Haem Flashcards
1
Q
Which protein is deficient in haemophilia A?
A
Factor VIII deficiency
2
Q
Which protein deficiency leads to pro-thrombotic disease?
A
Protein C deficiency
3
Q
What blood disorders result due to the excess in the following:
a) erythrocytes,
b) granulocytes,
c) lymphocytes,
d) platelets?
A
a) polycythaemia
b) leukaemia (CML) or reactive eosinophilia
c) leukaemia (CLL)
d) essential thrombocythemia
4
Q
What blood disorders result due to deficiency in the following:
a) erythrocyte,
b) lymphocyte,
c) platelets?
A
a) anaemia
b) lymphopenia (HIV)
c) idiopathic thrombocytopenic purpura (ITP)
5
Q
Causes of high neutrophils
A
Corticosteroids (due to demargination) Underlying neoplasia Tissue inflammation Myeloproliferative/leukaemia disorder Pyogenic infection
6
Q
Causes of reactive eosinophilia
A
Parasitic infection Allergic diseases (asthma, RA) Underlying neoplasms (Hodgkin's, T cell lymphoma) Drug reaction (erythema multiforme)
7
Q
Mutations in what lead to the following:
a) increase cellular proliferation,
b) impair/block cellular differentiation,
c) prolong cell survival (anti-apoptosis)?
A
a) tyrosine kinase signal-inducing genes
b) nuclear transcription factors (e.g. retinoic acid receptor alpha)
c) apoptosis genes, leads to lymphomas
8
Q
Many spicules seen on blood film
What is observed and what may be causing this?
A
Acanthocytes (spur/spike cells)
Liver disease, hypersplenism, abetalipoproteinemia
9
Q
Small dot on the peripheries of RBC seen
What is observed and what may be causing this?
A
Basophilic RBC stippling; accelerated erythropoiesis/defective Hb synthesis
Lead poisoning, megaloblastic
anaemia, myelodysplasia, liver
disease, haemoglobinopathy e.g.
thalassaemia
10
Q
Cell looks like sea urchin with regular spicules
What is observed and what may be causing this?
A
Burr cells (echinocyte)
Often artefact cell if blood sat in EDTA prior to film being made
Uraemia, GI bleed, stomach carcinoma
11
Q
Inclusions on very edge of RBCs due to denatured Hb
What is observed and what may be causing this?
A
Heinz bodies
Glucose-6-phosphate dehydrogenase deficiency, chronic liver disease
12
Q
Basophilic (purple spot) nuclear remnants in RBCs
What is observed and what may be causing this?
A
Howell-Jolly bodies; note much bigger purple spots in nucleated RBCs
Post-splenectomy or hyposplenism (e.g. sickle cell disease, coeliac disease, congenital, UC/Crohn's, myeloproliferative disease, amyloid) Megaloblastic anaemia, hereditary spherocytosis
13
Q
Hyposegmented neutrophil with 2 lobes like a dumbell
What is observed and what may be causing this?
A
Pelger Huet Cells
Congenital (lamin B Receptor mutation) Acquired (myelogenous leukaemia and myelodysplastic syndromes [pseudo-pelger in MDS])
14
Q
Red cells stacked on each other
What is observed and what may be causing this?
A
Rouleaux formation
Chronic inflammation, paraproteinaemia, myeloma
15
Q
Fragmented parts of RBCs, irregularly shaped with sharp edges and no central pallor
What is observed and what may be causing this?
A
Schistocytes
Microangiopathic anaemia, e.g.
DIC, haemolytic uraemic syndrome,
thrombotic thrombocytopenic
purpura, pre-eclampsia
16
Q
Smaller, sphere shaped RBC
What is observed and what may be causing this?
A
Spherocytes
Hereditary spherocytosis,
Autoimmune Haemolytic Anaemia
17
Q
Central pallor straight/curved rod-like shape, RBCs look like ‘smiling faces’ or ‘fish mouths’
What is observed and what may be causing this?
A
Stomatocytes
Artefacts during slide preparations
Hereditary stomatocytosis, high alcohol intake, liver disease
18
Q
Bull’s eye appearance in central pallor of RBC
What is observed and what may be causing this?
A
Target cells (codocyte)
Liver disease, hyposlepnism, thalassamia, IDA
19
Q
Hb in anaemia
A
Men
<135 g/L / 13.5 g/dL
Women
<115 g/L / 11/5 g/dL
20
Q
Signs and sx in anaemia
A
Sx
- fatigue, dyspnoea, faint, palpitations, headache, tinnitus, anorexia
Signs
- pallor, tachycardia
21
Q
Causes of microcytic anaemia
A
Iron deficiency
Anaemia of chronic disease
Sideroblastic
Thalassaemia
22
Q
Causes of normocytic anaemia
A
Acute blood loss Anaemia of chronic disease Bone marrow failure Renal failure Hypothyroidism Haemolysis Pregnancy
23
Q
Causes of iron deficiency anaemia
A
Blood loss
- GI loss, colon cancer, peptic ulcers, menorrhagia
Increased use
- pregnancy, growing children
Decreased intake
- veggies/vegans, elderly suboptimal diet
Decreased absorption
- coeliac, post-gastro surgery
Intravascular haemolysis
- microangiopathic, haemolytic anaemia, PNH
24
Q
Mx plan if no clear cause for iron deficiency anaemia?
A
OGD + colonoscopy, urine dip, coeliac investigations
25
Mechanism of anaemia of chronic disease
Ferritin increases in inflammatory state, holds in iron
Additionally inflammatory markers reduce EPO receptor production thus EPO synthesis
Also inflammatory markers stimulate hepcidin production, decreasing iron absorption from the gut + increasing iron accumulation in macrophages
26
What is sideroblastic anaemia?
Result of ineffective erythropoiesis
- iron loading in bone marrow causing iron deposition to endocrine, liver, and cardiac systems
Ring sideroblasts seen in marrow (iron deposited in mitochondria in ring around nucleus)
Caused by myelodysplastic/myeloproliferative disorders, following chemo, irradiation, alcohol excess, lead excess, anti-TB drugs
27
How do you treat sideroblastic anaemia?
Remove cause
| Pyridoxine (vitamin B6 promotes RBC production)
28
Which plasma iron study is more useful if the pt is in an inflammatory state?
Transferrin saturations > ferritin
Ferritin is an acute phase protein that increases with inflammation so check CRP with every ferritin to confirm accuracy
29
What would the plasma iron studies be for the following:
a) iron deficiency,
b) anaemia of chronic disease,
c) chronic haemolysis,
d) haemochromatosis,
e) pregnancy,
f) sideroblastic anaemia?
Order: Iron // TIBC // Ferritin
a) low // high // low
b) low // low // high
c) high // low // high
d) high // low-normal // high
e) high // high // normal
f) high // normal // high
30
What investigations should you do in the case of pancytopenia?
B12/folate/iron
Abdominal exam to assess spleen
- ?myelofibrosis
Reticulocyte count
- ?aplastic anaemia
Blood film
- ?leukaemia
- ?myelodysplasia
Myeloma screen
Parovirus blood PCR
- immunocompromised pts
Review medications
Bone marrow biopsy if no clear cause indicated
31
Megaloblastic causes of macrocytic anaemia
B12 deficiency
Folate deficiency
Cytotoxic drugs
32
Non-megaloblastic causes of macrocytic anaemia
```
Alcohol (seen without anaemia also)
Reticulocytosis (in haemolysis)
Liver disease
Hypothyroidism
Pregnancy
```
33
Other causes of macrocytosis of RBCs
Myelodysplasia
Myeloma
Myeloproliferative disorders
Aplastic anaemia
34
What would you see on a megaloblastic blood film?
```
Hypersegmented polymorphs
Leucopenia
Macrocytosis
Anaemia
Thrombocytopenia with megalobalsts
```
35
Clinical features of B12 deficiency
Glossitis, angular cheilosis
Irritable, depression, psychosis, dementia
Paraesthesia, peripheral neuropathy (loss of vibration and proprioception first, absent ankle reflex, spastic paraperesis, subacute combined degeneration of spinal cord)
36
What is pernicious anaemia?
Autoimmune atrophic gastritis
- achlorhydria, lack of gastric intrinsic factor
Testing
- parietal cell antibodies (90%)
- intrinsic factor antibodies (50%)
Treat
- replenish stores with IM hydroxocobalamin (B12)
37
Causes of B12/folate deficiencies
Poor diet
- vegan
Malabsorption
- post gastrectomy, coeliac disease, tropical sprue, crohn's
- pernicious anaemia (B12)
Drugs (folate)
- alcohol, anti-epileptics (phenytoin), methotrexate, trimethoprim
38
What is the normal life span of a RBC?
120 days
39
What changes do you see in all haemolytic anaemias?
```
Increased unconjugated bilirubin
Increased urobilinogen
Increased LDH
Reticulocytosis (increased MCV and polychromasia)
May have pigmented gallstones
```
40
What changes do you see in intravascular haemolytic anaemia?
Increased free plasma Hb
Decreased haptoglobin (binds free Hb)
Haemoglobinuria (dark red piss)
Methaemalbuminaemia (haem + albumin in blood)
41
What changes do you see in extravascular haemolytic anaemia?
Splenomegaly
42
What do you expect to happen to the reticulocyte count in haemolytic anaemia?
Increased/high
If pt acutely anaemia, you would expect bone marrow to respond thus pump out reticulocytes to make up for the lost RBCs
43
What complications are associated with an erythroid hyperplasic state?
Susceptible to parvovirus B19 (aplastic crisis)
Risk of iron overload
Risk of osteoporosis
44
When would you see a low reticulocyte count in a haemolytic anaemia pt?
Parvovirus B19 infection
- virus infects developing erythroid progenitor cells in bone marrow
- production of RBCs switched off
- low reticulocyte count
- results in aplastic crisis in pts with shortened RBC survival
45
Name causes of inherited haemolytic anaemias
Membrane defect
- hereditary spherocytosis
- hereditary elliptocytosis
Enzyme defect
- G6PD deficiency
- pyruvate kinase deficiency
Haemoglobinopathies
- sickle cell disease
- thalassaemias
46
Name causes of acquired haemolytic anaemias
Immune
- autoimmune (warm or cold)
- alloimmune (haemolytic transfusion reactions)
Non-immune
- mechanical (e.g. metal valves, trauma)
- paroxysmal nocturnal haemoglobinuria
- microangiopathic haemolytic anaemia (e.g. HUS, TTP)
- infections (i.e. malaria), drugs
47
Name an inherited haemolytic anaemia due to a membrane defect that leads to malaria protection
South East Asian Ovalocytosis
- autosomal recessive incompatible with life
- heterozygotes typically asx and malaria protection
48
Mutations in which membrane proteins lead to:
a) hereditary spherocytosis
b) hereditary elliptocytosis
a) autosomal dominant, spectrin or ankyrin deficiency
| b) autosomal dominant, spectrin mutation
49
Which hereditary elliptocytosis is autosomal recessive?
Hereditary pyropoikilocytosis
| - abnormally sensitive to heat
50
How is hereditary spherocytosis diagnosed?
Spherocytes seen on blood film
Lysis in hypotonic solutions (increased osmotic fragility)
-ve DAT Coombs
Flow cytometry (dye binding test)
51
Tx for hereditary spherocytosis
Splenectomy
| Folic acid
52
What are pts with hereditary spherocytosis at increased risk of?
Parvovirus B19 -> aplastic crisis
Gallstones due to increased unconjugated bilirubin
Sepsis if had splenectomy
53
What dye is used in flow cytometry to diagnose hereditary spheroctysois?
Eosin-5-malemide
| - reduced binding to surface of RBCs in those with h spherocytosis compared to unaffected person
54
Blood film in hereditary spherocytosis
No central pallor
Microcytic
Densely stained (hyperchromic)
Polychromasia
55
Blood film of G6PD deficiency during acute haemolysis
Contracted cells
Nucleated red cells
Bite cells (evidence a Heinz body has been formed and removed by spleen)
Hemighosts (Hb retracted to one side of cell)
*in steady state, blood film is normal
56
How is G6PD deficiency acquired?
X-linked leading to RBC enzyme defect
- hemizygous males
- homozygous females
57
Clinical features of G6PD deficiency
Neonatal jaundice (can lead to kernicterus)
Acute haemolysis
Chronic haemolytic anaemia
58
What type of haemolytic anaemia do you see in G6PD deficiency?
Intravascular haemolysis (dark urine)
59
Name triggers of acute haemolysis in those with G6PD deficiency
```
Oxidant drugs
- antimalarials, antibiotics, dapsone, vitamin K
Infections
Fava beans (ingestion/inhalation both)
Naphthalene mothballs (potent oxidant)
```
60
When is it anaemia during pregnancy?
Hb < 110 g/l 1st trimester
Hb < 105 g/l 2nd and 3rd trimester
Hb < 100 g/l postpartum
61
What haem factors are increased in pregnancy?
```
Plasma volume
Red cell mass
MCV
WCC
Factors VII, VIII, IX, X, XII
```
62
What haem factors are decreased in pregnancy?
```
Hb
Haematocrit
Platelets
Factor XI
Protein S
```
63
What is HELLP syndrome?
Haemolysis, elevated liver enzyes, low platelets
- life-threatening complication of pre-eclampsia
- type of MAHA (increased AST, ALT, low plts, normal APTT, PT)
Mx: supportive, delivery of fetus
64
What is haemolytic disease of the newborn (HDN)?
When maternal Ab level is high that it destroys fetal red cells if they have corresponding red cell Ag, it leads to fetal anaemia and jaundice (HDN)
65
Which Ig can cross the placenta?
IgG
66
How do we prevent haemolytic disease of the newborn?
Anti-D prophylaxis for RhD -ve women
- routine: 28 and 34 weeks
- sensitising event occurs: abortion, miscarriage, abdo trauma, ECV, amniocentesis
- delivery: if baby is RhD +ve
67
When do you see Heinz bodies?
Formed from denatured Hb due to oxidative haemeolysis
Seen transiently because cells containing Heinz bodies are quickly removed by the spleen
68
G6PD tx
```
Avoid precipitants
Transfuse if severe
Genetic screening (rare subtypes give chronic haemolysis for which splenectomy is good treatment)
```
69
How may pyruvate kinase deficiency present?
Severe neonatal jaundice
Splenomegaly
Haemolytic anaemia
70
What is PKD?
Pyruvate kinase deficiency
- autosomal recessive
- most common defect in the glycolytic pathway
71
Which mutation leads to sickle cell disease?
Autosomal recessive
Single base mutation: GAG -> GTG / Glu -> Val
Codon 6 of beta chain leads to HbS instead of HbA
72
What type of sickle cell disease are the following?
a) HbSS
b) HbAS
c) HbSC
d) HbS/B
HbSS - severe, sickle cell anaemia
HbAS - sickle cell trait, asx except under stress
HbSC - sickle-Hb C disease, one inherited from each parent
HbS/B - sickle beta thalassaemia, one inherited from each parent
73
When does sickle cell disease manifest?
3-6 months when fetal HbF decreases
74
What features of sickling may you see in sickle cell disease?
Vaso-occlusion + infarction
- stroke
- infections (hyposplenism, CKD)
- crises (splenic, sequestration, chest and pain)
- kidney (papillary necrosis, nephrotic)
- liver (gallstones)
- eyes (retinopathy)
- dactylitis (impaired growth)
- mesenteric ischaemia
- priapism
75
Clinical features of haemolytic anaemia
```
Pallor
Jaundice
Splenomegaly
Pigmenturia (dark urine)
FHx
```
76
Laboratory findings of haemolytic anaemia
```
Anaemia
Increased reticulocytes
Polychromasia
Hyperbilirubinaemia
Increased plasma LDH (intravascular haemolysis)
Reduced/absent haptoglobins (intravascular haemolysis)
Haemoglobinuria
Haemosiderinuria
```
77
What features of sickle cell disease would you expect to see in a child?
Strokes
Splenomegaly + splenic crises
Dactylitis
78
What features of sickle cell disease would you expect to see in a teenager?
Impaired growth
Gallstones
Psych issues
Priapism
79
What features of sickle cell disease would you expect to see in an adult?
Hyposplenism
CKD
Retinopathy
Pulmonary hypertension
80
Diagnosis of sickle cell disease
Blood film
- sickle cell, target cells
Sickle solubility test
Hb electrophoresis
Guthrie test (birth)
81
Tx of acute sickle cell disease
```
Opioid analgesia
Blood transfusion (exchange transfusion)
```
82
Tx of chronic sickle cell disease
Pencillin V, pneumovax, HIB vaccine
Folic acid
Hydroxycarbamide
Regular exchange transfusions
Carotid doppler in early childhood to detect turbulent flow
Crizanlizumab (new drug being trialled)
Allogeneic stem cell transplant (other countries do this)
83
What mutation leads to beta thalassaemia?
Point mutations leading to decreased B-chain synthesis (spectrum of disease) and excess alpha-chains
84
What phenotypes of beta thalassaemia are there?
B0 - no expression of gene
B+ - some expression of gene
B - normal gene
B-thalassaemia minor (B+/B+ or B0/B+)
B-thalassaemia intermediate (B+/B or B0/B)
B-thalassaemia major (B0/B0)
85
How does B-thalassaemia minor present?
Asx carrier
| Mild anaemia
86
How does B-thalassaemia intermediate present?
Moderate anaemia
Splenomegaly
Bony deformity
Gallstones
87
How does B-thalassaemia major present?
```
3-6 months severe anaemia
Failure to thrive
Hepatosplenomegaly (extramedullary erythropoiesis)
Bony deformity
Severe anaemia + heart failure
```
88
Diagnosis of beta thalassaemia
Guthrie test at birth -> Hb electrophoresis
89
Tx for beta thalassaemia
Major form
- blood transfusions with iron chelation to stop iron overload
- folic acid
90
What mutation leads to alpha-thalassaemia?
Deletions leading to reduce alpha-chain synthesis and excess beta-chains
4 alpha genes
91
What types of alpha-thalassaemia are there?
a-thalassaemia trait (1/2 genes deleted)
- asx, mild anaemia
```
HbH disease (3 genes deleted)
- moderate anaemia, splenomegaly
```
```
Hydrops foetalis (4 deleted)
- incompatible with lie
```
92
Name autoimmune (Coombs +ve) causes of acquired haemolytic anaemias
Warm (WAIHA)
- idiopathic
- lymphoma, CLL, SLE, methyldopa
Cold agglutinin disease
- idiopathic
- lymphoma, infections (EBV, mycoplasma)
Paroxysmal cold haemoglobinuria
- viral infection (measles, syphilis, VZV)
93
Features of warm autoimmune haemolytic anaemia
+ve Coombs test
37oC
IgG-mediated
Spherocytes
94
Features of cold agglutinin disease
+ve Coombs test
< 37oC
IgM-mediated
Often with Raynaud's
95
Tx for warm autoimmune haemolytic anaemia
Steroids
Splenectomy
Immunosuppression
96
Tx for cold agglutinin disease
Treat underlying condition
Avoid the cold
Chemotherapy if lymphoma
97
Why is paroxysmal cold haemoglobinuria self-limiting?
Donath-Landsteiner antibodies stick to RBCs in cold, resulting in complement-mediated haemolysis in rewarming
IgG-mediated and these dissociate at higher temperatures than IgM thus self-limiting
98
Name nonimmune (Coombs -ve) causes of acquired haemolytic anaemias
Paroxysmal nocturnal haemoglobinuria
Microangiopathic haemolytic anaemia (MAHA)
- HUS, TTP, DIC, pre-eclampsia, eclampsia
99
What causes paroxysmal nocturnal haemoglobinuria?
Acquired loss of protective surface GPI markers on RBCs
Leads to complement-mediated lysis and chronic intravascular haemolysis, especially at night
100
Features of paroxysmal nocturnal haemoglobinuria
Morning haemoglobinuria
Thrombosis
- Budd-Chiari syndrome
101
Diagnosis of paroxysmal nocturnal haemoglobinuria
Immunophenotype shows altered GPI
Ham's test (in vitro acid-induced lysis)
102
Tx of paroxysmal nocturnal haemoglobinuria
Iron/folate supplements
Prophylactic vaccines/abx
Eculizumab (spenny) prevents complement from binding RBCs
103
What is MAHA?
Mechanical RBC destruction due to forced RBCs through fibrin/platelet mesh in damaged vessels
104
What would you see in a blood film for MAHA?
Schistocytes
105
What is TTP?
Thrombotic thrombocytopenic purpura
- haematological emergency requiring emergency plasma exchange
- type of MAHA
106
What sx do you see in TTP?
Pentad
1. MAHA
2. Fever
3. Renal impairment (less pronounced than HUS)
4. Neuro abnormalities
5. Thrombocytopenia
107
What causes TTP?
Antibodies against ADAMTS13 lead to long strands of VWF
These act like cheese wire in blood vessels and cut up RBCs -> MAHA
108
What is HUS?
Haemolytic uraemic syndrome
- E. coli toxin damages endothelial cells -> fibrin mesh -> damages RBCs
- often seen in children & elderly
109
What sx do you see in HUS?
MAHA
Diarrhoea
Renal failure
No neuro problems
110
What responses do vessel injury stimulate?
1. Blood vessel vasoconstriction
2. Platelet activation
3. Activation of coagulation cascade
111
Life span of a platelet
7-10 days
112
How can platelets adhere to exposed sub-endothelial structures?
Direct via Glp-Ia that binds to collagen in exposed wall
Indirectly via Glp-Ib that binds to vWF in exposed wall (most common and important one)
113
How do platelets attach to each other?
Via GlIb/IIIa (fibrinogen receptor)
114
What do platelets release when they bind to exposed wall?
Release ADP and thromboxane A2 which promote platelet aggregation
115
Effects of thrombin
Activates fibrinogen
Activates platelets
Activates procofactors (5, 8)
Activate zymogens (7, 11, 13)
116
Describe the intrinsic pathway
```
Factors all converted into a version which sets off next factor:
12
11
9 (8 co factor)
10 (common pathway, 5 co factor)
```
This usually happens in vitro during clotting studies
117
Describe the extrinsic pathway
Tissue factor activation results in
7
10 (common pathway, 5 co factor)
More important pathway in body that sets off coagulation cascade
118
Describe the common pathway
10 (5 co-factor)
Prothrombin -> thrombin
Fibrinogen -> fibrin
Stable fibrin clot made
119
What does APTT measure?
Activated partial thromboplastin time
- intrinsic pathway
- monitor heparin therapy
120
What does PT measure?
Prothrombin time
- extrinsic pathway
- monitor warfarin therapy (INR)
121
Which coagulation factors are vit K-dependent?
2, 7, 9, 10
Protein C
Protein S
122
How does the body breakdown fibrin clots?
Tissue plasminogen activator (tPA) converts plasminogen to plasmin
Plasmin breaks down fibrin into degradation products
123
What is an important inhibitor of fibrin breakdown?
Thrombin-activatable fibrinolysis inhibitor (TAFI)
124
Role of protein C and S
Inactivate factors 5 and 8 to stop thrombin generation
125
Classifications of aplastic anaemia
IDIOPATHIC: Vast majority (70-80%)
INHERITED (rare):
- Dyskeratosis congenita (DC)
- Fanconi anaemia (FA)
- Shwachman-Diamond syndrome
SECONDARY:
- Radiation: Predictable
- Drugs: Predictable: (cytotoxic agents)
- Idiosyncratic: chloramphenicol, NSAIDS
- Viruses (idiosyncratic): Hepatitis viruses
- Immune: SLE
126
What is aplastic anaemia linked with?
Leukaemia
| Paroxysmal nocturnal haemoglobinuria
127
Inherited pancytopenia conditions
Fanconi Anaemia (FA)
Dyskeratosis congenita (DC)
Shwachman-Diamond Syndrome (SDS)
Familial aplastic anaemia (autosomal and X-linked forms)
Myelodysplasia
Non-haematological syndromes (Down’s, Dubowitz’s)
128
Clinical Presentation of Bone Marrow Failure
Triad of Bone Marrow Failure Findings
1. Anaemia: fatigue, breathlessness
2. Leukopenia: infections
3. Thrombocytopaenia: bleeding/bruising
129
DDx of pancytopenia and hypocellular marrow
```
Hypoplastic MDS/AML
Hypocellular ALL
Hairy cell leukaemia
Mycobacterial (usually atypical) infection
Anorexia nervosa
Idiopathic thrombocytopenic purpura
```
130
Mx of aplastic anaemia
```
Supportive
- transfusions, abx, iron chelation
Drugs
- promote recovery: growth factors and oxymethalone (androgen)
Immunsuppresants
- idiopathic AA
Stem cell transplant
```
131
Features of Fanconi Anaemia
```
Autosomal recessive
Pancytopenia
Presents 5-10 yrs
Skeletal abnormalities, renal malformations, microophathalmia, short stature, skin pigmentation
Myelodysplastic syndrome (30%)
AML risk (10% progress)
```
132
Features of Dyskeratosis Congenita
X-linked, chromosome instability due to telomere shortening
Skin pigmentation, nail dystrophy, oral leukoplakia
BM failure
133
Features of Schwachman-Diamond syndrome
Autosomal recessive
Primarily neutrophilia
Skeletal abnormalities, endocrine and pancreatic dysfunction, hepatic impairment, short stature
AML risk
134
Features of Diamond-Blackfan syndrome
Pure red-cell aplasia: normal WCC and platelets
Presents at 1 yr/neonatal
Dysmorphology
135
Inherited single cytopaenia conditions
```
Diamond-Blackfan syndrome
Kostmann’s syndrome
Shwachman-Diamond Syndrome (SDS)
Reticular dysgenesis
Amegakaryocytic thrombocytopenia with absent radii (TAR)
```
136
Clinical features of multiple myeloma
CRAB
Calcium high
- groans, moans, stones, bones
Renal failure
- amyloidosis, necrotic syndrome
Anaemia
- pancytopenia
Bones
- pain, osteoprosis, osteolytic lesions, freactures
+ Hyperviscosity syndrome
137
Describe what multiple myeloma is
Neoplasia of plasma cells (effector B cell antibodies) of bone marrow
Leads to production of monoclonal immunoglobulin - the paraprotein - namely IgG
138
Bence Jones proteins
Dx?
Multiple myeloma
- present in urine
- monoclonal globulin protein/immunoglobulin light chain
139
Ix findings for multiple myeloma
Dense narrow band on serum electrophoresis
Rouleaux on blood film (RBC stacking)
CRAB sx
Bence Jones protein in urine
ESR elevated
>10% plasma cells in bone marrow
140
Staging system for multiple myeloma
Durie-Salmon staging system
141
Emergency presentations of multiple myeloma patients
Cord compression
Hypercalcaemia
Renal failure
142
Tx for multiple myeloma
Treat CRAB sx (i.e. bisphosphonates)
Induce remission of autologous stem cell transplant to prolong remission as NOT CURABLE (5-7 yr survival) using:
- immunomodulatory drugs
- steroids
143
Timeline of disease to multiple myeloma
Monoclonal gammopathy of uncertain significance (MGUS)
- <30g/l M-spike
- < 10% clonal plasma cells
Smouldering myeloma
- >30g/l M-spike
- > 10% clonal plasma cells
Multiple myeloma
- loads plasma cells and M-spike + CRAB sx + organ damage
- remitting-relapsing
144
How may systemic amyloidosis present?
```
Macroglossia
Carpal tunnel syndrome
Peripheral neuropathy
Heart failure
Renal failure
```
145
What is Waldenstrom's macroglobinaemia?
Lymphoplasmacytoid lymphoma (LPL)
- non-Hodgkin's lymphoma that produces monoclonal serum IgM infiltrating lymph nodes and bone marrow
- systemic sx, hyperviscosity syndrome
146
Which +ve expressions do you get for myeloma cells?
CD138
CD38
Monotypic cytoplasmic immunoglobulin
Light chain restriction
147
Characteristics of myelodysplastic syndromes
Peripheral cytopenia
Qualitative abnormalities of cell maturation
Risk of AML transformation
Seen in the elderly and develops over weeks/months
BY DEFINITION PTS HAVE < 20% BLASTS
148
Clinical features of myelodysplastic syndromes
BM failure and cytopenias
- infection, bleeding, fatigue
Hypercellular BM
Defective cells
149
What could be seen in a blood film of a pt with myelodysplastic syndrome?
RBC
- ring sideroblasts
WBC
- hypogranulation
- Pseudo-Pelger-huet anomaly (hyposegmented neutro)
Platelets
- micromegakaryocytes
- hypolobated nuclei
150
Tx for myelodysplastic syndrome
Supportive
- transfusions, EPO, G-CSF, abx
Biological modifiers
- immunosuppressive drugs, lenalidomide, azacytidine
Chemotherapy
- similar to AML
Allogeneic SCT
151
Prognosis of myelodysplastic syndroe
Depends on International Prognostic Scoring System
- BM blast %
- Karyotype
- Degree of cytopenia
Mortality rule of 1/3
- 1/3 die from infection
- 1/3 bleeding
- 1/3 acute leukaemia
152
Define lymphoma
Tumour of lymphoid cells
153
Define myeloma
Tumour of plasma cells
154
Name the different leukaemias
Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)
155
Main clinical feature of leukaemia
Bone marrow function failure
- anaemia
- thrombocytopenia = bleeding
- neutropenia = infection
156
AML subtype M3 is prone to
*Acute promyelocytic leukaemia
DIC
Haemorrhage
157
AML subtype M4 & 5 are prone to
Monoblasts/monocytes infiltrating skin & gums
| Hypokalaemia
158
Which flow cytometry markers are useful for ALL?
CD34 = precursor/stem cells
CD3, 4, 8 = T lymphocytes
CD19, 23 = B lymphocytes
159
Which flow cytometry markers are useful for AML?
CD34 = precursor/stem cells
| CD33, 13, MPO = myeloid cells
160
Compare blood films in ALL vs AML
ALL
- high WCC (blasts)
- often tails/blebs of cytoplasm tails
AML
- High WCC (blasts)
- AUER RODS
161
Targeted tx in ALL
T-lymphocytes
- nelarabine
- CAR-T cells
B-lymphocytes
- blinatumumab
- imatinib (9;22 translocation)
162
Targeted rx in AML
ATRA
- acute promyelocytic leukaemia
Midostaurin
- FLT3 mutation
Gemtuzumab
- CD33 immunotherapy
Enasidenib
- IDH mutations
163
How CML is commonly diagnosed
Incidental finding on routine bloods
- large number of differentiated cells
OR
Present with malaise, wt loss, infections & bruising
164
Tx for CML
Imatinib (95% remission rate)
165
Positive findings in CML
+ve Philadelphia chromosome
- 9;22
- PCR for BCR-ABL fusion gene
High WCC
- neutrophils, basophils
Hypercellular BM
- myelocytes and mature granulocytic cells
166
Phases of CML
1. Chronic phase
- < 5% blasts, WBC increases over years
- imatinib response very high
2. Accelerated phase
- > 10% blasts, splenomegaly
- less responsive to therapy
3. Blast phase
- > 20% blasts, resembles ALL
- tx similar to ALL
167
Diagnostic finding for CLL on blood film
Smear cells
| - smear CLLS get it
168
Monoclonal population seen in CLL
CD5+
| CD23+
169
Bad prognostic factors in CLL
LDH raised
CD38 +ve
11q23 deletion
170
Good prognostic factors in CLL
Hypermutated Ig gene
Low ZAP-70 expression
13q14 deletion
171
One way CLL is staged
Binet Staging
A = high WBC, < 3 groups of enlarged lymph nodes, no tx required
B = > 3 groups enlarged lymph nodes
C = anaemia or thrombocytopenia
172
Tx for CLL
Watchful waiting
Supportive (infection, transfusions)
1st line if p53 deletion
- alemtuzumab
ibrutinib
idalasisib + transplant
173
Summary of lymphoma types
Hodgkin's (20%)
Non-Hodgkin's (80%)
- B cell
- T cell
174
B cell lymphomas
Non-Hodgkin types
- Burkitt's
- Diffuse Large B-cell (DLBC)
- Mantle cell
- Follicular
- Mucosal associated lymphoid tissue (MALT)
175
T cell lymphomas
Non-Hodgkin type
- anaplastic large cell lymphoma
- peripheral T-cell lymphoma
- adult T cell leukaemia/lymphoma
- enteropathy-associated T cell lymphoma (EATL)
- cutaneous T cell lymphoma
176
Presentation of lymphomas
Painless lymphadenopathy
Multiple sites affected
Constitutional sx
Hodgkin's can have pain in affected nodes after alcohol
177
Staging of lymphomas
Ann-Arbor
1. one LN region (can include spleen)
2. 2+ LN regions on same side of diaphragm
3. 2+ LN regions on opposite sides of diaphragm
4. Extranodal sites (liver, BM)
A. No constitutional sx
B. Constitutional sx
178
Reed-Sternberg cell on lymph node biopsy
Dx?
Hodgkin's lymphoma
179
What cell stains do we use for suspected lymphoma biopsy?
CD15
| CD30
180
Bi-nucleate cell on background of lymphocytes and reactive cells
What is this?
Reed-Sternberg cell
| - can be multinucleate
181
Tx for Hodgkin's lymphoma
1. Combination chemo
- most cases
- excellent prognosis younger you are
2. Radiotherapy
- alongside chemo in bulky/limited disease
3. Intensive chemo and autologous SCT
- relapsed pts
182
Autologous vs allogenic SCT
Autologous
- patient OWN SCs
- used more in multiple myeloma and lymphoma (particularly relapse)
- no GHD risk, lower risk of infection
Allogenic
- HLA-matched donor SC
- used more in leukaemia
- GVHD, opportunistic infections infertility, secondary malignancy risk
183
High grade NH lymphomas
Burkitt's
Diffuse large B-cell
Mantle cell
184
Low grade NH lymphomas
Follicular
Marginal zone
Small lymphocytic
185
Which type of lymphoma is it from the following histology findings on lymph node biopsy?
a) starry sky appearance
b) angular/clefted nuclei
c) nodular appearance
d) bi-nucleate cell on background of lymphocytes and reactive cells
e) sheets of large lymphoid cells
a) Burkitt's
b) Mantle cell lymphoma
c) Follicular
d) Hodgkin's*
e) Diffuse large B cell (DLBC)
* the rest of the lymphomas are non-Hodgkin's
186
Types of Burkitt's lymphoma
Endemic: EBV-associated in Africa
Sporadic: EBV-associated outside Africa
Immunodeficiency: Non-EBV associated, HIV/post-tranplant pts
187
Which lymphomas are associated with the following translocations?
a) t(14;18)
b) t(8;14)
c) t(11;14)
a) Follicular
b) Burkitt's
c) Mantle cell lymphoma
188
Which conditions are associated with MALT?
H. pylori = gastric MALT
Sjorgen's syndrome = parotid lymphoma
MALT is a result of chronic antigen stimulation that's why
189
Tx for B-cell lymphomas
Rituximab (anti CD20 found on B cells)
Auto-SCT for relapses
190
Tx for T-cell lymphomas
Alemtuzumab (anti CD52 found on T cells)
191
Aggressive lymphoma with large 'epithelioid' lymphocytes that occurs in children and young adults
t(2;5) and alk-1 protein expression found
Which lymphoma?
Anaplastic large cell lymphoma
192
Aggressive lymphoma with large T-cells that occurs in middle-aged and elderly
Which lymphoma?
Peripheral T-cell lymphoma
193
Aggressive lymphoma that occurs after HTVL-1 infection, commonly in Caribbean and Japanese pts
Which lymphoma?
Adult T cell leukaemia/lymphoma
194
Lymphoma associated with longstanding coeliac disease
Enteropathy-associated T cell lymphoma
195
Lymphoma associated with mycosis fungoides
Cutaneous T cell lymphoma
196
Name chronic myeloproliferative diseases and how they can be classified
Philadelphia chromosome -ve:
- polycythaemia vera
- essential thrombocytopenia - idiopathic myelofibrosis
Philadelphia chromosome +ve:
- chronic myeloid leukaemia
197
Myeloproliferation vs myelodysplasia vs leukaemia
Myeloproliferation
- proliferation with FULL differentiation
Myelodysplasia
- proliferation with NO/LITTLE differentiation
Leukaemia
- ineffective proliferation with ineffective differentiation
*degree of overlap
198
Mutation associated with myeloproliferative disorders that are Ph -ve
JAK2
199
Causes of polycythaemia
Primary
- polycythaemia vera
- familial polycythaemia
Secondary
- disease states (renal Ca)
- high altitude
- chronic hypoxia, e.g. COPD
200
Causes of pseudo polycythaemia
Plasma volume reduced
- dehydration
- burns
- vomiting
- diarrhoea
- cigarette smoking
201
Cause of polycythaemia rubra vera
JKA2 V617F point mutation resulting in erythroid precursors dominating bone marrow
202
Positive ix findings for polycythaemia rubra vera
Raised Hb, HCT, platelets, WCC (neutrophils, basophils)
| Low serum EPO
203
Tx for polycythaemia rubra vera
Venesection
Hydroxycarbamide (maintenance)
Aspirin (CVD risk)
204
Features of myelofibrosis
Elderly
Pancytopenia-related sx
Hepatosplenomegaly due to extramedullary haematopoiesis
Can present with Budd-Chiari syndrome
205
Positive ix findings for myelofibrosis
Blood film
- tear-drop poikilocytes/dacrocytes
- leukoerythroblasts
Bone marrow
- fibrosis, 'dry tap'
Molecular
- JAK2 +ve 60%
- MPL mutation
206
Tx of myelofibrosis
Supportive
- blood products
- splenectomy
Stem cell transplant only curative option
Ruloxitinib, hydroxycarbamide, thalidomide, steroids
207
Features of essential thrombocytosis
Incidental finding in 50%
Venous and arterial thrombosis (gangrene, haemorrhage)
Erythromelalgia
Splenomegaly, dizziness, headaches, visual disturbances
208
Positive ix findings for essential thrombocytosis
Platelet count
- > 600 x 10^9
Blood film
- large platelets
- megakaryocyte fragments
Increased BM megakaryocytes (not reactive)
209
Tx for essential thrombocytosis
Aspirin (CVD risk)
Anagrelide (reduce formation of plts)
Hydroxycarbamide
210
Indications for RBC transfusion
1. Hb 70g/l if asx, 80g/l if sx
- higher threshold if CHD
2. Major blood loss
3. Treat iron/folate/B12 deficiency first unless active bleeding
211
Indications for platelet transfusion
1. Consumptive disorders
- TTP, DIC, HIT
2. Transfuse when plts < 10 bn/L
3. Pre procedure, i.e. chemo/surgery
* DO NOT give if actively bleeding
212
Indications for FFP transufsion
**Try use Vit K first if appropriate**
Use to replace clotting factors in severe liver disease or undergoing massive transfusion (avoid dilution)
- do not use if active bleeding or undergoing procedure, i.e. surgery
213
Acute adverse reactions to transfusions
Immune
- ABO
- Febrile non-haemolytic
- Allergic/anaphylaxis
- Transfusion related acute lung injury
Non-immune
- Bacterial infection
- Transfusion associated cardiac overload
214
Delayed adverse reactions to transfusions
Immune
- Delayed haemolytic transfusion reaction
- Port-transfusion purpura
- Transplant-associated GVHD
Non-immune
- Viral infections
- Iron overload
215
Based on the clinical sx, which acute transfusion reaction is most likely in the following patients?
a) Mild fever with urticaria
b) Shock with bleeding and dark urine
c) Shock with significantly high fever
d) Shock with SOB and raised JVP
e) Shock with SOB and normal JVP
a) Mild allergic reaction
b) ABO incompatibility
c) Bacterial infection of unit
d) Transfusion associated cardiac overload
e) Transfusion related acute lung injury
216
Which immunoglobulins are associated with the following adverse reaction to transfusions?
a) Anaphylaxis
b) ABO incompatibility
c) Delayed haemolytic transfusion reaction
a) IgA deficiency increases risk
b) IgM-mediated resulting in intravascular haemolysis
c) IgG-mediated resulting in extravascular haemolysis
217
Compare TACO and TRALI
Both
- pulmonary oedema, SOB, occur within hours
TACO
- increased JVP, pulmonary capillary wedge pressure
TRALI
- absence of heart failure signs
218
Breast Ca pt who has undergone chemo required major blood transfusion post-mastectomy
2 days later they have new onset diarrhoea, jaundice, and skin changes to their hands and feet
Top ddx?
Transfusion-associated graft-versus-host disease
- Lymphocytes attack HLA antigens in gut, liver, skin, bone marrow
- Severe diarrhoea, liver failure, skin desquamation, bone marrow failure
- FATAL
219
Which adverse reaction is more likely with platelet transfusions?
Bacterial contamination
220
Clinical features of platelet disorders
```
Superficial bleeding into skin, mucosal membranes
- nosebleed, gum, vaginal, GI tract
- small, superficial bruises
Bleeding immediately after after injury
Petechiae
```
221
Clinical features of coagulation disorders
Bleeding into deep tissues, muscles, joints
- haemarthrosis
- large, deep bruises
Delayed but severe bleeding after injury
Bleeding often prolonged
222
Congenital vascular defects
Osler-Weber-Rendu syndrome
| Connective tissues disease (Ehlers-Danlos syndrome)
223
Acquired vascular defects
Senile purpura
Infection (meningococcal, measles, dengue fever)
Steroids
Scurvy (perifollicular haemorrhages)
224
Decreased platelet function disorders
Acquired
- aspirin
- cardiopulmonary bypas
- uraemia
Congenital
- storage pool disease
- thrombasthenia (glycoprotein deficiency)
225
Low platelet function disorders
Decreased production
- bone marrow failure
Increased destruction
- autoimmune ITP
- drugs (heparin, DIC, HUS, TTP)
226
3 year old presents with multiple bruising across arms and legs. Mum notes a viral infection 2 weeks ago. He is otherwise fit and well.
Platelet count < 20, 000
What is the mx plan?
Acute ITP
- self-limiting
- reassure parents
- safety net regarding any massive/concerning bleeds, especially if any trauma occurs
227
53 year old women comes in complaining of recurrent nosebleeds and increased bruising across her thighs and elbows over last few months. She has a background of RA.
Platelet count < 50, 000
What is the mx plan?
Chronic ITP
- associated with AI disease, CLL, HIV
- spontaneous remission uncommon, considered indolent disease
- can consider IVIg, steroids, splenectomy
228
Diagnosis of haemophilias
```
Increased APTT
Normal PT
Decreased factor assay:
- 8 -> haemophilia A
- 9 -> haemophilia B
```
229
Mx of haemophilias
Avoids NSAIDs and IM injections
A:
Desmopressin (vWF release which is f8 carrier)
Factor 8 concentrates
B:
Factor 9 concentrates
230
Von Willebrand Disease classes
Type 1
- low levels of vWF
Type 2
- deficiency in function of vWF
Type 3
- ABSENT vWF; presents like haemophilia
231
Diagnosis of vWF disease
Increased APTT, normal PT/INR (could both be normal)
Decreased factor 8
Decreased vWF Ag (normal in type 2 but reduced function)
Normal platelet count
232
Mx of vWF disease
Prophylaxis indicated in some pts
| Bleeds: desmopressin, vWF, factor 8 concentrates
233
What is vit K needed for?
Factors 2, 7, 9, and 10
| Protein C, S, and Z
234
Causes of vit K deficiency
Warfarin
Malabsorption/malnutrition
Abx therapy (kills gut flora)
Biliary obstruction (reduces absorption of vit K)
235
Clotting study results in DIC
Prolonged APTT, PT, TT
Decreased fibrinogen platelets
Increased FDP, D-dimer
Schistocytes
236
Mx for vit K
IV vit K or FFP for acute haemorrhage
237
Mx for DIC
Treat underlying cause (sepsis, malignancy, trauma, obstetric complications, toxins)
Transfusions of FFP, platelets, cryo
Anticoagulation with heparin
238
Liver disease results in the reduction of which haem factors?
2, 5, 7, 9, 10, 11
Fibrinogen
Reduced absorption of vit K
Abnormal platelet function
239
Virchow's triad
Vessel wall
Blood composition
Blood flow (stasis)
240
The risk of thrombosis is increased by:
```
A. Reduced prothrombin
B. Thrombocytopaenia
C. Reduced protein C
D. Elevated anti-thrombin
E. Increased fibrinolysis
```
C. Reduced protein C
241
Which factor confers the highest risk of thrombosis?
1. Factor V Leiden
2. Antithrombin deficiency
3. Family history of thrombosis
4. Reduced Factor VII Levels
5. 3-hour plane flight
2. Antithrombin deficiency
NOTE: thrombotic risk factors can combine to cause a massively increased risk.
242
Which agent has a delayed anticoagulant effect?
1. Vitamin K
2. Unfractionated heparin
3. Warfarin
4. Low molecular weight heparin
5. Aspirin
3. Warfarin
Warfarin takes a few days to start working because the factors have a half-life of around 2-3 days.
243
How does warfarin achieve its anticoagulant effect?
1. Reduction of plasma protein C and protein S
2. Blocks phospholipid synthesis
3. Reduction of plasma procoagulant factors
4. Acts as a cofactor for antithrombin
5. Inhibits factors II, VII, IX and X
3. Reduction of plasma procoagulant factors
244
Which patient is most likely to benefit from long-term anticoagulation after their DVT?
1. 57-year-old man after flying from Moscow
2. 27-year-old woman during pregnancy
3. 33-year-old woman on OCP
4. 77-year-old man after hip replacement
5. 30-year-old man after a long walk
5. 30-year-old man after a long walk
This is because there isn't an obvious external factor that you can attribute the DVT to
245
A 32-year-old woman develops a DVT after the removal of an ovarian cyst. Her brother and father have had a DVT.
1. Testing for antithrombin deficiency
2. Recommend HRT
3. Continue long-term anticoagulation
1. Testing for antithrombin deficiency
246
A 29-year-old man collapses at work following a pulmonary embolism. He has no family history.
1. Test for Factor V Leiden
2. Daily aspirin
3. Continue long-term anticoagulation
4. Heparin injections for long-haul flights
3. Continue long-term anticoagulation
247
A 38-year-old woman has had a previous DVT while taking the COCP. She has a second DVT during her second pregnancy.
1. Test for Factor V-Leiden
2. Hormone Replacement Therapy
3. Continue long-term anticoagulation
4. Fixed low-dose warfarin
1. Test for Factor V-Leiden
Fixed low-dose warfarin is not very good because warfarin has very variable bioavailability.
248
67-year-old man presents with DVT and weight loss, started on LMWH. Which should he receive?
1. Abdo-pelvic CT scan
2. Switch to DOAC
3. Switch to warfarin
1. Abdo-pelvic CT scan
If you come with idiopathic thromboembolic disease and you are > 60 years, you should be offered a CT scan to see if there is any underlying cause.
249
Well's score results and mx
0
- consider other diagnosis
1-2
- D-dimer; if high: USS/CTPA; if low, rule out
3+
- USS affected limb for DVT/CTPA for PE
250
DVT prophylaxis
Daily subcut LMWH low dose
| Ted stockings
251
Tx of DVT/PE
High dose LMWH
+ warfarin/DOACs
LMWH stopped when INR 2-3
Tx is for 3 months minimum
- recurrent VTEs need lifelong tx
252
Why should you continue LMWH when warfarin is commenced post-DVT/PE?
Warfarin also affects protein C/S thus leads to a procoagulant state in the first few days before its anticoagulant effect (2, 7, 9, 10 inhibitor)
253
How does heparin work?
Potentiates antithrombin III
| - inactivates thrombin and f 9, 10 and 11
254
Heparin side effects and antidote
Bleeding
Heparin induced thrombocytopenia
Osteoporosis with long-term use
Antidote: protamine sulphate
255
How does warfarin work?
Inhibits reductase enzyme needed for active form of vit K to produce f 2, 7, 9, 10 and proteins C, S and Z
256
Target INRs:
a) 1st episode DVT/PE, AF
b) Recurrent DVT/PR, mechanical prosthetic valve
a) 2.5
| b) 3.5
257
How do you reverse warfarin action?
STOP WARFARIN
Slow IV vit K
Prothrombin complex concentrate (octaplex/beriplex over 30 mins)
- if not available, give FFP
258
Which drug reverses dabigatran action?
Idracizumab
259
Which drug reverses rivaroxaban and apixaban?
Andexanet alfa
| - really spenny not common at all
