;17
| PML-RARa (type 1 mutation)
47
What is a characteristic feature of APML?
| Why does this occur?
Haemorrhage - because APML is associated with DIC & hyperactive fibrinolysis
48
In what way are the promyelocytes in APML abnormal
Contain multiple Auer rods - these are pathognomonic of myeloid leukaemias
(Large, crystalline cytoplasmic inclusion bodies)
49
Describe how the variant version of APML is different from the original variation
Variant form has granules that are below the resolution of a light microscope
Also tend to have bilobed nuclei
50
Give a type 1 & type 2 mutatation for APML
Type 1: FLT3-ITD
| Type 2: PML-RARa
51
Which stain can be used to distinguish myeloid leukaemias from other leukaemias?
What other similar stains that are not used as frequently?
Myeloperoxidase
Less frequent:
Sudan black
Non-specific esterase
52
List the clinical features of AML?
Bone marrow failure (anaemia, neutropaenia, thrombocytopaenia)
Local infiltration (splenomegaly, hepatomegaly, gum infiltration, lymphadenopathy, CNS, skin)
Hyperviscosity if WBC very high (can cause retinal haemorrhages & exudates)
53
Outline the tests that may be used to diagnose AML
```
Blood film
- Neutrophilia
- Myeloblasts
Bone marrow aspirate
Cytogenic studies (done in every patient)
Molecular studies & FISH
```
54
What is aleukaemic leukaemia?
When there are no leukaemic cells in the peripheral blood but the bone marrow has been replaced them
55
Outline the supportive care given for AML
```
RBCs
Platelets
FFC/cryoprecipitate in DIC
Abx
Allopurinol (prevent gout)
Fluid & electrolyte balance
Chemotherapy
```
56
What are the principles of treatment in AML?
```
Damage the DNA of the leukaemic cells
Leave normal cells unaffected
Combination chemo always used
Usually given as 4-5 courses (2x remissin induction + 2/3x consolidation)
Treatment usually lasts around 6mths
```
57
List some determinants of prognosis in AML
```
Patient characteristics
Morphology
Immunophenotyping
Cytogenetics
Response to treatment
```
58
Outline clinical features of ALL
Bone marrow failure
| Local infiltration
59
What is a key difference in the origin of B-lineage & T-lineage ALL?
B-lineage starts in the bone marrow
| T-lineage can start in the thymus (which may be enlarged)
60
List some investigations used in the diagnosis of ALL
FBC & blood film
Bone marrow aspirate
Immunophenotyping
Cytogenetic/molecular analysis
61
What are the 4 phases of chemo for ALL?
Remission induction
Consolidation & CNS therapy
Intensification
Maintenance
62
How long does chemo for ALL usually take? Why is it longer in M?
2-3yrs
| Longer in M because testes are site of accumulation of lymphoblasts
63
Who receives CNS-directed chemo? How can this be given?
All patients
| Can be given intrathecally or high dose of chemo can be given that penetrates BBB
64
Outline the supportive care for ALL
Blood products
Abx
General medical care (central line, gout management, hyperkalaemia management, sometimes dialysis)
65
Which factors are procoagulant?
| Which are anticoagulant?
Procoagulant:
- Platelets
- Endothelium (products & subendothelium)
- vWF
- Coagulation cascade
Anticoagulant:
- Fibrinolysis
- Antithrombins
- Protein C/S
- Tissue factor pathway inhibitor
66
Which 3 responses are stimulated by vessel injury?
```
Vasoconstriction
Platelet activation (forms primary haemostatic plug)
Activation of the coagulation cascade
```
67
What are the 2 main functions of the endothelium?
Synthesis of prostacyclin, vWF, plasminogen activators, & thrombomodulin
Maintain barrier between blood & procoagulant subendothelial structures
68
How many platelets are produced by each megakaryocyte?
| What is the life span of platelets?
4000 produced
10 days
N.B: This is important because means the effect of antiplatelet drugs lasts for 10 days after stopping the drug
69
What are glycoproteins?
Cell surface proteins through which platelets can interact with the endothelium, vWF, & other platelets
70
What do dense granules contain?
Energy stores (ADP, ATP) - found in platelets
71
Which features of platelets enable them to massively expand their SA?
Open cannalicular system & microtubules & actomyosin
72
What are the 2 ways in which platelets can adhere to subendothelial structures
Directly - Via GlpIa
| Indirectly - Via binding of GlpIb to vWF
73
Which factors, released by platelets after adhesion, promote platelet aggregation?
ADP
| Thromboxane A2
74
How do platelets bind to each other?
GlpIIb/IIIa
| Also binds to fibrinogen via this receptor
75
Describe the effects of aspirin & other NSAIDs on the arachidonic acid pathway
Aspirin = irreversible COX inhibitor
| Other NSAIDs reversibly inhibit COX
76
What is the rate-limiting step for fibrin formation?
Factor Xa
77
What are the effects of thrombin?
Activates fibrinogen
Activates platelets
Activates profactors (FV & FVIII)
Activates zymogens (FVII, FXI, FXIII)
78
Name the complex that is responsible for activating prothrombin to thrombin
Prothrombinase complex
79
Outline the initiation phase of the clotting cascade
Damage to the endothelium results in exposure of tissue factor binds FVII -> FVIIa
TF-FVIIa complex activates FIX & FX
FXa binds to FVa resulting in the first step of the coagulation cascade
80
Outline the amplification phase of the clotting cascade
FVa & FXa result in production of small amount of thrombin
This thrombin activates platelets
Thrombin also activates FXI which activates FIX, and FVIII which recruits more FVa
FVa, FVIIIa, FIXa will bind to the activated platelet
81
Outline the propogation phase of the clotting cascade
FVa, FVIIIa, FIXa recruit FXa
Results in generation of large amount of thrombin (thrombin burst)
Enables formation of stable fibrin clot
82
Why is the prothrombinase complex important?
Allows prothrombin activation at a much faster rate
83
What is required for adequate production/absorption of Vit K?
Bacteria in gut produce Vit K
| Fat-soluble so bile needed for Vit K to be absorbed
84
What is the most common cause of Vit K deficiency?
Warfarin
85
Name 2 factors that convert plasminogen to plasmin
Tissue plasminogen activator
| Urokinase
86
Name a factor that inhibits tissue plasminogen activator & urokinase
Plasminogen activater inhibitor 1 & 2
87
Name 2 factors that directly inhibit plasmin
Alpha-2 antiplasmin
| Alpha-2 macroglobulin
88
What is the role of thrombin-activatable fibrinolysis inhibitor (TAFI)?
Inhibitor of fibrin breakdown
89
Describe the action of antithrombins
Bind to thrombin 1:1 & this complex excreted in urine
90
What is the most thrombogenic hereditary condition?
Antithrombin deficiency
91
Outline the role of protein C & protein S
Trace amounts of thrombin generated at start of clotting cascade activate thrombomodulin
Allows protein C to bind to thrombomodulin through endothelial protein C receptor
Protein C then fully activated in presence of protein S
Fully activated protein C will inactivate FVa & FVIIIa
92
State & explain 2 causes of activated protein C resistance
```
Mutated FV (e.g. FV Leiden) - resistant to breakdown by protein C
High levels of FVIIIa
```
93
What is the role of tissue factor pathway inhibitor?
TFPI neutralises TF-FVIIa complex once it has initiated the clotting cascade
94
What is the difference between immediate & delayed bleeding with regards to the underlying pathological process?
Immediate - issue with the primary haemostatic plug (platelets, endothelium, vWF)
Delayed - issue with the coagulation cascade
95
Describe the key clinical differences between platelet disorders (immediate bleeding) & coagulation factor disorders (delayed bleeding)
Platelet disorders
- Bleeding from skin & mucous membranes
- Petechiae
- Small, superficial ecchymoses
- Bleeding after cuts & scratches
- Bleeding immediately after surgery/trauma
- Usually mild
Coagulation factor disorders
- Bleeding into soft tissues, joints, & muscles
- No petechiae
- Large, deep ecchymoses (typical lesion in coagulation disorders)
- Haemarth roses
- No bleeding from cuts & scratches
- Delayed bleeding from surgery & trauma
- Often severe
96
When is treatment for platelet disorders required?
Platelet count <30x10^9/L (associated with spontaneous haemorrhage)
97
Why is it important to look at platelets under the microscope in thrombocytopaenia?
To distinguish from pseudothrombocytopaenia (platelets clumped together giving erroneously low result)
Also allows identification of other abnormalities (e.g. Grey platelet syndrome - large platelets)
98
What can cause a decrease in platelet number?
| What can cause defective platelet function?
Number
- Decreased production
- Decreased survival (ITP)
- Increased consumtpion (DIC)
- Dilution
Function
- Acquired (e.g. aspirin)
- Congenital (e.g. thombasthaenia)
- Cardiopulmonary bypass
99
What can cause immune-mediated thrombocytopaenia?
```
Idiopathic
Drug-induced e.g. quinine, rifampicin
Connective tissue disorder e.g. SLE
Lymphoproliferative disorder
Sarcoidosis
```
100
List 2 non-immune mediated conditions that cause thrombocytopaenia
DIC
| MAHA
101
Describe the pathophysiology of ITP
Auto-Ab generated against platelets
| Platelets tagged by auto-Ab then destroyed by reticuloendothelial system (liver, spleen, bone marrow)
102
What are the main differences between acute & chronic ITP
Acute
- Mainly children
- Usually preceding infection
- Abrupt onset of symptoms
- Lasts 2-6wks
- Spontaneously resolves
Chronic
- Mainly occurs in adults
- More common in F
- Can be abrupt or indolent
- Doesn't resolve spontaneously
103
How is ITP treated?
Mainly with steroids & IVIG based on the platelet count
104
Give some e.g.s of thrombocytopaenia that can be diagnosed by blood film
Vit B12 deficiency
| Acute leukaemia
105
What clotting study abnormality would be seen in haemophilia?
```
Prolonged APTT
(Intrinsic & common pathway - FVIII (a) & FIX (b) most common)
```
106
What is the most common coagulation disorder? What is its inheritance pattern?
Von Wilebrand disease
Autosomal dominant - type 1 & 2
Autosomal recessive - type 3
107
Describe the relationship between vWF & FVIII
Binding of FVIII to vWF protects FVIII from being destroyed
| N.B: Type 3 vWD has very similar phenotype to haemophilia A (because absent vWD leads to low FVIII)
108
What is vitamin K required for?
Synthesis of FII, VII, IX, & X
| Synthesis of protein C, S, & Z
109
List some causes of Vit K deficiency
Malnutrition
Biliary obstruction
Malabsorption
Abx therapy
110
Outline the pathophysiology of DIC
Release of thromboplastic material into circulation causes widespread activation of coagulation & fibrinolysis
Results in increased vascular deposition of fibrin, which leads to thrombosis of small & mid-size vessels with organ failure
Depletion of platelets & coagulation factors leads to bleeding
111
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)
112
Describe the typical clotting study results in DIC
```
Prolonged APTT & PT
Decreased fibrinogen
Increased fibrin degradation products
Decreased platelets
Schistocytes (due to shearing of RBCs as pass through fibrin mesh)
```
113
Outline treatment of DIC
```
Treat underlying cause
Anticoagulation with heparin
Platelet transfusion
FFP
Coagulation inhibitor concentrate
```
114
Describe how liver disease leads to bleeding disorders
Decreased synthesis of FII, VII, IX, X, XI, & fibrinogen
Dietary Vit K deficiency
Dysfibrogenaemia
Enhanced haemolysis (decreased alpha-2 antiplasmin)
DIC
Thrombocytopaenia due to hypersplenism
115
Outline the treatment of:
- Prolonged PT/APTT
- Low fibrinogen
- DIC
Prolonged PT/APTT
- Oral Vit K
- FFP infusion
Low fibrinogen
- Cryoprecipitate
DIC
- Replacement therapy
116
What may need to be given in severe warfarin overdose?
Prothrombin complex concentrate (PCC) - contains Vit K-dependent clotting factors
117
What are Janus Kinases?
Family of 4 tyrosine kinase receptors associated with haemopoietic cell growth factor receptors
Have a kinase domain & a catalytically inactive pseudokinase domain with regulatory function
118
Describe what happens when growth factors bind to Janus Kinase receptors
Binding of growth factors leads to JAK activation, which activates STAT pathway
STAT = transcription factor that moves to nucleus & promotes transcription of genes associated with cell growth & proliferation
119
What is a chronic myeloproliferative disorder?
Group of clonal disorders of haemopoietic stem cells characterised by overproduction of 1/> mature myeloid cellular elements in the blood
Trend towards increased fibrosis in bone marroww
Some cases will develop into acute leukaemia
120
Outline the usual presentation of myeloproliferative disorders
Preponderance to thrombosis
Splenomegaly
Hepatomegaly
121
List some chronic myeloproliferative disorders
```
Polycythaemia vera
Essential thrombocythaemia
Idiopathic myelofibrosis
Idiopathic erythrocytosis
Chronic granulocytic leukaemia
```
122
What are the key differences between:
- Myeloproliferative disorder
- Leukaemia
- Myelodysplastic syndrome
Myeloproliferative disorder
- Proliferation with full differentiation
Leukaemia
- Proliferation with little/no differentiation
Myelodysplastic syndrome
- Abnormal proliferation & abnormal differentiation
123
What is polycythaemia vera?
Myeloproliferative disorder characterised by increased RBC production (independent of normal control mechanisms) with compensatory increase in plasma vol
Often accompanied by a degree of increased platelets & granulocytic cells
124
Describe the clinical presentation of polycythaemia vera
Incidental finding
Symptoms of hyperviscosity (headaches, visual disturbances, fatigue, dyspnoea)
Increased histamine release (aquagenic pruritis, peptic ulceration)
Splenomegaly
Plethora
Erythromelalgia (red, painful extremities)
Thrombosis
Retinal vein engorgement
Gout
125
Outline the typical investigation findings polycythaemia vera including bone marrow biopsy appearance and a diagnostic investigation finding
High Hb, Hct, MCV, plasma vol, & platelets
No circulating immature cells
Bone marrow biopsy:
- Increased cellularity (mainly erythroid cells)
- Slight reticulin fibrosis & megakaryocyte abnormalities
Diagnostic investigation finding:
- Presence of JAK2 V617F mutation
126
What is pseudopolycythaemia?
Reduced plasma vol in presence of normal amount of Hb results in apparently raised Hb
127
On which exon is JAK2 V617F found?
| Which other JAK mutation is a significant finding & which condition is it associated with?
Exon 14
Other:
- Exon 12 mutation
- Associated with idiopathic erythrocytosis - isolated erythrocytosis with low EPO
128
What are some causes of JAK2 V617F -ve polycythaemia?
Pseudopolycythaemia
| True polycythaemia secondary to increased EPO (e.g. hypoxia, renal disease, tumours)
129
Outline the principles of treatment of polycythaemia vera
```
Reduce viscosity & keep Hct <45%
- Venesection
- Cytoreductive therapy
Aim to reduce risk of thrombosis
- Aspirin
- Keep platelets <400x10^9/L (same as essential thrombocythaemia treatment)
```
130
Outline the prognosis of idiopathic erythrocytosis & polycythaemia vera
Idiopathic erythrocytosis - no adverse prognosis if Hct maintained
Polycythaemia vera - most survive 10yrs, causes of death include thrombosis, leukaemia, & myelofibrosis
131
What is essential thrombocythaemia?
| How does it typically present?
Myeloproliferative disorder mainly involving megakaryocyte lineage (platelet count >600x10^9/L)
Typical clinical presentation:
- Incidental finding
- Thrombosis (e.g. stroke, DVT, gangrene)
- Bleeding
- Headaches, dizziness, visual disturbances
132
What proportion of essential thrombocythaemia patients have JAK2 mutations?
50%
133
Outline the treatment options for essential thrombocythaemia?
Aspirin
Anagrelide (specific inhibitor of platelet formation - may accelerate myelofibrosis)
Hydroxycoarbamide - may be leukaemogenic
Alpha-interferon - may be used in patients <40yo
134
What factor is important in determining risk level in essential thrombocythaemia?
Age (> -> higher risk)
| Also platelet count & whether symptomatic or not
135
Describe the prognosis of essential thrombocythaemia
Normal life span
Leukaemic transformation in about 5% after 10yrs
Myelofibrosis uncommon
136
Define chronic idiopathic myelofibrosis
| Describe the typical clinical presentation
Clonal myeloproliferative disease with proliferation mainly of megakaryocytes & granulocytic cells, associated with reactive bone marrow fibrosis & extramedullary haemopoiesis
Typical presentation
- Incidental finding
- Cytopaenias
- Thrombocytosis
- Splenomegaly (can be massive)
- Hepatomegaly
- FLAWS
- Gout
137
Describe the 2 stages of myelofibrosis
```
Pre-fibrotic = mild blood changes with hypercellular marrow
Fibrotic = splenomegaly, blood changes, dry tap, prominent fibrosis, & later osteosclerosis
```
138
Describe the appearance & features of myelofibrosis on blood film
Leukoerythroblastic picture
Tear drop poikilocytes
Dry tap
Trephine biopsy will show increased reticulin or collagen fibrosis, prominent megakaryocyte hyperplasia & new bone formation
139
Outline the treatment options for myelofibrosis
Symptomatic treatment (e.g. transfusions for anaemia)
Splenectomy
Cytoreductive therapy (hydroxycarbamide & thalidomide)
Bone marrow transplant (in younger patients)
140
Describe the prognosis of myelofibrosis
Median 3-5yr survival
141
What effect does JAK2 V617F mutation have on janus kinases?
Inactivates pseudokinase domain thereby removing inhibition of activation so it becomes constitutively activated
142
How can lymphoma cause jaundice?
Direct liver involvement
Compression of the bile duct
Causing AI haemolytic anaemia
143
Which types of anaemia can be caused by cancer?
Fe deficiency (occult blood loss e.g. GI cancers, urinary tract cancers)
Anaemia of chronic disease
Haemolytic anaemia
Leucoerythroblastic anaemia
144
Which types of cancer are associated with causing secondary polycythaemia?
Renal cell carcinoma
Liver cancer
Due to production of EPO
145
What are the typical lab findings of Fe deficiency anaemia?
Low ferritin
Low transferrin saturation
High TIBC
146
What is leucoerythroblastic anaemia
Anaemia characterised by RBC & white cell precursors
147
What are the morphological features of leucoerythroblastic anaemia seen on blood film?
Teardrop RBCs (aniso- & poikilocytosis)
Nucleated RBCs
Immature myeloid cells
148
What does leucoerythroblastic anaemia tend to be caused by?
Bone marrow, infiltration (leukaemia, lymphoma, myeloma, solid tumours, myelofibrosis, miliary TB, severe fungal infection)
149
What are the 2 main groups of haemolytic anaemia? List some e.g.s
Inherited (defects with cell)
- Hereditary spherocytosis (membrane problem)
- G6PD (enzyme problem)
- Sickle cell disease, thalassaemia (Hb problem)
Acquired (defects with environment)
- Immune-mediated
- Non-immune mediated e.g. infection (e.g. malaria), MAHA
150
Which test distinguishes immune-mediated & non-immune mediated haemolytic anaemia?
DAT or Coombs' test
| DAT +ve means haemolytic anaemia mediated through immune destruction of RBCs
151
What morphological change is seen on the blood film of patients with AI haemolytic anaemia?
Spherocytes
152
List some systemic diseases that can cause AI haemolytic anaemia
Cancer involving immune system (e.g. lymphoma)
Diseases of immune system (e.g. SLE)
Infections (disturb immune system)
153
List some key features of MAHA
Usually caused by underlying adenocarcinoma
RBC fragments
Low platelets
DIC/bleeding
154
Outline the mechanism of MAHA
Underlying adenocarcinoma produces procoagulant cytokines that activate clotting cascade
Leads to DIC & formation of fibrin strands in various parts of microvasculature
RBCs pushed through these fibrin strands & fragment
N.B: Always consider underlying adenocarcinoma in any patient presenting with MAHA
155
List some causes of secondary polycythaemia
Cancer (renal, hepatocellular, bronchial)
High altitude
Hypoxic lung disease
Congenital cyanotic heart disease
156
List some causes of neutrophilia
```
Corticosteroids (due to demargination)
Underlying neoplasia
Tissue inflammation (e.g. colitis, pancreatitis)
Myeloproliferative/leukaemia disorder
Infection
```
157
List some infections that typically don't cause neutrophilia
Brucella
Typhoid
Many viral disease
158
List some key features of reactive neutrophilia on blood film
Band cells (immature neutrophils - presence of band cells show bone marrow has been signalled to release more WBCs)
Toxic granulation
Clinical signs of infection/inflammation
159
List some causes of monocytosis
Bacteria: TB, Brucella, typhoid
Viral: CMV, VZV
Sarcoidosis
Chronic myelomonocytic leukaemia
160
List some causes of reactive eosinophilia
Parasitic infection
Allergy (e.g. asthma, rheumatoid arthritis)
Underlying neoplasms (e.g. Hodgkin's lymphoma, T cell lymphoma, NHL)
Drug reaction (e.g. erythema multiforme)
161
Which gene mutation causes chronic eosinophilic leukaemia?
FIP1L1-PDGFRa fusion gene
162
Which type of virus typically causes basophilia?
Pox viruses
163
List some causes of reactive lymphocytosis
```
Infection (EBV, CMV, toxoplasmosis, rubella, HSV)
AI disease (N.B: More likely to cause lymphopaenia)
Sarcoidosis
```
164
How would the lymphocytes seen on blood film due to viral infection be different from leukaemia/lymphoma?
Viral infection: Reactive or atypical lymphocytes (EBV)
| CLL or NHL: Small lymphocytes & smear cells1
165
What is light chain restriction?
Individual B cells will either express kappa or lambda light chains (not both)
In response to infection, will get polyclonal B cell response so will be roughly even mixture of kappa & lambda light chains
In lymphoproliferative disorders, monoclonal proliferation of B cell expressing only 1 type of light chain (e.g. kappa) will mean proportion of kappa to lambda will increase (e.g. showing overwhelming majority of kappa)
166
What are the consequences of thromboembolism?
Death (5% mortality)
Recurrence
Thrombophlebitic syndrome (recurrent pain, swelling, & ulcers)
Pulmonary HTN
167
What are the components of Virchow's triad?
Blood composition (viscosity - Hct, protein/paraprotein)
Vessel wall
Blood flow
168
List some anticoagulant molecules produced by endothelium
```
Thrombomodulin
Endothelial protein C receptor
Tissue factor pathway inhibitor
Heparans
N.B: Doesn't normally produce tissue factor
```
169
What antiplatelet factors are produced by endothelium?
Nitrous oxide
| Prostacyclin
170
Describe the mechanism by which stasis promotes blood flow
Leads to accumulation of activated factors which promotes platelet adhesion & promotes leucocyte adhesion & transmigration
Hypoxia has inflammatory effect on endothelium
171
Which drugs can be used to achieve immediate anticoagulation?
Name an anticoagulant that has a delayed effect
Immediate
- Heparin
- Direct acting anti-Xa & anti-IIa
Delayed
- Warfarin (2-3 days)
172
What is the mechanism of action of heparin?
| What is the antidote for heparin?
Increases anticoagulant activity by potentiating antithrombin III
Antidote: Protamine
173
List some disadvantages of heparin
Administered by injection
Risk of osteoporosis
Variable renal dependence
174
List some anti-Xa DOACs
| Name an anti-IIa DOAC
Anti-Xa
- Rivaroxaban
- Apixaban
- Edoxaban
Anti-IIa
- Dabigatrin
175
List some properties of DOACs
```
Oral administration
Immediate action (peak = 3-4hrs)
Useful in long-term
Short 1/2 life
No monitoring needed
```
176
Outline the mechanism of action of warfarin
Vit K epoxide reductase inhibitor meaning inhibits gamma-carboxylation of FII, VII, IX, X
Also causes reduction in protein C & protein S (initially a bit procoagulant)
177
How is warfarin monitored?
| How can the action of warfarin be reversed?
Monitoring: INR
Administering Vit K - takes 12hrs
Giving FII, VII, IX, X - immediate
178
List some methods of thromboprophylaxis
LMWH (e.g. tinzaparin 4500U, clexane 40mg OD)
TEDS
Flotron (intermittent compression)
Sometimes DOAC with/without aspirin (orthopaedics)
N.B: All hospital admissions should be risk assessed for VTE & receive heparin prophylaxis unless C/I
179
Outline DVT/PE treatment including life-threatening DVT/PE
Start LMWH (e.g. tinzaparin 175U/kg) + warfarin
Stop LMWH when INR >2 for 2 days
Alternative: Start a DOAC
Should be continued for 3-6mths
Life-threatening: Thrombolysis (used sparingly as increases risk of intracranial haemorrhage (4%) although reduces risk of post-phlebitic syndrome)
180
Define myelodysplastic syndrome
Biologically heterogeneous group of acquired haematological stem cell disorders
Development of clone of marrow stem cell with abnormal maturation resulting in functionally defective blood cells & reduction in cell counts
- Leads to cytopaenia, functional abnormalities of cell maturation & increased risk of transformation to leukaemia
181
How do myelodysplastic syndromes typically present?
Symptoms/signs of bone marrow failure developing over wks/mths
182
List & describe some blood & bone marrow features of the following myelodysplastic syndromes
Pelger-Huet anomaly (bilobed neutrophils)
Dysgranulopoiesis of neutrophils (failure of granulation)
Dyserythropoiesis of RBC (lack of separation between RBC precursors, presence of abnormal ring of cytoplasm around nucleus of precursor RBCs)
Dysplastic megakaryocytes (micromegakaryocytes)
Increased proportion of blast cells in bone marrow (normally <5%)
183
What might you see by staining with Perl's stain the bone marrow in myelodysplastic syndrome?
Ringed sideroblasts (accumulation of Fe around the nuclei or RBC precursors)
184
What is the presence of myeloblasts with large crystalline cytoplasmic inclusions suggestive of?
Acute myeloid leukaemia
| The crystalline structures are Auer rods
185
What are the 5 prognostic variables used to calculate prognostic risk using the Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes?
```
Bone marrow blast %
Karyotype
Hb
Platelets
Neutrophils
N.B: High risk considered >6, low risk <= 1.5
```
186
What are the usual causes of death in patients with myelodysplasia?
1/3 infection
1/3 bleeding
1/3 leukaemia
187
What are the 2 treatments that can prolong life in myelodysplastic syndromes?
What other treatments may be used?
Allogeneic stem cell transplantation
Intensive chemotherapy
N.B: As most MDS patients elderly, often cannot tolerate treatment
```
Others:
Supportive care (blood products, antimicrobials, growth factors (e.g. EPO, GM-CSF))
Biological modifiers
- Immunosuppression
- Azacytidine (hypomethylating agent)
- Decitabine
- Lenalidomide (used in 5q minus syndrome)
Oral chemo (e.g. hydroxyurea)
Low-dose chemo (SC low-dose cytarabine)
```
188
List some causes of primary bone marrow failure
Fanconi anaemia (multipotent stem cell)
Diamond-Blackfan syndrome (RBC progenitor)
Kostmann syndrome (neutrophil progenitor)
Acquired: Idiopathic aplastic anaemia (multipotent stem cell)
189
List some secondary causes of bone marrow failure
```
Marrow infiltration
Haematological malignancies
Solid tumours spreading to bone marrow
Radiation
Drugs
Chemicals (e.g. benzene)
AI
Infection (e.g. parvovirus B19)
```
190
List some inherited causes of aplastic anaemia, including the most common inherited cause
What is the most common cause overall?
Fanconi anaemia (most common inherited)
Schwachman-Diamond syndrome
Dyskeratosis congenita
Most common cause: idiopathic (70-80%)
191
What are some investigative features of aplastic anaemia?
Peripheral blood - cytopaenia
| Bone marrow - hypocellular
192
List some differential diagnoses for pancytopaenia & hypocellular bone marrow
```
Hypoplastic MDS/AML
Hypocellular AML
Hairy cell leukaemia
Atypical mycobacterial infection
Anorexia nervosa
ITP (although Hb & RBC will be normal)
```
193
What is the Camitta criteria for severe aplastic anaemia?
2 out of 3 peripheral blood features:
- Reticulocytes <1% (<20x10^9/L)
- Neutrophils <0.5x10^9/L
- Platelets <20x10^9/L
Bone marrow cellularity <25%
194
Outline the management approaches used for bone marrow failure
How does age influence management decisions?
Seek & remove cause
Supportive (blood products, abx, Fe chelators)
Immunosuppressive therapy (antithymocyte 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
Immunosuppressive therapies tend to be used for older patients
Stem cell transplantation tends to be used in younger patients (80% cure rate)
195
List some complications that occur after immunosuppressive therapy for aplastic anaemia
Relapse (35% in 15yrs)
Clonal haematological disorders - 20% risk in 10yrs (myelodysplasia, leukaemia, paroxysmal nocturnal haemoglobinuria)
Solid tumours (3% risk)
196
What is the inheritance pattern of Fanconi anaemia?
Autosomal recessive or X-linked recessive
197
List some somatic abnormalities seen in Fanconi anaemia
What proportion of patients would be expected to have these abnormalities?
```
Short stature
Hypopigmented spots/cafe -au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hypogonadism
Developmental delay
```
Only present in 70% patients
198
List some complications of Fanconi anaemia
```
Aplastic anaemia (90%)
Myelodyspolasia
Leukaemia
Cancer (epithelial)
Liver disease
```
199
What are the characteristic features of dyskeratosis congenita?
Bone marrow failure
Cancer predisposition
Somatic abnormalities
200
What are the 3 main somatic features of dyskeratosis congenita?
Abnormal skin pigmentation
Nail dystrophy
Leucoplakia
201
Which genes are involved in dyskeratosis congenita & what are the inheritance patterns?
X-linked recessive (most common) - DKC1 gene
Autosomal dominant - TERC
Autosomal recessive - no mutation identified
N.B: Abnormal telomeric structure & function heavily implicated in dyskeratosis congenita
202
What are the different prevalences of Hodgkin's lymphoma & Non-Hodgkin lymphoma?
```
NHL = 80%
Hodgkin = 20%
```
203
Outline the processes by which immunoglobulins & T cell receptors become capable of identifying a wide variety of Ags
Germline VDJ genes undergo recombination in bone marrow to generate wide repertoire of specificities
In germinal centres, 2nd stage of DNA alteration involving isotype switching & somatic hypermutation (point mutations) generates even more diversity
204
What is main downside of the processes that generate variety in immunoglobulins & T cell receptors?
Recombination errors & new point mutations can occur
Lymphocytes are reliant on apoptosis to keep their massive proliferation under control (90% lymphocytes die in germinal centres)
If mutation turns off apoptosis, can lead to malignancy or AI
205
List some oncogenes implicated in lymphoma/leukaemia
Bcl2
Bcl6
Cyclin D1
c-Myc
206
List some e.g.s of how constant antigenic stimulation can lead to lymphoma
H. pylori -> gastric MALT marginal zone NHL of stomach
Sjogren syndrome -> marginal zone NHL of parotid
Coeliac disease -> small bowel T cell lymphoma, enteropathy-associated T cell non-Hodgkin's lymphoma
207
List 2 e.g.s 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)
- Caused by viral genome integrating into T cell genome & driving proliferation
EBV infection & immunosuppression
- EBV established latent infection in B cells which kept in check by cytotoxic T cell (kill EBV Ag-expressing B cells)
- Loss of T cell function (e.g. HIV, post-transplant immunosuppression) can lead to EBV-driven lymphoma
208
What are the main markers used for B & T cells?
T cell:
- CD3
- CD5
B cell:
- CD20
209
Why is non-Hodgkin lymphoma often disseminated at presentation?
Neoplastic lymphoid cells circulate in blood leading to disseminated disease at presentation
N.B: Lymphoid neoplasms can disrupt normal immune functioning leading to immunodeficiencies
210
Give an e.g. of chromosomal translocation diagnostic of lymphoma
11;14 = Mantle cell lymphoma
211
Give an e.g. of chromosomal translocation that is prognostic in lymphoma
2;5 = anaplastic large cell lymphoma
212
List some types of low-grade lymphoma
Name a type of intermediate-grade lymphoma
Name a type of high-grade lymphoma
Low-grade
- Follicular lymphoma
- Small lymphocytic lymphoma (CLL)
- Marginal zone lymphoma
- Mantle cell lymphoma
Intermediate-grade
- Burkitt's lymphoma
High-grade
- Diffuse large B cell lymphoma
213
How does follicular lymphoma typically present?
Lymphadenopathy in middle-aged or elderly patients
| N.B: Usually indolent but can transform into high-grade lymphoma
