Haematology Flashcards
1
Q
What is von Willebrand’s Disease?
A
Most (c) inherited bleeding disorder
AD inheritance
Low levels of vWF in the blood
vWF -> promotes platelet adhesion to damaged endothelium, carrier for F8
2
Q
Investigation for von Willebrand’s Disease?
A
prolonged bleeding time
APTT may be prolonged
factor 8 levels may be moderately reduced
defective platelet aggregation with ristocetin (for an unknown reason this antibiotics causes vWF to bind to plts. This is reduced if less vWF in blood)
3
Q
Management of von Willebrand’s Disease?
A
Tranexamic acid for mild bleeding
desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
factor VIII concentrate
4
Q
What is antithrombin 3 deficiency?
A
an inherited cause of thrombophilia - AD
Antithrombin III inhibits several clotting factors, primarily thrombin, factor X and factor IX
5
Q
Features of antithrombin 3 deficiency?
A
Recent venous thromboses
arterial thromboses do occur but are uncommon
6
Q
Management of antithrombin 3 deficiency?
A
Warfarin
Heparinisation during pregnancy (monitor FXa)
Antithrombin III concentrates (often used during surgery or childbirth)
7
Q
What is the inheritance pattern of haemophilia and what is the difference between A and B?
A
Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have no FH. Haemophilia A = deficiency of factor 8 whilst in haemophilia B = lack of factor 9
8
Q
Features of haemophilia?
A
- haemoarthroses, haematomas
* prolonged bleeding after surgery or trauma
9
Q
Blood tests in haemophilia?
A
- prolonged APTT
* bleeding time, thrombin time, prothrombin time normal
10
Q
When would you use irradiated blood products?
A
Irradiated blood products are used to avoid transfusion-associated graft versus host disease
11
Q
Three main RF for transfusion-associated graft versus host disease (TA-GvHD)?
A
- Volume and age of transfused blood
- Immunodeficiency, especially that involving T-cells and cell-mediated immunity e.g. Hodgkin’s disease
- Similar HLA haplotype sharing
12
Q
What is the presentation of transfusion-associated graft versus host disease (TA-GvHD) and what might you see on biopsy?
A
diarrhoea, liver damage, and rash
A biopsy of skin or BM can be diagnostic. A biopsy specimen of the skin will show abundant NECROTIC KERATINOCYTES. BM shows marked hypocellularity with macrophage infiltration
ta-GVHD is a rare and usually fatal complication of blood transfusion in which lymphocytes from the transfused blood component attack the recipient’s tissues, especially the skin, BM and GI tract
13
Q
What is the MOA of Cyclophosphamide and are its adverse effects?
A
Alkylating agent - causes cross-linking in DNA
SEs: Haemorrhagic cystitis (incidence reduced by the use of hydration and mesna), myelosuppression, transitional cell carcinoma
14
Q
What is the MOA of Methotrexate and are its adverse effects?
A
Inhibits dihydrofolate reductase and thymidylate synthesis
Myelosuppression, mucositis, liver fibrosis
NOT lung fibrosis
15
Q
Doses of adrenaline in anaphylaxis?
A
< 6 months -> 100 - 150 micrograms (0.1 - 0.15 ml 1 in 1,000)
6 months - 6 years -> 150 micrograms (0.15 ml 1 in 1,000)
6-12 years -> 300 micrograms (0.3ml 1 in 1,000)
Adult and child > 12 years -> 500 micrograms (0.5ml 1 in 1,000)
16
Q
What is refractory anaphylaxis?
A
Resp/CVS problems that persist despite two doses of adrenaline
17
Q
What blood test can you take to see if a patient had a true anaphylactic reaction and how long after?
A
Serum tryptase up to 12hrs after attack
18
Q
In what percentage of patients does a biphasic reaction occur following anaphylaxis?
A
20%
19
Q
Which patients need 12 (instead of 6hrs) of post-anaphylaxis monitoring?
A
severe reaction requiring > 2 doses of IM adrenaline
patient has severe asthma
possibility of an ongoing reaction (e.g. slow-release medication)
patient presents late at night
patient in areas where access to emergency access care may be difficult
observation for at 12 hours following symptom resolution
20
Q
What is the most common inherited thrombophilia?
A
Factor V Leiden (activated protein C resistance)
21
Q
What is Factor 5 Leiden and what can it cause?
A
Due to a gain in function mutation
Factor 5 is part of the clotting cascade and contributes to clot formation
In this condition Factor 5 is broken down 10x more slowly than usual
‘Activated protein C’ is responsible for the breakdown in factor 5. Therefore it is the resistance to ‘activated protein C’ that causes the condition
Results in an increased risk of VTEs
22
Q
What is a leukaemoid reaction?
A
A rise in WCCs (>50) that results from an insult/infection (and not a malignancy)
23
Q
How do you differentiate between a leukomoid reaction and CML?
A
Leukaemoid reaction:
high leucocyte alkaline phosphatase score (substance found within mature WBCs)
toxic granulation (Dohle bodies) in the white cells
‘left shift’ of neutrophils i.e. three or fewer segments of the nucleus
CML: low leucocyte alkaline phosphatase score (WBCs are underdeveloped and not mature)
24
Q
What is the most common age for patients to develop CML?
A
40-60yrs
25
What are the three phases of CML?
Chronic phase - >90% Dx, median 3yrs long, few symptoms
Accelerated phase - 2-15months, increasing arrest of cell maturation
Blastic phase -> 3-6months, leads to death (resembles an acute leukaemia)
26
Investigations for CML?
Raised granulocytes - neutr, eosino, basophils (at different stages of maturation +/- thrombocytosis)
Decreased leukocyte alkaline phosphatase (substances found within mature WBCs - as more are at immature stages then less alk phosphatase will be found)
Blood film
BM aspirate
Philadelphia chromosome - due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11), BCR
27
Management of CML?
Targeted molectular therapy - tyrosine kinase inhibitors e.g. imatinib
SC transplant
28
What are the investigations for CLL?
Raised lymphocytes
Blood film (mature lymphocytes, SMUDGE cells)
Immunophenotyping
29
Management of CLL?
Do nothing!
FCR
SC transplant
30
Poor prognostic factors for CLL?
```
male sex
age > 70 years
lymphocyte count > 50
prolymphocytes comprising more than 10% of blood lymphocytes
lymphocyte doubling time < 12 months
raised LDH
CD38 expression positive
TP53 mutation
```
31
What is a good prognostic factor for CLL?
Deletion of the long arm of chromosome 13 (del 13q)
32
What is methaemoglobinaemia?
Describes haemoglobin which has been oxidised from Fe2+ to Fe3+, there is tissue hypoxia as Fe3+ cannot bind oxygen
33
Which way is the oxygen dis curve shifted in methaemoglobinaemia?
to the left
The subunits of hemoglobin that are not oxidized bind oxygen more tightly, and, therefore, release it less readily. These hemoglobin have a high affinity for oxygen and shift the oxygen dissociation curve to the left
34
Congenital and acquired causes of methaemoglobinaemia?
Congenital:
haemoglobin chain variants: HbM, HbH
NADH methaemoglobin reductase deficiency (which is normally involved in converting methaemoglobin to haemoglobin)
Acquired causes (met = meth so all drugs)
drugs: sulphonamides, nitrates (including recreational nitrates e.g. amyl nitrite 'poppers'), dapsone, sodium nitroprusside, primaquine (all p's)
chemicals: aniline dyes
35
What are features of methaemoglobinaemia?
'chocolate' cyanosis (colour of blood)
dyspnoea, anxiety, headache
severe: acidosis, arrhythmias, seizures, coma
normal pO2 but decreased oxygen saturation
36
Management of methaemoglobinaemia?
Congenital: NADH - methaemoglobinaemia reductase deficiency: ascorbic acid
Acquired: IV methylthioninium chloride (methylene blue)
37
What is ITP?
Body produces Abs to platelet antigens (© glycoprotein 2b/3a) -> platelet destruction
Also marrow failure -> means plt production is not appropriately increased
38
What are the two forms of ITP?
Acute –
• mainly in children, lasts <6 months, d/t immune complexes
• Follows a viral infection (© varicella)
• Equal genders
Chronic –
• mainly in adults, lasts >6 months, d/t specific IgG antiplatelet Abs
• Women > men
39
Features of ITP?
Mucosal/skin bleeding – epistaxis, oral bleeding, menorrhagia
Characteristic purpuric rash
Afebrile
Signs of raised ICP (d/t increased brain bleeds)
40
Investigations in ITP?
```
Low platelets
Megathrombocytes (enlarged plts)
Megakaryocytes – platelet precursors found in the bone marrow (normal/raised)
PT, PTT, coagulation time = normal
Platelet IgG
```
41
Management of ITP?
Acute –
Children: usually resolves spontaneously (w/in 2 months)
Adults: rarely resolves spontaneously
Chronic –
Plts <30 but no catastrophic bleeding:
Prednisolone
o Mandatory to perform a BM biopsy before commencing steroids (r/o leukaemia)
Catastrophic bleeding:
IV methylprednisolone
Platelet transfusion
IV Ig - raises plt level quicker than steroids so can be used in acute bleeding/pre-operative
Splenectomy prev required in 50%, now less common (plts that have been bound by autoAbs are taken up by macrophages in the spleen so removal keeps more plts in circulation)
30% of these relapse – may benefit from cyclophosphamide, azathioprine, vincristine etc
Platelet transfusion only required in emergencies to induce haemostasis
42
What is Evan's syndrome?
ITP in association with autoimmune haemolytic anaemia (AIHA)
43
What percentage of factor 8 activity would give you a diagnosis of haemophilia?
Factor Activity in Hemophilia depending on severity
Mild: 5-30% of Normal Activity
Moderate: 1-5% of Normal Activity
Severe: <1% of Normal Activity
44
What can causes hereditary angioedema and what is the inheritance pattern?
What is the probable mechanism?
C1 esterase inhibitor deficiency
Autosomal dominant
Probably caused by uncontrolled release of bradykinin
45
What would you do to investigate in hereditary angioedema?
C1-INH level is low during an attack
| low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool
46
Symptoms of hereditary angioedema?
First sign may be a painful maculopapular rash
Followed by painless, non-pruritic swelling (of upper airways/skin/abdo organs occasionally)
Usually no urticaria
47
Management of hereditary angioedema?
IV C1-inhibitor concentrate, FFP if this is not available
| Prophylaxis: anabolic steroid Danazol may help
48
Indications for treatment of CLL?
progressive marrow failure: the development/worsening of anaemia +/or thrombocytopenia
massive (>10 cm) or progressive lymphadenopathy
massive (>6 cm below left costal margin) or progressive splenomegaly
progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
systemic symptoms: WL > 10% in previous 6 months, fever >38ºC for > 2 weeks, extreme fatigue, night sweats
AI cytopaenias e.g. ITP
49
When would you use RAST testing?
Radioallergosorbent test (RAST)
Determines the amount of IgE that reacts specifically with suspected or known allergens through a blood test
Chosen > skin prick if v young infant, risk of severe reaction to skin prick, severe eczema/psoriasis, pts taking antihistamines
50
What is the inheritance pattern of G6PD deficiency?
X-linked recessive
51
What is the mechanism of action in G6PD deficiency?
↓ G6PD (metabolite of glucose) occurs because the genetic condition causes G6PD to form with a shorter half-life → ↓ reduced NADPH (which is responsible for reactivating glutathione) → without activated glutathione free radicals aren't mopped up which can directly break down RBCs and haemoglobin
52
What are the features of G6PD deficiency?
neonatal jaundice, intravascular haemolysis, gallstones are common
splenomegaly may be present
53
What would you see on investigation in G6PD deficiency?
Heinz bodies on blood films. Bite and blister cells may also be seen
Heinz bodies are abnormal proteins on the wall of the cell membranes. These are recognised by macrophages which 'bite' a chunk out of the RBCs
G6PD enzyme assay -> levels checked 3m after acute episode
54
What can precipitate an attack in G6PD deficiency?
Broad (fava) beans
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
55
Which ethnicities are more likely to suffer from G6PD deficiency?
African + Mediterranean
56
Which ethnicities are more likely to suffer from spherocytosis?
Northern Europeans
57
What occurs in spherocytosis and what is the inheritance pattern?
AD
Defect of RBC cytoskeleton -> the normal biconcave disc shape is replaced by a sphere-shaped RBC
RBC survival reduced as destroyed by the spleen
Results in extravascular haemolysis
58
Presentation of spherocytosis?
failure to thrive
jaundice, gallstones
splenomegaly
aplastic crisis precipitated by parvovirus infection
59
What might you see in the blood results in spherocytosis?
spherocytes
Raised mean corpuscular haemoglobin concentration [MCHC]
Increase in reticulocytes
60
What are the definitive investigations for spherocytosis?
If the diagnosis is ambiguous -> EMA binding test (EMA binds to proteins on RBCs, less so in SC as less RBCs) and the cryohaemolysis test (measure the rate of RBC breakdown at different temps - in SC, RBCs breakdown at lower temps)
for atypical presentations -> electrophoresis analysis of RBC membranes is the method of choice
If you have significant lab test, clinical features and FH, no more investigations are needed
61
What would be the result of a direct coombs test in spherocytosis?
Direct coombs test = negative
62
Management of spherocytosis?
acute haemolytic crisis:
treatment is generally supportive
transfusion if necessary
longer term treatment:
folate replacement
splenectomy
63
What medication do you use to treat CLL?
Fludarabine, Cyclophosphamide and Rituximab (FCR)
64
What is protein C deficiency and what is the inheritance pattern? Defining symptom?
Autosomal codominant
Causes an increase in VTEs
Skin necrosis occurs on starting warfarin -> warfarin causes a reduction in biosynthesis of protein C, results in a temporary procoagulant state. Thrombosis occurs in venules which leads to skin necrosis
Concurrent use of heparin usually stops this
Skin necrosis can also occur with protein S def (however this is a less common condition)
65
What is haptoglobin and what is its significance in sickle cell disease?
Haptoglobin is made in the liver and binds to free haemoglobin in the blood in order to assist its clearance
If there is RBC breakdown, there will be more haemoglobin to bind to, and therefore the levels of haptoglobin go down in SCA
66
What is responsible for increased/decreased MCHC?
Increased
hereditary spherocytosis
autoimmune haemolytic anemia
```
Decreased
microcytic anaemia (e.g. iron deficiency)
```
67
What is Chediak Higashi Syndrome?
AR inheritance
Results in a decrease in phagocytosis
Affected children have 'partial albinism' and peripheral neuropathy. Recurrent bacterial infections are seen
68
What is Wiskott Aldrich Syndrome?
Primary immunodeficiency due to a combined B- and T-cell dysfunction
Condition caused by reduced number and size of platelets -> these defective platelets are cleaned up, leading to thrombocytopenia
Results in increased bleeding (thrombocytopaenia), infection risk and cancer risk (lymphomas)
Also get eczema
Mnemonic WATER - WAsp gene, Thrombocytopaenia, Eczema, Recurrent infection
X-linked, defect in WAS gene
Tx = stem cell transplant
69
What do you see on microscopy in Chediak Higashi Syndrome?
Giant granules in neutrophils and platelets
70
What are the common features of DiGeorge syndrome?
Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
71
What is common variable immunodeficiency?
Due to defect in B cell maturations
| Hypogammaglobulinemia is seen. May predispose to autoimmune disorders (e.g. IBD) and lymphoma
72
What is a follicular lymphoma?
Slow-growing B-cell lymphoma that accounts for 20-30% of all non-Hodgkin's lymphomas
73
What is TTP?
Thrombotic Thrombocytopaenic Purpura
Abnormally large + sticky multimers of vWF cause platelets to clump together that obstruct organs and result in fluctuating ischaemia
In TTP there is a deficiency of ADAMS 13 which breakdowns large multimers of von Willebrand's factor (see image in notes)
74
How to manage TTP?
TTP is life threatening – must be treated as an emergency, untreated mortality of 90%
Give plasma exchange using FFP
IV methylpred - after PEX completed
75
How do you treat heparin-induced thrombocytopenia (HIT)?
Intravenous argatroban
76
What are the symptoms of TTP?
```
Pentad: FART N
Fever
Anaemia
Renal impairment (haematuria, uraemia)
Thrombocytopaenia
Neurological (headache, confusion)
```
77
Which enzyme is responsible for TTP?
Deficiency of ADAMTS13 (cleaves vWF) – means too much vWF
78
What is the most common infection transmitted through platelet transfusion?
Bacterial - product stored at room temperature
79
What is Waldenstrom's macroglobulinaemia?
Type of non-Hodgkin's
Lymphoma - abnormally large numbers of B cells which differentiate into IgM
++ IgM makes the blood thick (hyperviscous)
80
What are the symptoms of Waldenstrom's macroglobulinaemia?
```
The thickened blood causes changes in the flow through the vessels. Can cause small vessels to break resulting in bleeding gums/retina (visual disturbances)
Also:
systemic upset: weight loss, lethargy
hepatosplenomegaly
lymphadenopathy
cryoglobulinaemia e.g. Raynaud's
```
81
What is the investigation of choice in Waldenstrom's macroglobulinaemia?
Electrophoresis - look for a monoclonal IgM paraproteinaemia
82
What can cause a thrombocytosis?
Can act as an acute phase reactant
Malignancy
Essential thrombocytosis
Hyposplenism
83
What are the feature of essential thrombocytosis?
Plts >600
Venous/arterial thrombosis
Haemorrahge
Characteristic burning of the hands
84
How to treat essential thrombocytosis?
Hydroxyurea – reduces the platelet count
Interferon-alpha – used in younger patients, inhibits growth of megakaryotypes
Low-dose aspirin – can be used to reduce thrombotic risk
85
Difference between thrombocytosis, thrombophilia and thrombocytopaenia?
thrombocytosis - too many plts
thrombophilia - tendency to clot
thrombocytopaenia - too few plts
86
What are the different types of sickle-cell crisis?
* thrombotic, 'painful crises' - infarcts occur in organs incl bone
* sequestration - sickling within organs pooling of blood and worsening anaemia, assoc with increased reticulocytes
* acute chest syndrome - sickling of RBC in lungs causing pulmonary infarcts
* aplastic - body not making enough RBC to replace old ones, caused by parvovirus, BM suppression causes a reduced reticulocyte count
* haemolytic - fall in Hb due to increased rate of haemolysis
87
What is Deferoxamine and when is it used?
In sickle-cell patients who are regularly transfused -> it is an iron chelation therapy used to enhance iron excretion and removes excessive tissue iron
88
What are the features of cyanide poisoning?
'classical' features: brick-red skin, smell of bitter almonds
acute: hypoxia, hypotension, headache, confusion
chronic: ataxia, peripheral neuropathy, dermatitis
89
Treatment of cyanide poisoning?
100% O2
| IV hydroxocobalamin
90
What happens to the oxygen dis curve in carbon monoxide poisoning?
The oxygen saturation of haemoglobin decreases leading to an early plateau in the oxygen dissociation curve (CO binding is irreversible)
Also shifts to the left as CO has a higher affinity for haemoglobin than O2
91
Features/symptoms of CO toxicity?
```
headache: 90% of cases
nausea and vomiting
vertigo
confusion
subjective weakness
severe toxicity: 'pink' skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death
```
92
Ix for carbon monoxide poisoning?
Pulse oximetry can be misleading
Do a gas
Measure levels of carboxyhaemoglobin
93
Mx of carbon monoxide poisoning?
100% O2
| Consider hyperbaric chamber for severe cases
94
Feature and management in organophosphate poisoning?
```
Features can be predicted by the accumulation of acetylcholine (mnemonic = SLUD)
Salivation
Lacrimation
Urination
Defecation/diarrhoea
cardiovascular: hypotension, bradycardia
also: small pupils, muscle fasciculation
```
Mx - atropine
95
What is a mantle cell lymphoma?
typically an aggressive, rare, form of non-Hodgkin lymphoma that arises from cells originating in the “mantle zone" (the middle ring within a lymph node)
96
Which chromosome is responsible for alpha-thalassaemia?
2 separate alpha-globulin genes are located on each chromosome 16
Any of 1-4 can be affected
97
What would the bloods look like if only 1 or 2 alleles were affected in alpha-thalassaemia?
hypochromic and microcytic
| Hb level typically normal
98
What would the bloods look like if 3 alleles were affected in alpha-thalassaemia?
hypochromic microcytic anaemia with splenomegaly -> known as Hb H disease
May see Heinz bodies
99
What would happen if 4 alleles were affected in alpha-thalassaemia?
Death in utero would occur (hydrops fetalis, Bart's hydrops)
100
What chromosome is responsible for beta-thalassaemia major?
Lack of beta chains on chromosome 11
101
What are the features of beta-thalassaemia major?
presents in first year of life with failure to thrive + hepatosplenomegaly
microcytic anaemia
HbA2 & HbF raised
HbA absent (also known as Hb a2b2 i.e. normal Hb)
102
What is HbA?
HbA is the most common type of RBC (made up for 2xalpha and 2xbeta chains)
103
How to manage beta-thalassaemia?
repeated transfusion, can → iron overload
| s/c infusion of desferrioxamine
104
What is beta-thalassaemia trait? What is the inheritance pattern and what are the main features?
hypochromic, microcytic anaemia -> microcytosis disproportionate to the anaemia
Autosomal recessive
HbA2 raised
105
In what conditions can target cells be found?
SCA/thalassaemia
Iron-deficiency anaemia
Hyposplenism
Liver disease
106
What might you see on microscopy in myelofibrosis?
'Tear-drop' poikilocytes
107
In which conditions might you see spherocytes on microscopy?
Hereditary spherocytosis
| Autoimmune hemolytic anaemia
108
In which conditions might you see basophilic stippling on microscopy?
```
Lead poisoning
Thalassaemia
Sideroblastic anaemia
Myelodysplasia
(LSTM - London School of Tropical Medicine)
```
109
In what condition might you see Howell-Jolly bodies?
Hyposplenism
110
In what condition might you see Heinz bodies?
G6PD deficiency
| Alpha-thalassaemia
111
In which conditions might you see schistocytes ('helmet cells')?
```
Intravascular haemolysis (TTP, HUS)
Mechanical heart valve
Disseminated intravascular coagulation
```
112
In which conditions might you see 'Pencil' poikilocytes?
Iron deficiency anaemia
113
SEs of hydroxychloroquine?
Bull's eye retinopathy - may result in severe and permanent visual loss
114
What is myelofibrosis?
a type of cancer
thought to be caused by hyperplasia of abnormal megakaryocytes
the resultant release of platelet derived GF is thought to stimulate fibroblasts (fibroblasts secrete collagen which are used to maintain structure of many tissues)
This causes scarring of the bone marrow
115
What are the features of myelofibrosis?
1. Enlarged spleen/liver
2. Thrombocytopaenia, anaemia, leukopenia
3. Constitutional symptoms i.e weakness/fatigue, WL, night sweats
116
What is found on lab investigations in myelofibrosis + genetic mutation?
anaemia
high WBC + platelet count early in disease
Or low WBC/platelets
Blood film - 'tear-drop' poikilocytes
unobtainable BM biopsy - 'dry tap' therefore trephine biopsy needed
high urate and LDH (reflect increased cell turnover)
JAK2 mutation
117
What is myelodysplasia?
A rare condition where:
- haemopoetic stem cells differentiate into blast cells rather than down the usual line of differentiation
- these often die in the bone marrow and 'push' out cells undergoing the usual line of differentiation
118
What are the MOA and SEs of Cisplatin?
MOA - causes cross-linking in DNA
| SE - ototoxicity, peripheral neuropathy, hypomagnesaemia
119
Causes of microcytic anaemia?
Iron-deficiency, alpha/beta thalassaemia
120
Causes of iron-def anaemia?
```
Inadequate intake
Poor intestinal absorption (coeliac)
Excessive blood loss (GI/menorrhagic/Ca)
Increased requirements (pregnancy/rapid growth)
```
121
What would you see on blood film in iron-def anaemia?
RBCs of varying sizes/shapes, 'pencil cells'
122
What are the features of alpha-thalassaemia?
Anaemic symptoms - pallor/SOB/fatigue
| Can be skeletal deformities + hepatosplenomegaly
123
Treatment for alpha-thalassaemia?
Severe: blood transfusions (with iron chelating agents if >10 transfusions to remove excess iron)
Hb Barts: intrauterine transfusions, followed by BM transplantation
124
What is the mechanism by which B-thal causes symptoms?
Decreased B-chains causes alpha-chains to build up and clump together + damage RBC membrane -> haemolysis + release of heme which breaks into iron + unconjugated bilirubin -> jaundice + 2* haemochromatosis -> hypoxia also occurs which leads to increased RBC production in BM and spleen -> skull, face, liver and spleen to enlarge
125
What would you see on skull XR in thalassaemia?
Hair-on-end appearance
126
Causes of normocytic anaemia?
```
Anaemia of chronic disease
Combined haematinic deficiency
Acute blood loss (inc reticulocytes)
Haemolytic anaemia (inc reticulocytes)
Aplastic anaemia (dec reticulocytes)
Sickle-cell anaemia
```
127
What is sideroblastic anaemia? What are the causes?
RBCs fail to completely form haem (so iron cannot attach itself or carry O2)
Iron then gets deposited into mitochondria (these cells are called sideroblasts)
Congenital - microcytic
Acquired (alc, lead, TB meds) - macrocytic
128
Causes of macrocytic anaemia?
```
Megaloblastic:
- Pernicious anaemia
- folate deficiency
Non-megaloblastic:
- Myelodysplastic disease
- Myeloproliferative disease (CML, polycythemia vera)
- Reticulocytosis
- Pregnancy
- Hypothyroidism
- Alcohol/liver disease
```
129
What causes pernicious anaemia?
There are a number of causes of B12 deficiency, PA = a type of B12 deficiency due to autoimmune disease caused by Abs to intrinsic factor and gastric parietal cells (produce IF)
130
What age/sex is more common in pernicious anaemia?
Women > men
| Patient > 60
131
What are the symptoms of pernicious anaemia?
TRIAD
- anaemia - SOB/pallor/fatigue etc
- GI symptoms: diarrhoea/constipation, loss of bladder/bowel function
- Neuro symptoms: peripheral neuropathy, loss if vibration sense or proprioception
```
Other:
'Lemon tinge' to skin due to pallor + mild jaundice
Glossitis
Angular stomatitis
High stepping gait
```
132
Treatment of pernicious anaemia?
1 mg of IM hydroxocobalamin 3 times each week for 2 weeks, then once every 3 months
+/- folic acid supplement, if deficient
133
Source of folate?
Green vegetables, liver, nuts
134
Presentation of folate deficiency?
Same as vit B12 (more rapid in onset as stores are much smaller)
135
Blood film in folate deficiency?
Hypersegmented neutrophils
136
Management of folate deficiency?
Short course of folic acid PO
137
Why do you give folate at the time of conception and how long should you give it for?
Helps to prevent neural tube defects -> continue 5mg daily for 1st trimester
138
What should you remember when treating folate deficiency?
Do not give folate without checking B12
| If patients are low B12 and you give folate, it can precipitate subacute combined degeneration of the spinal cord
139
Where does B12 bind to IF and where is it absorbed?
Binds to IF in the second segment of the duodenum
| Absorbed in the terminal ileum
140
What is the genetic cause of SCA?
Point mutation in codon 6 of B-globin gene - coded AA changes from glutamine -> valine
141
What can cause anaemia of chronic disease?
Renal failure, Ca, inflammation diseases e.g. RA
142
What is the inheritance pattern of spherocytosis and elliptocytosis?
Autosomal dominant
143
What are the characteristic cells seen on blood film in AML?
Auer rods
144
Which is the commonest Ca in children?
ALL
145
What is a myeloma?
an abnormal proliferation of a single clone of plasma cells, resulting in the production of Igs that cause the dysfunction of many organs
146
Which type of Igs are found in myeloma and what is the peak age of onset?
2/3rds = IgG, 1/3rd = IgA
| Peak age = 70yrs
147
What is the presentation of myeloma?
CRAB
C: hypercalcaemia
R: renal impairment (d/t increase in the Tamm-Hors-fall protein deposition in the distal loop of Henle etc)
A: anaemia/neutropaenia/thrombocytopaenia
B: osteolytic bone lesions - may cause back pain, pathological fractures or vertebral collapse (d/t increased osteoclast activity from abnormal Ig signalling)
148
Investigations in myeloma?
Serum protein electrophoresis – see a monoclonal band/paraprotein
Urine protein electrophoresis – see Bence Jones proteins (free Ig light chains of kappa or lambda type)
Imaging – X-rays: ‘punched-out’ lytic lesions (rain-drop skull, vertebral collapse, fractures, osteoporosis)
Bone marrow biopsy – increase in plasma cells
149
How to manage myeloma?
```
Supportive:
Analgesia
Bisphosphonates
Local radiotherapy
Correct anaemia – transfusion/EPO
Correct renal failure – ensure adequate fluid intake, dialysis
Treat infections – broad-spec abx
May need regular IVIg infusions
```
```
Chemo:
VAD regime (Vincristine, Adriamycin, Dexamethasone)
```
150
Complications of myeloma?
Hypercalcaemia, spinal cord compression, hyperviscosity, acute renal injury
151
What is the most useful marker of prognosis in myeloma?
B2-microglobulin - tumour marker
>5.5 = poor
Usually a blood test
Low levels of albumin are also assoc with poor prognosis
152
Investigations of pernicious anaemia?
```
IF Abs (first-line)
Gastric parietal Abs
```
153
What is haptoglobin?
A substance produced in the liver which binds to free haemoglobin in the blood and helps it to clear.
Therefore if ++ haemoglobin in blood stream because of RBC haemolysis, there will be more haptoglobin binding/excretion and lower levels in the blood
154
What is hemopexin?
Binds to free heme to transport it to the liver
155
What causes PRV?
Clonal proliferation of a BM stem cell -> increase in RBC volume
156
Common age for PRV?
Common 60 years
157
Common mutation in PRV?
JAK2 mutation present in 95% of patients – causes the haemopoietic stem cell to be constantly switched on and divide
158
Symptoms of PRV?
* Hyper-viscosity
* Red/red-blue tinge of nose, ear, lips, mouth
* Pruritis, typically after a hot bath (due to histamine release from excess basophils and mast cells)
* Splenomegaly
* Flushing
* Gout, kidney stones
159
Investigations in PRV?
Often has raised neutrophils/basophils and platelets
| Typically low EPO levels
160
Treatment of PRV?
Aspirin
1st-line: Venesection
Hydroxyurea (slight increased risk of secondary leukaemia)
161
Complications of PRV?
Predisposes individual to blood clots
Progression to myelofibrosis (when cell dysfunction turns into bone marrow suppression) or acute leukaemia (AML) may occur
162
What can cause TTP?
post-infection e.g. urinary, gastrointestinal
pregnancy
drugs: ciclosporin, oCP, penicillin, clopidogrel, aciclovir
tumours
SLE
HIV
163
What is Bruton's (x-linked) congenital agammaglobulinaemia?
Genetic problem causes a severe block in B cell development
Recurrent bacterial infections are seen
Absence of B-cells with reduced Igs of all classes
164
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Primary immunodeficiency:
neutrophil disorders (3)?
B-cell disorders (3)?
T-cell disorders (1)?
B + T-cell disorders (4)?
```
Neutro:
Chronic granulomatous disease, Chediak-Higashi syndrome, Leukocyte adhesion deficiency
B-cell:
Common variable immunodeficiency, Bruton's (x-linked) congenital agammaglobulinaemia, Selective immunoglobulin A deficiency
T-cell:
DiGeorge syndrome
B+T:
Severe combined immunodeficiency, Ataxic telangiectasia, Wiskott-Aldrich syndrome, Hyper IgM Syndromes
165
What is chronic granulomatous disease?
Causes recurrent pneumonias and abscesses, particularly due to catalase-positive bacteria (e.g. Staphylococcus aureus and fungi (e.g. Aspergillus)
Negative nitroblue-tetrazolium test
Abnormal dihydrorhodamine flow cytometry test
166
What is selective immunoglobulin A deficiency?
Most common primary antibody deficiency. Recurrent sinus and respiratory infections
Associated with coeliac disease and may cause false negative coeliac antibody screen
Severe reactions to blood transfusions may occur (anti-IgA antibodies → anaphylaxis)
167
What is ataxic telangiectasia?
Autosomal recessive. Features include cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia
168
Transfusion related complications?
Immunological: acute haemolytic, non-haemolytic febrile, allergic/anaphylaxis
infective
transfusion-related acute lung injury (TRALI)
transfusion-associated circulatory overload (TACO)
other: hyperkalaemia, iron overload, clotting
169
What is the pathophysiology of non-haemolytic febrile reaction in blood transfusions?
Thought to be caused by Abs reacting with white cell fragments in the blood product and cytokines that have leaked from the blood cell during storage
More common in platelet transfusions
170
Management of non-haemolytic febrile reaction in blood transfusions?
Slow or stop the transfusion
Paracetamol
Monitor
171
Which type of deficiency can predispose people to anaphylaxis blood trans reactions?
IgA deficiency
Unsure why: possibly because anti-IgA Abs circulate and therefore react to IgA in the donated blood
172
What is transfusion-related acute lung injury (TRALI)?
Non-cardiogenic pulmonary oedema thought to be secondary to increased vascular permeability caused by host neutrophils that become activated by substances in donated blood
173
Features and management of TRALI?
Hypoxia, pulmonary infiltrates on chest x-ray, fever, hypotension
Stop the transfusion
Oxygen and supportive care
174
What is paroxysmal nocturnal haemoglobinuria?
An acquired disorder leading to in vascular haemolysis. It is thought to be caused by increased sensitivity of cell membranes to complement due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI).
175
What are the features of paroxysmal nocturnal haemoglobinuria?
PNH - caused by stem cells producing defective Hb which breaks down easily, therefore:
haemolytic anaemia
haemoglobinuria: classically dark-coloured urine in the morning (urine has concentrated overnight during sleep)
Depending on severity, if BM severely effected - may be pancytopaenia
Also get thrombosis e.g. Budd-Chiari syndrome
176
Diagnosis of paroxysmal nocturnal haemoglobinuria?
flow cytometry of blood to detect low levels of CD59 and CD55
177
Management of paroxysmal nocturnal haemoglobinuria?
Blood product replacement
Anticoagulation
eculizumab - trial
stemcell transplant
178
What occurs in hodgkin's lymphoma?
caused by malignant proliferation of lymphocytes, these accumulate in the LNs or infiltrate other organs
179
Characteristic cells in hodgkin's lymphoma?
REED-STERNBERG cells
180
Features of Hodgkin's lymphoma?
Painless lymphadenopathy (cervical, supraclavicular, axillary, inguinal)
-> Can cause severe pain on alcohol consumption
B symptoms – fever, night sweats, weight loss, fatigue
Generalised pruritis
Chest discomfort, cough, SOB -> with mediastinal LN involvement
Hepatosplenomegaly
Emergency presentation: infection, SVCO
181
Most common type of Hodgkin's and non-Hodgkin's lymphoma?
Non-Hod: Diffuse large B-cell lymphoma
| Hod: Nodular sclerosing
182
Ann Arbor staging in Hodgkin's lymphoma?
Stage 1: involvement of single LN region
Stage 2: involvement of 2+ LN regions on same side of diaphragm
Stage 3: involvement of LNs on opposite sides of diaphragm, may include spleen
Stage 4: Diffuse extra lymphatic disease
Add A or B if evidence of systemic symptoms
183
Management of Hodgkin's lymphoma?
Chemotherapy – ABVD
| For relapsed disease: Chemo + autologous SC transplant
184
Chemo side effects?
Myelosuppression, nausea, alopecia, infection, infertility
185
Radio side effects?
increased risk of 2* malignancies, IHD, hypothyroidism, fibrosis
186
Causes of non-Hodgkin's lymphomas?
Immunodeficiency – drugs e.g. chemo
HIV
Certain conditions – SLE, RA
H. pylori, HH8, hep C
187
Example of high and low grade non-Hodgkin's lymphomas?
High grade e.g. diffuse large B cell
| Low grade e.g. MALT lymphoma
188
Features of non-Hodgkin's lymphomas?
Superficial lymphadenopathy (75%)
B symptoms – less common than in Hodgkin’s
Pancytopaenia – infections, anaemia, bleeding
1) Gastric MALT/non-MALT lymphomas – MALT are caused by H. pylori, presentation usually late with anorexia, WL
2) Small bowel lymphomas – diarrhoea, vomiting, abdo pain, WL, poor prognosis
3) Other sites: bone, CNS, lung
189
Management of non-Hodgkin's lymphomas?
Low-grade lymphomas – non-aggressive, often incurable (Waldenström macroglobulinemia)
• Local radiotherapy if localised disease
• Watchful waiting for asymptomatic patients
• Rituximab
• Rituximab + chemo
High-grade – aggressive, often curable (e.g. Burkitt’s)
• R-CHOP (highest risk regime for neutropenic sepsis)
• Other chemos/radiotherapy
• SC transplant
190
Most common type of non-Hodgkin's lymphoma?
diffuse large B cell
191
Causes of raised leucocyte alkaline phosphatase?
```
myelofibrosis
leukaemoid reactions
polycythaemia rubra vera
infections
steroids, Cushing's syndrome
pregnancy, oral contraceptive pill
```
192
Causes of low leucocyte alkaline phosphatase?
chronic myeloid leukaemia
pernicious anaemia
paroxysmal nocturnal haemoglobinuria
infectious mononucleosis
193
What is the link between antithrombin 3 deficiency and heparin?
Antithrombin 3 binds to heparin and enhances its effects = inhibition of clotting factors. However if there is a deficiency in AT3 then there won't be any to bind to - therefore to treat the condition (primarily in pregnancy) you need much higher levels of heparin
194
What are the features of lead poisoning?
Abdominal pain
Peripheral neuropathy
blue lines on gum margin
195
Investigations in suspected lead poisoning?
Blood lead levels - >10 mcg/dl are considered significant
FBC: microcytic anaemia
Blood film: basophilic stippling and clover-leaf morphology
raised serum and urine levels of delta aminolaevulinic acid may be seen
urinary coproporphyrin is also increased
in children, lead can accumulate in the metaphysis of the bones
196
Management of lead poisoning?
various chelating agents are currently used:
PO dimercaptosuccinic acid (DMSA)
PO D-penicillamine
197
What is acute intermittent porphyria?
AD condition
Caused be a defect in the enzyme porphobilinogen deaminase (involved in the synthesis of haem). Without this the precursors build up (delta aminolaevulinic acid and porphobilinogen)
198
What is the presentation of acute intermittent porphyria?
abdominal and neuropsychiatric symptoms in 20-40 year olds
| Urine turns red when standing
199
Diagnosis of acute intermittent porphyria?
raised urinary porphobilinogen (elevated between attacks and to a greater extent during acute attacks)
raised serum levels of delta aminolaevulinic acid and porphobilinogen
200
Which chemical mediator is mainly responsible for the tissue oedema seen in patients in hereditary angioedema?
Uncontrolled release of bradykinin
201
What is Meig's syndrome?
triad of benign ovarian tumor (fibroids) with ascites and pleural effusion that resolves after resection of the tumor
May be elevated CA 125
202
Causes of intravascular haemolysis?
```
mismatched blood transfusion
G6PD deficiency
red cell fragmentation: heart valves, TTP, DIC, HUS
paroxysmal nocturnal haemoglobinuria
cold autoimmune haemolytic anaemia
```
203
Causes of extravascular haemolysis?
haemoglobinopathies: SCA, thalassaemia
hereditary spherocytosis
haemolytic disease of newborn
warm autoimmune haemolytic anaemia
204
Who are the universal donors for blood products/FFP?
For Blood = O negative
For FFP = AB negative
Because AB won’t have the anti-A and anti-B Abs in the plasma
205
What is meant by warm vs cold AIHA?
Autoimmune haemolytic anaemia (AIHA) may be divided in to 'warm' and 'cold' types, according to at what temperature the antibodies best cause haemolysis
Remember Ghana and Manchester
206
What is warm AIHA?
Haemolysis occurs best at body temperature
Extravascular haemolysis occurs in spleen
Usually IgG abs
Causes: AI: e.g. SLE
neoplasia: e.g. lymphoma, CLL
drugs: e.g. methyldopa
Mx: steroids, immunosuppression, splenectomy
207
What is cold AIHA?
Haemolysis occurs best at 4*c
Intravascular haemolysis usually occurs
Usually IgM abs
May be Raynaud's and acrocynaosis
Causes: neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
208
Which type of AML is associated with good prognosis and what is the chromosome translocation?
good prognosis: t(15;17)
| Acute promyelocytic leukaemia M3
209
What is DIC?
```
When both intrinsic and extrinsic pathway are triggered
Increased thrombin (clots) and plasmin (bleeding) occur
The release of tissue factor in DIC mediates this process
```
210
What can trigger DIC?
Infections and sepsis
Obstetric complications e.g. HELLP syndrome
Malignancy
Trauma
211
What would you see on blood results in DIC?
```
Low platelets
PROLONGED: APTT, prothrombin and bleeding time
Raised fibrin degradation products
Low fibrinogen
Schistocytes (fragmented part of RBC)
```
212
What are both PT and APTT a measure of?
Prothrombin time = time to clot via the extrinsic pathway (PE)
aPTT = time to clot via the intrinsic pathway (AI)
213
Causes of hyposplenism?
```
splenectomy
sickle-cell
coeliac disease, dermatitis herpetiformis
Graves' disease
systemic lupus erythematosus
amyloid
```
214
Which medication is used to prevent haemorrhage cystitis in cyclophosphamide use?
Mesna
215
How to differentiate MGUS from myeloma?
normal immune function
normal B2 microglobulin levels
lower level of paraproteinaemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA)
stable level of paraproteinaemia
no clinical features of myeloma (e.g. lytic lesions on x-rays or renal disease/bone pain)
216
What is the risk of MGUS turning into myeloma?
50% by 15 years
217
What is IgG4 related disease?
Similar to sarcoidosis in that it can affect lots of different organs
Various diseases can be categoried as IgG related:
Riedel's Thyroiditis
AI pancreatitis
Mediastinal and Retroperitoneal Fibrosis
Kuttner's Tumour (submandibular glands) & Mikulicz Syndrome (salivary and lacrimal glands)
Possibly sjogren's and primary biliary cirrhosis
218
What is hairy cell leukaemia? More common in male/female?
Hairy cell leukaemia is a rare malignant proliferation disorder of B cells
Usually classified as a subtype of CLL
More common in males
219
What are the symptoms of hairy cell leukaemia?
the "hairy cells" (malignant B lymphocytes) accumulate in the bone marrow, interfering with the production of normal cells - causing pancytopaenia
Also accumulate in the spleen - splenomegaly
skin vasculitis in 1/3 patients
220
What are the investigations in hairy cell leukaemia?
TAP and TRAP
'dry tap' despite bone marrow hypercellularity
tartrate resistant acid phosphotase (TRAP) stain positive
221
Management of hairy cell leukaemia?
chemotherapy is first-line: cladribine, pentostatin
| immunotherapy is second-line: rituximab, IF-alpha
222
What is cryoglobulinaemia?
Igs which undergo reversible precipitation at 4*c, dissolve when warmed to 37*c. One-third of cases are idiopathic
223
What are the three different types of cryoglobulinaemia?
```
type I (25%): monoclonal - IgG or IgM
associations: multiple myeloma, Waldenstrom macroglobulinaemia
Only type associated with raynauds
```
```
type II (25%): mixed monoclonal and polyclonal: usually with rheumatoid factor
associations: hepatitis C, rheumatoid arthritis, Sjogren's, lymphoma
```
```
type III (50%): polyclonal: usually with rheumatoid factor
associations: rheumatoid arthritis, Sjogren's
```
224
What are two blood results that would make you suspect cryoglobulinaemia?
```
low complement (esp. C4)
high ESR
```
225
How to manage cryoglobulinaemia?
immunosuppression
| plasmapheresis
226
In a question with both Hep C and low complement, what condition should you think of?
Cryoglobulinaemia
227
How long do you treat a DVT for with warfarin?
provoked (e.g. recent surgery): 3 months
| unprovoked: 6 months
228
In MGUS, how would you know if the condition has turned into waldenstrom's macroglobulinaemia or MM?
Waldenstrom's macroglobulinaemia - Organomegaly with no bone lesions
Multiple myeloma - Bone lesions with no organomegaly
229
What class of drugs is co-trimoxazole in?
Sulphonamides
