Clinical Haematology/Oncology Flashcards
(197 cards)
1
Q
Causes of intravascular haemolysis
A
mismatched blood transfusion G6PD deficiency* red cell fragmentation: heart valves, TTP, DIC, HUS paroxysmal nocturnal haemoglobinuria cold autoimmune haemolytic anaemia
2
Q
Causes of extravascular haemolysis
A
haemoglobinopathies: sickle cell, thalassaemia
hereditary spherocytosis
haemolytic disease of newborn
warm autoimmune haemolytic anaemia
3
Q
Features of AML
A
anaemia: pallor, lethargy, weakness
neutropenia: whilst white cell counts may be very high, functioning neutrophil levels may be low leading to frequent infections etc
thrombocytopenia: bleeding
splenomegaly
bone pain
4
Q
Poor prognostic factors of AML
A
> 60 years
20% blasts after first course of chemo
cytogenetics: deletions of chromosome 5 or 7
5
Q
Acute promyelocytic leukaemia M3
A
associated with t(15;17)
fusion of PML and RAR-alpha genes
presents younger than other types of AML (average = 25 years old)
Auer rods (seen with myeloperoxidase stain)
DIC or thrombocytopenia often at presentation
good prognosis
6
Q
French-American-British classification of AML
A
MO - undifferentiated M1 - without maturation M2 - with granulocytic maturation M3 - acute promyelocytic M4 - granulocytic and monocytic maturation M5 - monocytic M6 - erythroleukaemia M7 - megakaryoblastic
7
Q
Megaloblastic causes of macrocytic anaemia
A
vitamin B12 deficiency
folate deficiency
8
Q
Normoblastic causes of macrocytic anaemia
A
alcohol liver disease hypothyroidism pregnancy reticulocytosis myelodysplasia drugs: cytotoxics
9
Q
Target cells
A
Sickle-cell/thalassaemia
Iron-deficiency anaemia
Hyposplenism
Liver disease
10
Q
‘Tear-drop’ poikilocytes
A
Myelofibrosis
11
Q
Spherocytes
A
Hereditary spherocytosis
Autoimmune hemolytic anaemia
12
Q
Basophilic stippling
A
Lead poisoning
Thalassaemia
Sideroblastic anaemia
Myelodysplasia
13
Q
Howell-Jolly bodies
A
Hyposplenism
14
Q
Heinz bodies
A
G6PD deficiency
Alpha-thalassaemia
15
Q
Schistocytes (‘helmet cells’)
A
Intravascular haemolysis
Mechanical heart valve
Disseminated intravascular coagulation
16
Q
‘Pencil’ poikilocytes
A
Iron deficency anaemia
17
Q
Burr cells (echinocytes)
A
Uraemia
Pyruvate kinase deficiency
18
Q
Acanthocytes
A
Abetalipoproteinemia
19
Q
Monoclonal antibodies
A
CA-125 - Ovarian cancer
CA 19 -9 pancreatic cancer
Ca 15-3 Breast cancer
20
Q
Tumour antigens
A
PSA
Alfa-feto protein - hepatocellular carcinoma, teratoma
Carcinoembryonic antigen - colorectal ca
S-100 - schwannoma, melanoma
Bombesin - small cell lung ca, gastric ca, neuroblastoma
21
Q
Causes of thrombocytosis
A
reactive: platelets are an acute phase reactant - platelet count can increase in response to stress such as a severe infection, surgery. Iron deficiency anaemia can also cause a reactive thrombocytosis
malignancy
essential thrombocytosis (see below), or as part of another myeloproliferative disorder such as chronic myeloid leukaemia or polycythaemia rubra vera
hyposplenism
22
Q
What is essential thrombocytosis
A
myeloproliferative disorders which overlaps with chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis. Megakaryocyte proliferation results in an overproduction of platelets.
23
Q
features of essential thrombocytosis
A
platelet count > 600 * 109/l
both thrombosis (venous or arterial) and haemorrhage can be seen
a characteristic symptom is a burning sensation in the hands
a JAK2 mutation is found in around 50% of patients
24
Q
Management of essential thrombocytosis
A
hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count
interferon-α is also used in younger patients
low-dose aspirin may be used to reduce the thrombotic risk
25
Poor prognostic factors in 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
```
26
Chromosomal changes in CLL
deletion of the long arm of chromosome 13 (del 13q) is the most common abnormality, being seen in around 50% of patients. It is associated with a good prognosis
deletions of part of the short arm of chromosome 17 (del 17p) are seen in around 5-10% of patients and are associated with a poor prognosis
27
Chromosomal changes in CML
Phillidelphia chromosome
It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein that has tyrosine kinase activity in excess of normal.
28
Features of CML
anaemia: lethargy
weight loss and sweating are common
splenomegaly may be marked → abdo discomfort
an increase in granulocytes at different stages of maturation +/- thrombocytosis
decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)
29
Management of CML
imatinib is now considered first-line treatment
inhibitor of the tyrosine kinase associated with the BCR-ABL defect
very high response rate in chronic phase CML
hydroxyurea
interferon-alpha
allogenic bone marrow transplant
30
Microcytic anaemia - causes
```
iron-deficiency anaemia
thalassaemia*
congenital sideroblastic anaemia
anaemia of chronic disease (more commonly a normocytic, normochromic picture)
lead poisoning
```
31
What is tranexamic acid
Tranexamic acid is a synthetic derivative of lysine. Its primary mode of action is as an antifibrinolytic that reversibly binds to lysine receptor sites on plasminogen or plasmin. This prevents plasmin from binding to and degrading fibrin.
32
What is G6PD deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red blood cell enzyme defect. It is more common in people from the Mediterranean and Africa and is inherited in an X-linked recessive fashion. Many drugs can precipitate a crisis as well as infections and broad (fava) beans
33
pathophysiology of G6PD deficiency
G6PD is the first step in the pentose phosphate pathway, which converts glucose-6-phosphate→ 6-phosphogluconolactone
this reaction also results in nicotinamide adenine dinucleotide phosphate (NADP) → NADPH
i.e. glucose-6-phosphate + NADP → 6-phosphogluconolactone + NADPH
NADPH is important for converting oxidizied glutathine back to it's reduced form
reduced glutathine protects red blood cells from oxidative damage by oxidants such as superoxide anion (O2-) and hydrogen peroxide
↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress
34
Features of G6PD deficiency
```
neonatal jaundice is often seen
intravascular haemolysis
gallstones are common
splenomegaly may be present
Heinz bodies on blood films. Bite and blister cells may also be seen
```
35
Drugs causing haemolysis in G6PD deficiency
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
36
Safe drugs in G6PD deficiency
```
penicillins
cephalosporins
macrolides
tetracyclines
trimethoprim
```
37
Abetalipoproteinemia
rare inherited disorder that impacts fab absorption from the intestines and reduces lipid mobilisation from the liver
causes Acanthocytes
38
severe combined immunodeficiency
combined B and T cell deficiency
39
Risk factors for Breast Cancer
BRCA1, BRCA2 genes - 40% lifetime risk of breast/ovarian cancer
1st degree relative premenopausal relative with breast cancer (e.g. mother)
nulliparity, 1st pregnancy > 30 yrs (twice risk of women having 1st child < 25 yrs)
early menarche, late menopause
combined hormone replacement therapy (relative risk increase * 1.023/year of use), combined oral contraceptive use
past breast cancer
not breastfeeding
ionising radiation
p53 gene mutations
obesity
previous surgery for benign disease (?more follow-up, scar hides lump)
40
Mechanism of Action for Cyclophosphamide
Alkylating agent - causes cross-linking in DNA
41
Adverse Effects of cyclophosphamide
Haemorrhagic cystitis, myelosuppression, transitional cell carcinoma
42
Mechanism of action of bleomycin
Degrades preformed DNA
43
Adverse effects of bleomycin
lung fibrosis
44
Mechanism of action for Anthracyclines (e.g doxorubicin)
Stabilizes DNA-topoisomerase II complex inhibits DNA & RNA synthesis
45
Adverse effects of anthracyclines e.g. doxorubicin
Cardiomyopathy
46
Blood film abnormalities
Hyposplenism
```
siderotic granules
target cells
acanthocytes
Howell-Jolly bodies
Pappenheimer bodies
```
47
Blood film abnormalities
Thalassemia
Heinz bodies
basophilic stippling
target cells
48
Blood film abnormalities
Iron Deficiency Anaemia
target cells
| pencil poikilocytes
49
CLL investigations
full blood count:
lymphocytosis
anaemia
blood film: smudge cells (also known as smear cells)
immunophenotyping is the key investigation
50
Clinical features of CLL
often none: may be picked up by an incidental finding of lymphocytosis
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than chronic myeloid leukaemia
51
What is CLL
Chronic lymphocytic leukaemia (CLL) is caused by a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%). It is the most common form of leukaemia seen in adults.
52
types of hogkins lymphoma
nodular sclerosing- most common
mixed cellularity- reed sternburg cells
lymphocyte predominant- best prognosis
lymphocyte depleted- worst prognosis
53
aetiology of congenital sideroblastic anaemia
Delta-aminolevulinate synthase-2 deficiency
54
What is congential sideroblastic anaemia
condition where red cells fail to completely form haem, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired.
55
Acquired causes of sideroblastic anaemia
myelodysplasia
alcohol
lead
anti-TB medications
56
investigations of sideroblastic anaemia
```
full blood count
hypochromic microcytic anaemia (more so in congenital)
iron studies
high ferritin
high iron
high transferrin saturation
blood film
basophilic stippling of red blood cells
bone marrow
Prussian blue staining will show ringed sideroblasts
Pyroxidine may be useful
```
57
Features of CLL
often none: may be picked up by an incidental finding of lymphocytosis
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than chronic myeloid leukaemia
58
Investigations for CLL
often none: may be picked up by an incidental finding of lymphocytosis
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than chronic myeloid leukaemia
59
cause of CLL
monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%). It is the most common form of leukaemia seen in adults.
60
Blood film abnormalities
| Caused by hyposplenism
```
siderotic granules
target cells
acanthocytes
Howell-Jolly bodies
Pappenheimer bodies
```
61
blood film abnormalities
| caused by intravascular haemolysis
schistocytes ('helmet cells')
62
blood film abnormalities
| liver disease
target cells
63
blood film abnormalities
| Thalassaemia
Heinz bodies
basophilic stippling
target cells
64
blood film abnormalities
| iron deficiency anaemia
target cells
| pencil poikilocytes
65
treatment of essential thrombocytosis
hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count
interferon-α is also used in younger patients
low-dose aspirin may be used to reduce the thrombotic risk
66
Acute lymphoblastic leukaemia: good prognostic features
```
Del(9p)
Pre-B phenotype
low initial WBC
French-American-British (FAB) L1 type
common ALL
```
67
Acute lymphoblastic leukaemia
| poor prognostic factors
```
FAB L3 type
T or B cell surface markers
Philadelphia translocation, t(9;22)
age < 2 years or > 10 years
male sex
CNS involvement
high initial WBC (e.g. > 100 * 109/l)
non-Caucasian
```
67
Acute lymphoblastic leukaemia
| poor prognostic factors
```
FAB L3 type
T or B cell surface markers
Philadelphia translocation, t(9;22)
age < 2 years or > 10 years
male sex
CNS involvement
high initial WBC (e.g. > 100 * 109/l)
non-Caucasian
```
68
Causes of massive hepatomegaly
```
myelofibrosis
chronic myeloid leukaemia
visceral leishmaniasis (kala-azar)
malaria
Gaucher's syndrome
```
69
C-MYC
Burkitt Lymphoma
70
BCL-2
Follicular lymphoma
71
Types of Burkitt's Lymphoma
Burkitt's lymphoma is a high-grade B-cell neoplasm. There are two major forms:
endemic (African) form: typically involves maxilla or mandible
sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV
72
Burkitt's lymphoma
| Microscopy findings
'starry sky' appearance: lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells
73
complications of tumour lysis syndrome
```
hyperkalaemia
hyperphosphataemia
hypocalcaemia
hyperuricaemia
acute renal failure
```
74
Treatment of tumour lysis syndrome
Rasburicase (a recombinant version of urate oxidase, an enzyme which catalyses the conversion of uric acid to allantoin*)
75
Mechanism of action
| Fluorouracil (5-FU)
Pyrimidine analogue inducing cell cycle arrest and apoptosis by blocking thymidylate synthase (works during S phase)
76
Fluorouracil (5-FU) adverse reactions
Myelosuppression, mucositis, dermatitis
77
Anti-metabolites (chemo)
Methotrexate
Fluorouracil (5-FU)
6-mercaptopurine Purine analogue that is activated by HGPRTase, decreasing purine synthesis Myelosuppression
Cytarabine
78
Mechanism of action: Methotrexate
Inhibits dihydrofolate reductase and thymidylate synthesis
79
Methotrexate Adverse effects
Myelosuppression, mucositis, liver fibrosis, lung fibrosis
80
Mechanism of action 6-mercaptopurine
Purine analogue that is activated by HGPRTase, decreasing purine synthesis
81
Adverse effects: 6-mercaptopurine
Myelosuppression
82
Mechanism of action Cytarabine
Pyrimidine antagonist. Interferes with DNA synthesis specifically at the S-phase of the cell cycle and inhibits DNA polymerase
83
Adverse effects of Cytarabine
Myelosuppression, ataxia
84
Chemotherapy: acts on microtubules
Vincristine, vinblastine, Docetaxel
85
Mechanism of action
| Vinchrinstine, vinblastine
Inhibits formation of microtubules
86
Adverse effects vincristine
Reversible peripheral neuropathy, paralytic ileus
87
Adverse effects vinblastine
myelosuppression
88
Mechanism of action Docetaxel
Prevents microtubule depolymerisation & disassembly, decreasing free tubulin
89
Adverse effects docetaxel
Neutropaenia
90
Cyclophosphamide- alkylating agent chemotherapy
Alkylating agent - causes cross-linking in DNA
91
Cyclophosphamide adverse effects
Haemorrhagic cystitis, myelosuppression, transitional cell carcinoma
92
Cytotoxic antibiotics
Bleomycin, anthracyclines (e.g. doxorubicin)
93
Mechanismof action Bleomycin
Degrades preformed DNA
94
Adverse effects: Bleomycin
Lung fibrosis
95
Mechanism of action
| Anthracyclines (e.g doxorubicin)
Stabilizes DNA-topoisomerase II complex inhibits DNA & RNA synthesis
96
Adverse reactions Anthracyclines (e.g. doxorubicin)
Cardiomyopathy
97
Topoisomerase inhibitors mechanism of action
Inhibits topoisomerase I which prevents relaxation of supercoiled DNA
98
Examples of topoisomerase inhibitors
Irinotecan
99
Adverse effects of irinotecan
myelosuppression
100
Cisplatin- mechanism of action
Causes cross-linking in DNA
101
Cisplatin - adverse effects
Ototoxicity, peripheral neuropathy, hypomagnesaemia
102
Hydroxyurea (hydroxycarbamide) mechanism of action
Inhibits ribonucleotide reductase, decreasing DNA synthesis
103
Hydroxyurea adverse effects
myleosuppression
104
Causes of normocytic anaemia
```
anaemia of chronic disease
chronic kidney disease
aplastic anaemia
haemolytic anaemia
acute blood loss
```
105
What is mantle cell lymphoma
sub type of B cell lymphoma
106
Genetics of Mantle Cell Lymphoma
```
CD5+, CD19+, CD22+, CD23-, CD10-
associated translocation (11;14) causing over-expression of the cyclin D1 (BCL-1) gene
```
107
Features of mantle cell lymphoma
widespread lymphadenopathy
| poor prognosis
108
What is paroxysmal nocturnal haematuria
an acquired disorder leading to haemolysis (mainly intravascular) of haematological cells. It is thought to be caused by increased sensitivity of cell membranes to complement (see below) due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI). Patients are more prone to venous thrombosis
109
Pathology of paroxysmal nocturnal haematuriaFeat
GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation
110
Features of paroxysmal nocturnal haematuria
haemolytic anaemia
red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
thrombosis e.g. Budd-Chiari syndrome
aplastic anaemia may develop in some patients
111
Diagnosis of paroxysmal nocturnal haematuria
flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham's test as the gold standard investigation in PNH
Ham's test: acid-induced haemolysis (normal red cells would not)
112
Management of paroxysmal nocturnal haematuria
blood product replacement
anticoagulation
eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis
stem cell transplantation
113
blood film abnormalities - intravascular haemolysis
schistocytes ('helmet cells')
114
Blood film abnormalities - thalassemia
Heinz bodies
basophilic stippling
target cells
115
Lead poisoning- clinical features
```
abdominal pain
peripheral neuropathy (mainly motor)
fatigue
constipation
blue lines on gum margin (only 20% of adult patients, very rare in children
```
116
Lead poisoning
acute intermittent porphyria, lead poisoning should be considered in questions giving a combination of abdominal pain and neurological signs. Lead poisoning results in defective ferrochelatase and ALA dehydratase function.
117
Lead poisoning - investigations
blood lead level, blood film- basophilic stippling, clover leaf morphology, full blood count: microcytic anaemia, raised serum and urine levels of delta aminolaevulinic acid, urinary coproporphyrin is also increased (urinary porphobilinogen and uroporphyrin levels are normal to slightly increased)
in children, lead can accumulate in the metaphysis of the bones although x-rays are not part of the standard work-up
118
Management of Lead poisoning
dimercaptosuccinic acid (DMSA)
D-penicillamine
EDTA
dimercaprol
119
What is Waldenstrom's macroglobulinaemia
an uncommon condition seen in older men. It is a lymphoplasmacytoid malignancy characterised by the secretion of a monoclonal IgM paraprotein
120
Features of Waldenstrom's macroglobulinaemia
monoclonal IgM paraproteinaemia
systemic upset: weight loss, lethargy
hyperviscosity syndrome e.g. visual disturbance
the pentameric configuration of IgM increases serum viscosity
hepatosplenomegaly
lymphadenopathy
cryoglobulinaemia e.g. Raynaud's
121
Role of von Willebrand Factor
large glycoprotein which forms massive multimers up to 1,000,000 Da in size
promotes platelet adhesion to damaged endothelium
carrier molecule for factor VIII
122
What is von Willebrand's disease
Von Willebrand's disease is the most common inherited bleeding disorder. The majority of cases are inherited in an autosomal dominant fashion* and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas are rare
123
Types of von Willebrand's disease
type 1: partial reduction in vWF (80% of patients)
type 2*: abnormal form of vWF
type 3**: total lack of vWF (autosomal recessive)
124
Investigations of von Willebrand's
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristoce
125
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
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
126
What is Methaemoglobinaemia
Methaemoglobinaemia describes haemoglobin which has been oxidised from Fe2+ to Fe3+. This is normally regulated by NADH methaemoglobin reductase, which transfers electrons from NADH to methaemoglobin resulting in the reduction of methaemoglobin to haemoglobin. There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation curve is moved to the left
127
Congenital causes of Methaemoglobinaemia
haemoglobin chain variants: HbM, HbH
| NADH methaemoglobin reductase deficiency
128
Acquired causes of methaemoglobinaemia
drugs: sulphonamides, nitrates (including recreational nitrates e.g. amyl nitrite 'poppers'), dapsone, sodium nitroprusside, primaquine
chemicals: aniline dyes
129
Features of methaemoglobinaemia
'chocolate' cyanosis
dyspnoea, anxiety, headache
severe: acidosis, arrhythmias, seizures, coma
normal pO2 but decreased oxygen saturation
130
Management of methaemoglobinaemia
NADH - methaemoglobinaemia reductase deficiency: ascorbic acid
IV methylthioninium chloride (methylene blue) if acquired
131
stereotypical history of hereditary spherocytosis
a 10-year-old child with a history of neonatal jaundice develops pallor and jaundice after an upper respiratory tract infection associated with erythematous cheeks. Splenomegaly is noted on examination
132
Basics of hereditary spherocytosis
most common hereditary haemolytic anaemia in people of northern European descent
autosomal dominant defect of red blood cell cytoskeleton
the normal biconcave disc shape is replaced by a sphere-shaped red blood cell
red blood cell survival reduced as destroyed by the spleen
133
Presentation of hereditary spherocytosis
```
failure to thrive
jaundice, gallstones
splenomegaly
aplastic crisis precipitated by parvovirus infection
degree of haemolysis variable
MCHC elevated
```
134
Management of hereditary spherocytosis
```
acute haemolytic crisis:
treatment is generally supportive
transfusion if necessary
longer term treatment:
folate replacement
splenectomy
```
135
Cancer caused by nitrosamines
oesophageal and gastric
136
histology of hodgkin's lymphoma
giant B cells with bilobed nuclei that have prominent eosinophilic inclusions
136
histology of hodgkin's lymphoma
giant B cells with bilobed nuclei that have prominent eosinophilic inclusions
137
Neutrophil disorders: Chronic Granulomatous Disease
Lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species 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
138
Neutrophil disorders: Chediak-Higashi syndrome
Microtubule polymerization defect which leads to a decrease in phagocytosis Affected children have 'partial albinism' and peripheral neuropathy. Recurrent bacterial infections are seen
Giant granules in neutrophils and platelets
139
neutophil disorders: leukocyte adhesion disorders
Defect of LFA-1 integrin (CD18) protein on neutrophils Recurrent bacterial infections.
Delay in umbilical cord sloughing may be seen
Absence of neutrophils/pus at sites of infection
140
What is the underlying aetiology of acute intermittent porphyria?
Defect in porphobilinogen deaminase
141
what is the underlying aetiology of porphyria cutanea tarda
Defect in uroporphyrinogen decarboxylase
142
Aetiology of thrombotic thrombocytopenic purpura
Deficiency of ADAMTS13 (a metalloprotease enzyme)
143
Aetiology of ITP
Antibodies directed against the glycoprotein IIb/IIIa or Ib-V-IX complex
144
Hypersegmented neutrophils are associated with
megaloblastic anaemia
145
Poor prognosit factors ALL
```
FAB L3 type
T or B cell surface markers
Philadelphia translocation, t(9;22)
age < 2 years or > 10 years
male sex
CNS involvement
high initial WBC (e.g. > 100 * 109/l)
non-Caucasian
```
146
Stereotypical history of autoimmune haemolytic anaemia
a 60-year-old woman presents with cold peripheries. Investigations show a normocytic anaemia and a positive direct antiglobulin test
147
Warm autoimmune haemolytic anaemia
occurs at body temperature
Extravascular sites e.g. spleen
autoimmune disease: e.g. systemic lupus erythematosus*
neoplasia: e.g. lymphoma, CLL
drugs: e.g. methyldopa
Management options include steroids, immunosuppression and splenectomy
148
Cold automimmune haemolytic anaemia
usually IgM and causes haemolysis best at 4 deg C. Haemolysis is mediated by complement and is more commonly intravascular. Features may include symptoms of Raynaud's and acrocynaosis. Patients respond less well to steroids
Causes of cold AIHA
neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
149
mechanism of action of irinotecan
Inhibits topoisomerase I which prevents relaxation of supercoiled DNA
150
Mechanism of action docetaxel
Prevents microtubule depolymerisation & disassembly, decreasing free tubulin
151
Thrombotic thrombocytopenia purpura (pathogenesis)
abnormally large and sticky multimers of von Willebrand's factor cause platelets to clump within vessels
in TTP there is a deficiency of ADAMTS13 (a metalloprotease enzyme) which breakdowns ('cleaves') large multimers of von Willebrand's factor
overlaps with haemolytic uraemic syndrome (HUS)
152
Features of thrombotic thrombocytopenic purpura
```
rare, typically adult females
fever
fluctuating neuro signs (microemboli)
microangiopathic haemolytic anaemia
thrombocytopenia
renal failure
```
153
Causes of thrombotic thrombocytopenia purpura
post-infection e.g. urinary, gastrointestinal
pregnancy
drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
tumours
SLE
HIV
154
Underlying defect in Chronic granulomatous disease
Lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species
Causes recurrent pneumonias and abscesses
155
Neutrophil disorders
| Underlying defect in Chediak-Higashi syndrome
Microtubule polymerization defect which leads to a decrease in phagocytosis Affected children have 'partial albinism' and peripheral neuropathy. Recurrent bacterial infections are seen
Giant granules in neutrophils and platelets
156
Neutrophil disorders:
| Underlying defect in Leukocyte adhesion deficiency
Defect of LFA-1 integrin (CD18) protein on neutrophils Recurrent bacterial infections.
Delay in umbilical cord sloughing may be seen
Absence of neutrophils/pus at sites of infection
157
B Cell disorders: Common variable immunodeficiency
Many varying causes Hypogammaglobulinemia is seen. May predispose to autoimmune disorders and lymphona
158
B Cell disorders: Bruton's (x-linked) congenital agammaglobulinaemia
Defect in Bruton's tyrosine kinase (BTK) gene that leads to a severe block in B cell development X-linked recessive. Recurrent bacterial infections are seen
Absence of B-cells with reduced immunoglogulins of all classes
159
B cell disorders: Selective immunoglobulin A deficiency
Maturation defect in B cells 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 → analphylaxis)
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T cell disorders: DiGeorge syndrome
22q11.2 deletion, failure to develop 3rd and 4th pharyngeal pouches Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fun
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Combined B- and T- cell related disorders:
| Severe combined immunodeficiency
Many varying causes. Most common (X-linked) due to defect in the common gamma chain, a protein used in the receptors for IL-2 and other interleukins. Other causes include adenosine deaminase deficiency Recurrent infections due to viruses, bacteria and fungi.
Reduced T-cell receptor excision circles
Stem cell transplantation may be successful
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Combined B- and T-cell disorders: Ataxic telangiectasia
Defect in DNA repair enzymes Autosomal recessive. Features include cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia
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Combined B- and T- cell disorders Wiskott-Aldrich syndrome
Defect in WASP gene X-linked recessive. Features include recurrent bacterial infections, eczema, thrombocytopaenia.
Low IgM levels
Increased risk of autoimmune disorders and malignancy
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Combined B- and T- cell disorders: Hyper IgM Syndromes
Mutations in the CD40 gene
| Infection/Pneumocystis pneumonia, hepatitis, diarrhoea
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Carcinogens: Aflatoxin (produced by Aspergillus)
Associated with Liver- HCC
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Carcinogens: Aniline dyes
Bladder (transitional cell carcinoma)
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Carcinogens: Asbestos
Mesothelioma and bronchial carcinoma
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Carcinogens: Nitrosamines
Oesophageal and Gastric cancer
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Carcinogens: Vinyl chloride
Hepatic angiosarcoma
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What is mesna
2-mercaptoethane sulfonate Na
a metabolite of cyclophosphamide called acrolein is toxic to urothelium
mesna binds to and inactivates acrolein helping to prevent haemorrhagic cystitis
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What is mesna
2-mercaptoethane sulfonate Na
a metabolite of cyclophosphamide called acrolein is toxic to urothelium
mesna binds to and inactivates acrolein helping to prevent haemorrhagic cystitis
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Mechanism of action: doxorubicin
Stabilizes DNA-topoisomerase II complex, inhibits DNA & RNA synthesis
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Leukemoid reaction
active leucocytosis, often secondary to infection or inflammation
Raised leuocyte alkaline phosphatase (LAP) score.
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what is Waldenstrom's macroglobulinaemia
uncommon condition seen in older men. It is a lymphoplasmacytoid malignancy characterised by the secretion of a monoclonal IgM paraprotein
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Features of Waldenstrom's macroglobulinaemia
monoclonal IgM paraproteinaemia
systemic upset: weight loss, lethargy
hyperviscosity syndrome e.g. visual disturbance
the pentameric configuration of IgM increases serum viscosity
hepatosplenomegaly
lymphadenopathy
cryoglobulinaemia e.g. Raynaud's
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Methotrexate mechanism of action
inhibits dihydrofolate reductase and thymidylate synthesis
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DIC blood film
schistocytes due to microangiopathic haemolytic anaemia
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Hyposplenism blood film
Howell-Joey cells and siderocytes
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Aprepitant
anti-emetic which blocks the neurokinin 1 (NK1) receptor. It is a substance P antagonists (SPA). It is licensed for chemotherapy-induced nausea and vomiting (CINV) and for prevention of postoperative nausea and vomiting. It is also been shown to be effective in treating clinical depression
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Li-Fraumeni Syndrome
Autosomal dominant
Consists of germline mutations to p53 tumour suppressor gene
High incidence of malignancies particularly sarcomas and leukaemias
Diagnosed when:
* Individual develops sarcoma under 45 years
* First degree relative diagnosed with any cancer below age 45 years and another family member develops malignancy under 45 years or sarcoma at any age
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Features of methaemoglobinaemia
chocolate' cyanosis
dyspnoea, anxiety, headache
severe: acidosis, arrhythmias, seizures, coma
normal pO2 but decreased oxygen saturation
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Management of methaemoglobinaemia
NADH - methaemoglobinaemia reductase deficiency: ascorbic acid
IV methylthioninium chloride (methylene blue) if acquired
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What is methaemoglobinaemia
Methaemoglobinaemia describes haemoglobin which has been oxidised from Fe2+ to Fe3+. This is normally regulated by NADH methaemoglobin reductase, which transfers electrons from NADH to methaemoglobin resulting in the reduction of methaemoglobin to haemoglobin. There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation curve is moved to the left
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Presentation of acute intermittent porphyria
abdominal: abdominal pain, vomiting
neurological: motor neuropathy
psychiatric: e.g. depression
hypertension and tachycardia common
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Diagnosis of acute intermittent porphyria
classically urine turns deep red on standing
raised urinary porphobilinogen (elevated between attacks and to a greater extent during acute attacks)
assay of red cells for porphobilinogen deaminase
raised serum levels of delta aminolaevulinic acid and porphobilinogen
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Side effects of cisplatin
- platinum based chemo
- causes ototoxcitiy, peripheral neuropathy and hypomagneseaemia
- also associated with
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Features of Wap-Aldrich
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recurrent bacterial infections (e.g. Chest)
eczema
thrombocytopaenia
low IgM levels
WASP mutation
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Wasp-Aldrich pathophysiology
primary immunodeficiency due to a combined B- and T-cell dysfunction. It is inherited in a X-linked recessive fashion and is thought to be caused by mutation in the WASP gene.
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Hep C is associated with? ... purpuric rash
Cryoglobulinaemia
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What type of cryoglobulinaemia is Raynaurd's?
Type 1 - monoclonal - IgG or IgM
| associations: multiple myeloma, Waldenstrom macroglobulinaemia
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Investigations in von Willebrands
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
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Tumour lysis syndrom
High phosphate and potassium
| Low calcium
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Presentation of Haemolytic spherocytosis
```
failure to thrive
jaundice, gallstones
splenomegaly
aplastic crisis precipitated by parvovirus infection
degree of haemolysis variable
MCHC elevated
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Diagnosis of hereditary spherocytosis
EMA binding test
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Management of hereditary spherocytosis
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acute haemolytic crisis:
treatment is generally supportive
transfusion if necessary
longer term treatment:
folate replacement
splenectomy
steroids are not recommended
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