Haematology Flashcards
1
Q
Pathophysiology of Iron Deficiency Anaemia
A
Iron is needed for the formation of haem in RBC.
If you are iron deficient you have small, hypochromic red blood cells and there is a lack of effective erythrocytes leading to anaemia symptoms.
2
Q
What type of anaemia is iron deficiency anaemia
A
microcytic
3
Q
What is anaemia
A
low Hb concentration either due to a low red cell mass ( with or without a reduced haemoglobin concentration) or an increased plasma volume
4
Q
what is an example of a patient who may have anaemia with reduced Hb but increased red cell mass
A
third trimester of pregnancy
body produces more blood to support fetal growth, however if you are not getting enough iron then Hb conc may decrease as red cell mass increases
5
Q
what are the 2 consequences of anaemia
A
Reduced oxygen transport
Tissue hypoxia
6
Q
how does the body try and counteract anaemia
A
increasing tissue perfusion
increasing O2 transfer to tissues
Increasing red cell production
Tachycardia
7
Q
How do we keep red cell balance in the body
A
erythrocytes are produced then destroyed at the end of their life cycle of 120 days
reticulocytes are immature red blood cells and act as a marker of the balance between production and removal of red blood cells
8
Q
what are the three categories of anaemia
A
microcytic
normocytic
macrocytic
9
Q
what is microcytic anaemia
A
low MCV
presence of small, often hypochromic red blood cells in a peripheral blood smear
10
Q
three causes of microcytic anaemia
A
iron deficiency
chronic disease
thalassaemia
11
Q
what is normocytic anaemia
A
MCV within range
have normal sized red blood cells but you have a low number of them
12
Q
three causes of normocytic anaemia
A
acute blood loss
anaemia of chronic disease
combine haematinic deficiency (iron deficiency + B12 deficiency (combined the deficiencies cancel each other out so appears in normal range)
13
Q
what is macrocytic anaemia
A
high MCV
anaemia that causes unusually large red blood cells. RBC also have low Hb
14
Q
3 causes of macrocytic anaemia
A
FAT RBC
Fetus (pregnancy) Alcohol excess Thyroid disease (hypothyroidism) Reticulocytosis B12 deficiency/folate (main one) Cirrhosis and chronic liver disease
15
Q
Aetiology of iron deficient anaemia
A
Blood loss
Cancer
Increased demands seen in growth (puberty) and
pregnancy.
Poor diet
Malabsorption
Hookworm
16
Q
Symptoms of anaemia
A
Fatigue Dyspnoea Syncope Palpitations Headache Pallor
17
Q
Signs of chronic iron deficiency
A
Signs of chronic iron deficiency
Koilonychia (spoon nails)
Angular cheilosis (ulceration at the side of the mouth)
Atrophic glossitis
18
Q
Investigations in iron deficient anaemia
A
Serum ferritin (storgate marker for iron). It is an acute phase reactant so may not be accurate (as it can be elevated in the presence of inflammation).
Serum iron (is low)
Blood film:
pencil shaped cells
Hypochromic microcytic erythrocytes (increased pallor in the centre of the cell)
19
Q
Treatment for iron deficient anaemia
A
Treat the cause
Oral iron (ferrous sulfate) SE: nausea, black stools, diarrhoea or constipation Use IV iron if oral iron is contraindicated e.g in chronic renal failure
20
Q
Pathophysiology of anaemia of chronic disease
A
Microcytic and normocytic anaemia
Poor use of iron in erythropoiesis
Cytokine-induced shortening of RBC survival (shortened RBC lifespan → due to direct cellular destruction via toxins from cancer cells, viruses or bacteria)
Decreased production of and response to erythropoietin
21
Q
Aetiology of anaemia in chronic disease
A
Chronic infection
Vasculitis
Rheumatoid
Malignancy
Renal failure
22
Q
Investigations in chronic disease anaemia
A
Serum ferritin is normal or increased in microcytic anaemia
Blood film
B12
Folate
TSH
23
Q
Treatment of anaemia in chronic disease
A
Treat the underlying cause
Erythropoietin
24
Q
Pathophysiology of macrocytic anaemia
A
High MCV
Inhibition of DNA synthesis during RBC production. Leads to cell growth without division.
Anaemia that causes unusually large red blood cells
25
Pathophysiology of B12 deficient anaemia
Absorption of vitamin B12 occurs in the terminal ileum.
Needs intrinsic factor (secreted by the gastric parietal cells) for transport across the intestinal mucosa.
Deficient intrinsic factor → reduced vitamin B12 absorption → anaemia
26
3 causes of B12 deficient anaemia
Poor diet
Malabsorption
Autoimmune condition in which atrophic gastritis leads to lack of intrinsic factor secretion from destruction of parietal cells in the stomach.
Crohn’s, coeliac
Other autoimmune conditions
27
Signs of B12 deficient anaemia
```
B12 deficient signs
Lemon tinge
Glossitis (big beefy-red sore tongue)
Angular cheilosis
Neurological problems (irritability, depression, psychosis)
```
28
Investigations in B12 deficient anaemia
Schilling test for B12 deficiency
Bloods - FBC
Low Hb
Low WCC and platelets if severe
Serum B12 is decreased
Serum parietal cells autoantibodies
Blood film:
Macrocytic erythrocytes
Hypersegmented neutrophils
Bone Marrow investigation
Megaloblasts (developing red blood cells with delayed nuclear maturation relative to that of the cytoplasm) present
29
Treatment of B12 deficient anaemia
Hydroxocobalamin (vitamin B12) oral
30
Cause of folate deficient anaemia
Poor dietary intake
31
What is the difference in clinical presentation between B12 deficient anaemia and folate deficient anaemia?
symptoms of anaemia with no neuropathy signs like in B12 deficient anaemia
32
Investigations in folate deficient anaemia
Bloods
Red cell folate is low
Serum folate is low
Blood film
Macrocytic erythrocytes
Bone Marrow examination
Megaloblasts erythrocytes
33
Treatment for folate deficient anaemia
Treat the underlying cause
Oral folic acid for 4 months
34
Pathophysiology of haemolytic anaemias
Results from an increased destruction of erythrocytes with a reduction of the circulating lifespan.
There is a compensatory increase in bone marrow activity with premature release of reticulocytes
35
Aetiology of haemolytic anaemias
Name 1 inherited cause and 1 acquired cause
```
Inherited
Red cell membrane defect
Hb abnormalities (thalassaemia, sickle cell)
Metabolic defects
```
Acquired
Autoimmune
Mechanical destruction
Infections (malaria)
36
Clinical presentation of haemolytic anaemia
Symptoms of anaemia
| Haemolytic signs include: jaundice, gallstones and leg ulcers
37
Pathophysiology of sickle cell anaemia
Amino acid substitution in the gene coding for the beta globin chain.
Leads to the production of HbS rather than HbA
```
Homozygous individuals (SS) have sickle cell anaemia.
HbS polymerizes when deoxygenated causing erythrocytes to deform, producing sickle cells which are fragile and haemolyse, occluding small vessels and can result in a vaso-occlusive crisis.
```
38
investigation of haemolytic anaemia
```
Thorough history
FBC and blood film
Reticulocyte count
U&Es, LFTs, TSH
B12, folate, ferritin (checking for malabsorption)
```
39
what is the lifespan of a sickle cell
5-10 days
40
what feature do heterozygotes HbAS have
sickle cell trait which causes no disability and protects against P.falciparum malaria
41
when does sickle cell anaemia present and why
Production of foetal Hb is normal, disease doesn’t manifest until 6 months
42
Clinical presentation of sickle cell anaemia
Acute pain in hands and feet in early childhood (vaso-occlusion of small vessels + avascular necrosis of bone marrow)
Adults, affects the long bones, ribs, spine and pelvis
43
what 3 acute complications can arise in sickle cell anaemia and present
Painful crisis (blockage of blood vessels inside the bone)
Parvovirus infection in children (can be v dangerous as it leads decreased erythrocyte production (slapped cheek syndrome)
Stroke
Cognitive impairment
44
3 chronic complications in sickle cell anaemia
Renal impairment
Priapism in males
Splenic/hepatic sequestration (organs become engorged with erythrocytes leading to an acute fall in Hb and rapid organ enlargement)
45
Investigations for sickle cell anaemia
Bloods
FBC : low Hb with a high reticulocyte count
Blood film : sickled erythrocytes
46
How is sickle cell anaemia picked up in neonates
Identified in neonatal screening via a heel prick test. The diagnosis is made with Hb electrophoresis showing 80-95% HbSS and absent HbA `
47
what is painful crisis in sickle cell anaemia
blockage of blood vessels in bone causing pain as the bone marrow swells up
48
Treatment of sickle cell anaemia
Hydroxycarbamide prevents painful crises
Folic acid
Pain relief
Bone marrow transplant can be curative
49
Pathophysiology of thalassaemia
Diminished synthesis of one or more globin chains leading to a reduction in haemoglobin.
Imbalanced globin chain production leads to precipitation of globin chains within red cells or precursors resulting in cell damage, ineffective erythropoiesis and haemolysis)
50
difference between alpha and beta thalassaemia
alpha: reduced alpha chain synthesis from gene deletion. usually leads to death in utero.
beta: reduced beta chain synthesis from a point mutation.
51
presentation of beta thalassaemia major
6-12 months at age of presentation
severe anaemia causes : failure to feed, listless, crying, pale
- skull bossing and hepatosplenomegaly
52
Investigations in beta thalassaemia major
FBC
low Hb
low MCV
normal ferritin
Hb electrophoresis is diagnostic
Blood film
Large and small (irregular pale cells)
Nucleated red blood cells in the peripheral circulation
53
Treatment of beta thalassaemia major
Promote fitness and healthy diet
Regular life long transfusions
Iron chelation therapy
Endocrine supplementation and testing. Patients have an increased risk of diabetes due to pancreatic iron overload
54
what do you need to look out for when giving regular tranfusions to thalassaemia patients
need to monitor iron levels as consequence can be a progressive increase in body iron load leading to liver fibrosis and cirrhosis. Can also lead to cardiac hemosiderosis
55
what are membranopathies
Structural protein losses leading to an unstable erythrocyte cell membrane
56
name 2 membranopathoes
spherocytosis
| elliptocytosis
57
pathophysiology of elliptocytosis
RBC are elliptical in shape
58
pathophysiology of spherocytosis
spherical RBC that are less capable of being reshaped and can become trapped in the spleen
59
aetiology of membranopathies
autosomal dominant condition
60
clinical presentation of membranopathies
Can be asymptomatic and are generally mild conditions.
If severe (usually spherocytosis) :
Splenomegaly is detected in childhood
Predisposition to gallstones
Neonatal jaundice
61
Investigations in membranopathies
FBC - raised reticulocytes and reduced Hb
Blood film: spherocytes and reticulocytes
Serum bilirubin and urinary urobilinogen raised from haemolysis
62
Treatment for membranopathoes
Folic acid
Splenectomy if severe
63
two types of enzymopathies
glucose-6-phosphate dehydrogenase deficiency
pyruvate kinase deficiency
64
pathophysiology of G6PD deficiency
shortened erythrocyte lifespan as G6PD protects cells against oxidative damage
65
pathophysiology of pyruvate kinase deficiency
reduced ATP production causes reduced erythrocyte survival
66
aetiology of G6PD deficiency
X linked inheritance
67
what factors precipitate G6PD deficiency
broad beans, infection, henna and drugs
68
aetiology of PKD
autosomal recessive inheritance
69
clinical presentation of enzymopathies
Most are asymptomatic but may get oxidative crises due to decreased glutathione production, precipitated by other factors
G6PD: haemolysis, jaundice
PKD: homozygotes have neonatal jaundice. Later have haemolysis with splenomegaly +/- jaundice
70
Investigation of enzymopathies
Measurement of enzyme levels in the erythrocyte (enzyme assay)
Diagnosed by a screening test for NADPH
G6PD blood film
Bite and blister cells
71
Treatment of enzymopathies
Avoid precipitating factors
Folic acid
Transfusion if necessary
72
Pathophysiology of aplastic anaemia
Deficiency of all cell elements of the blood (pancytopenia) with hypocellularity (state of having abnormally few cells) of the bone marrow
Reduction in the number of pluripotent stem cells together with a fault in those remaining or an immune reaction against them so that they are unable to repopulate the bone marrow.
73
aetiology of aplastic anaemia
congenital
idiopathic
cytotoxic drugs
EBV, HIV, TB
74
clinical presentation of aplastic anaemia
anaemia symptoms
bone marrow failure signs:
increased susceptibility to infection, bruising and bleeding, bleeding gums, epistaxis
75
investigations in aplastic anaemia
what do they show?
FBC
Pancytopenia with low/absent reticulocytes
Bone marrow biopsy
Hypocellular marrow with increased fat spaces
76
Treatment for aplastic anaemia
Removal of causative agent
Bone marrow transplant care
Immunosuppressive therapy
Reduce the number of lymphocytes circulating in the bloodstream which stimulates the bone marrow to restart blood cell production
77
What is deep vein thrombosis
Formation of a thrombus in a deep vein which has the potential of embolising
78
pathophysiology of DVT (where do most venous thrombi begin?)
Most venous thrombi seem to begin at the valves.
Valves naturally produce a degree of turbulence because they protrude into the vessel lumen and may be damaged by trauma, stasis and occlusion. Thrombi grow. If blood pressure is allowed to fall it makes thrombosis more likely
79
aetiology of DVT
Disease or injury to the leg
Immobility
Broken bone
Obesity
Inherited disorders
Autoimmune disorders that increase the likelihood of blood clotting
Medicines that increase your risk of clotting (e.g the oral contraceptive pill)
Antiphospholipid syndrome
Lupus anticoagulant
80
symptoms of DVT
Non-specific
Pain on walking
Swelling of the calf or thigh - usually asymmetrical
81
signs of DVT
```
Tenderness
Swelling
Warmth
Discolouration
Pitting oedema
```
82
what investigations would you perform to diagnose DVT
Calculate Well's score
D-dimer
Ultrasound compression test in the proximal veins (diagnostic)
83
where in the lower limb would you get a sizeable clot formation
clot between the popliteal fossa and groin
84
what is Well's score
calculates the likelihood that a patient has a DVT.
2 or more = DVT likely
Less than 2 = DVT unlikely
Takes into account the history of the patient as well as clinical findings
85
why is a d-dimer test used and what are the limitations of its use
Normal test excludes diagnosis of DVT. Positive test does not confirm it.
Used after clinical assessment to determine who needs to go on to have an ultrasound
Only helpful in outpatients
86
what does an ultrasound compression test of the proximal veins show us
If cannot compress the vein with the probe then there is likely to be a clot
Diagnostic test
87
Prevention of DVT
Mechanical
Hydration
Early mobilisation
Compression stockings
Chemical
Low molecular weight heparin - once daily injection
88
What is the treatment plan for DVT
Initial treatment: Low molecular weight heparin s/c injection
Then: Oral warfarin for 6 months with an INR 2-3
OR Direct Oral AntiCoagulant (DOAC) oral medication e.g Rivaroxaban from onset
89
what is a pulmonary embolism
clot that has started in the leg, detached, gone through the heart and become lodged in the pulmonary arteries
90
symptoms of a pulmonary embolism
Breathlessness
Pleuritic chest pain
May have signs/symptoms of DVT
91
signs of a pulmonary embolism
```
Tachycardia
Tachypnoea
Pleural rub
Cyanosis
Severe dyspnoea
Hypotension
```
92
investigations for pulmonary embolism
Chest X-ray - usually normal. Done to look for signs of pneumonia
ECG : sinus tachycardia, done to exclude a cardiac cause
ABG: Type 1 resp failure
D-dimer
Ventilation/perfusion scan to show mismatch defects
CT pulmonary angiogram : diagnostic
93
Treatment of pulmonary embolism
Clot lysis
Low molecular weight heparin s/c injection once daily
Oral warfarin or a DOAC
94
define thrombosis
blood coagulation inside a vessel
95
what is the precursor for an acute arterial thrombotic event
- atherosclerosis
96
symptoms of arterial thrombosis
intermittent claudication - muscle pain in the lower limbs on exercise
walking impairment - fatigue, aching, cramping or pain in lower limb
relieved by rest
male impotence
ischaemic rest pain - severe unremitting pain in the foot esp at night - partially relieved by hanging the foot out of the bed
97
signs of peripheral arterial disease
```
6Ps
Pallor
Perishingly cold
Pulseless
Pain
Parasthesia
Paralysis
```
98
risk factors for venous thrombosis
```
previous history
family history
cancer
increasing age
immobilisation
smoking
BMI over 30
male
hypertension
```
99
why does immobilisation increase a persons risk for DVT
stasis of blood
100
why does smoking increase a persons risk of thrombosis
associated with a higher level of NO and free radicals and can damage the blood vessel, changing the intimal surface.
nicotine causes vasoconstriction of blood vessels
101
why is obesity a risk factor for thrombosis
state on chronic inflammation, changes blood constituents
| hyperlipidemia
102
why is hypertension a risk factor for thrombosis
change in the pattern of blood flow and damage to endothelium
103
describe the pharmacological mechanism of heparin
heparin binds to endogenous antithrombin and increases its activity.
This then inhibits thrombin action (IIa) and Xa clotting factor.
Coagulation cascade is inhibited
104
describe the pharmacological mechanism of aspirin
inhibits cyclo-oxygenase irreversibly
| inhibits thromboxane formation and therefore platelet aggregation
105
describe the pharmacological mechanism of warfarin
warfarin is a vitamin K reductase inhibitor
Reduced vitamin K isn't produced
gamma-carboxyglutamic acid cannot be produced
clotting factors II, VII, IX and X (1972) are not produced.
Inhibits and stops coagulation cascade
106
Pharmacological action of DOACs
directly act on clotting factor II or X to stop the coagulation cascade
107
Basic principles of the pathophysiology of leukaemia`
presence of rapidly proliferating immature blast blood cells (can be precursors of RBCs, platelets or white cells)
Cells divide rapidly but are non-functional so the body wastes energy making the cells. Less energy available to make useful cells.
Take up a lot of space in bone marrow
108
what is the commonest malignancy of childhood
acute lymphoblastic leukaemia
109
what are the peak ages for acute lymphoblastic leukaemia
0-4
15-25
over 70
110
pathophysiology of acute lymphoblastic leukaemia
Malignancy of the immature lymphoid cells.
Mutation causes the B or T lymphocyte cell lines to stop maturation and promote the uncontrolled proliferation of immature blast cells (myeloblasts and lymphoblasts)
Blast cells take up a lot of space in the bone marrow and so other cells get crowded out and causes : anaemia, thrombocytopenia, leukopenia.
Blast cells eventually spill out into the circulation, some settle in liver and spleen.
111
Aetiology of acute lymphoblastic leukaemia
Mutation - chromosomal translocation or abnormal chromosome number
112
Risk factors for acute lymphoblastic leukaemia
Down’s Syndrome
Ionising radiation
Exposure to alkylating chemotherapy
113
what is different in the cells affected in adults and children with acute lymphoblastic leukaemia
B cells = children
| T cells = adults
114
Clinical presentation of acute lymphoblastic leukaemia
Marrow Failure
- Anaemia due to decreased Hb : shortness of breath, tiredness, lightheadedness, palpitations
- Infection (decreased WCC) esp chest, mouth, perianal and skin
- Bleeding due to thrombocytopenia
Easy bruising and bleeding. Usually mucosal bleeding. Rash
Infiltration of leukemic cells into organs
- hepatosplenomegaly → abdominal fullness
- bone pain
- lymphadenopathy
- headache and cranial nerve palsies
- mediastinal masses with SVC obstruction
115
Diagnosis and investigations in acute lymphoblastic leukaemia
FBC : WCC high (increased circulating lymphocytes and lymphoblasts). Decreased circulating RBCs, platelets, mature neutrophils.
In acute leukaemia FBC changes quite rapidly
Blood film: characteristic blast cells on blood film and bone marrow (they have very little cytoplasm and areas that look slightly lighter in the nucleus)
Lymphoblasts are smaller cells with little cytoplasm and coarse chromatin.
Bone Marrow biopsy: blast cells
Chest XR and CT to look for mediastinal and abdominal lymphadenopathy
Lumbar puncture to look for CNS involvement
Check B12, folate and iron
116
what is characteristic for diagnosis for acute lymphoblastic leukaemia
blast cells on blood film and bone marrow
117
characteristics of lymphoblasts
smaller cells
coarse chromatin
little cytoplasm
118
Treatment of acute lymphoblastic leukaemia
Educate and motivate patient
Supportive
Blood/platelet transfusion
IV fluids
Allopurinol
If have an infection → give immediate IV antibiotics
Chemotherapy
Matched related allogeneic marrow transplantations
119
Pathophysiology of acute myeloid leukaemia
Neoplastic proliferation of blast cells derived from marrow myeloid elements (gives rise to basophils, eosinophils and neutrophils)
120
aetiology of acute myeloid leukaemia
Associated with radiation and Down’s syndrome
121
signs and symptoms of acute myeloid leukaemia
Bone marrow failure :
Anaemia
Infection
Bleeding (usually mucosal)
```
Infiltration :
Hepatomegaly
Splenomegaly
Gum hypertrophy
Skin involvement
```
Disseminated Intravascular Coagulation can occur in a subtype of AML where there is a release of thromboplastin
122
Diagnosis and tests used to investigate acute myeloid leukaemia
FBC: WCC is increased
Blood film :
Myeloblasts (large cells, fine chromatin, prominent nucleoli)
Bone marrow biopsy:
Myeloblast cells with Auer rods in the cytoplasm (crystals of coalesced granules)
Immunophenotyping : CC10
123
what differentiates AML from ALL
Auer rods in cytoplasm
124
complications of AML
infection - give prophylaxis!
| be alert to sepsis
125
Treatment of AML
Chemotherapy
Very intensive
Daunorubicin and cytarabine
Bone marrow transplant
Infection is a major issue so give prophylaxis
126
pathophysiology of chronic lymphocytic leukaemia
Neoplastic monoclonal proliferation of mature functionally abnormal B lymphocytes in the bone marrow and blood.
127
what is the hallmark sign of chronic lymphocytic leukaemia
progressive accumulation of a malignant clone of functionally incompetent B cells
128
aetiology of chronic lymphocytic leukaemia
mutations in cells chromosomes
129
symptoms of chronic lymphocytic leukaemia
often none and usually presents as a surprise finding on a routine FBC
Anaemia
Thrombocytopenia : bleeding and bruising
Neutropenia: more frequent bacterial infections, fever, pneumonia, sepsis
Severe: weight loss, sweats, anorexia
130
signs of chronic lymphocytic leukaemia
Enlarged rubbery non-tender nodes
Splenomegaly
Hepatomegaly
131
Complications of chronic lymphocytic leukaemia
Autoimmune haemolysis (leading to anaemia)
Increased infection risk due to hypogammaglobulinemia (low IgG)
Marrow failure
132
Tests for chronic lymphocytic leukaemia
FBC
- Low Hb
- Raised WCC with very high lymphocytes
- Low RBCs, platelets, neutrophils
Blood film
Smudge cells in peripheral smear (immature B cells) → DIAGNOSTIC
Immunophenotyping: looking for premature cells that express these proteins on their cell membrane :CD5, CD19, CD23
133
what is diagnostic on a blood film to diagnose chronic lymphocytic leukaemia
smudge cells in a peripheral smear (immature B cells)
134
Treatment of chronic lymphocytic leukaemia
Supportive
- Transfusions
- IV human immunoglobulin
Chemotherapy
Rituximab
Radiotherapy
Stem cell transplant
Bone marrow transplant
135
what ages are most likely diagnosed with chronic myeloid leukaemia
40-60 years
136
risk factors for chronic myeloid leukaemia
benzene and radiation exposure
137
pathophysiology of chronic myeloid leukaemia
Uncontrollable clonal proliferation of myeloid cells leading to premature cells.
Caused by the activated of tyrosine kinase activity from a genetic mutation leading to a fusion gene of BCR and ABL genes.
Premature leukocytes accumulate in the bone marrow until they spill out and enter the bloodstream.Some cells deposit in organs and some stay in circulation
138
aetiology of chronic myeloid leukaemia
t(9;22) Philadelphia chromosome translocation is diagnostic
139
symptoms of chronic myeloid leukaemia
- weight loss
- tiredness
- fever
- sweats
- bleeding
- abdominal discomfort
accelerated phase
- recurrent infections
- anaemia
- lymphadenopathy
- bleeding
140
signs of chronic myeloid leukaemia
splenomegaly
hepatomegaly
anaemia
bruising
141
investigations in chronic myeloid leukaemia
```
FBC
-very high WCC
- decreased Hb
- increased folate
Bone marrow aspirate
- hypercellular
- pseudo gaucher cells in bone marrow
```
142
what cell is found in the bone marrow of chronic myeloid leukaemia patients?
pseudo gaucher cells
143
what is the treatment for chronic myeloid leukaemia?
ORAL IMATINIB
144
what is the mechanism of action for the drug used to treat chronic myeloid leukaemia?
name 3 side effects?
specific BCR-ABL tyrosine kinase inhibitor
nausea, cramps, oedema, rash
145
what are lymphomas?
disorders caused by the malignant proliferation of lymphocytes
146
what is the normal physiology in B cell development?
1. starts in bone marrow (primary lymphoid organ)
precursor B cell --> naive B cell --> blood --> lymph nodes
2. B cells differentiate into plasma cells which are found in the medulla of the lymph nodes
147
what is the incidence of Hodgkin's Lymphoma?
It has a bimodal incidence
- Young adults (15-24)
- Elderly
148
what are the risk factors for developing Hodgkin's lympgoma
An affected sibling
EBV
Lupus
Post-transplantation
149
what is the aetiology of Hodgkin's lymphoma
Genetic mutation in the B-cell causes uncontrollable division and proliferation becoming a neoplastic cell
150
pathophysiology of Hodgkin's lymphoma?
An abnormal B-cell escapes regulation and starts to divide uncontrollably to become a neoplastic cell.
Neoplastic cells spread to nearby lymph nodes.
Neoplastic cells are surrounded by inflammatory cells and activate fibroblasts and eosinophils.
151
what differentiates Hodgkin's lymphoma from non-Hodgkin's lymphoma?
Hodgkin's has characteristic REED STERNBERG CELLS
| - have a mirror image nuclei
152
symptoms of Hodgkin's lymphoma
Enlarged, non-tender, rubbery superficial lymph nodes. Usually cervical.
Can have systemic syndromes as well (known as B symptoms) : fever, weight loss (unintentional loss of 10% of body weight over the last 6 months), night sweats, anorexia.
Pruritus
Lethargy
Compression syndromes (eg present with swollen leg as the glands can grow to compress lymphatics)
153
signs of Hodgkin's lymphoma
```
Lymphadenopathy
Cachexia (weakness and wasting of the body due to severe chronic illness)
Anaemia
Splenomegaly
Hepatomegaly
```
154
Investigations in Hodgkin's lymphoma?
1. Blood film and bone marrow aspirate
- REED-STERNBERG CELLS ARE DIAGNOSTIC
2. Lymph node biopsy
3. Imaging
-CXR
-CT scan of thorax, abdomen or pelvis - looking for other enlarged lymph nodes
4. Immunophenotyping
CD20 found on the surface of B lymphocytes only
155
why is immunophenotyping important in Hodgkin's lymphoma?
- diagnostic tool
| - gives indication about treatment as there is a targeted monoclonal antibody for CD20
156
Outline the staging of Hodgkin's lymphoma
I : single lymph node region
II : 2 or more nodal areas on same side of the diaphragm
III : involvement of nodes on both sides of the diaphragm
IV : spread beyond the lymph nodes (liver or bone marrow)
A: no systemic symptoms
B: presence of B symptoms (worse disease)
157
why is staging important?
influences treatment and prognosis
158
what is the treatment for a stage 1-2A Hodgkin's lymphoma?
short course chemotherapy + radiotherapy
159
what is the treatment for stage 2B-4 Hodgkin's lymphoma?
combination chemotherapy
160
what is the combination chemotherapy used in Hodgkin's lymphoma?
```
ABVD
Adriamycin
Bleomycin
Vinblastine
Dacarbazine
```
161
what is the pathology of Non-Hodgkin's Lymphoma (NHL)
Malignant proliferation of lymphocytes without Reed Sternberg cells
Most are derived from B cell lines
162
what are the two subtypes of NHL
```
Indolent/low grade NHL lymphoma
Follicular
Slow growing
Incurable
Neoplastic B cells
```
```
High grade/aggressive NH lymphoma
Diffuse Large B Cell Lymphoma is the most common
Often curable
often a short history
1/3 of cases have extranodal involvement
```
163
clinical presentation of NHL ?
Painless lymphadenopathy
B symptoms : fever, night sweats, weight loss
Pancytopenia from marrow involvement (anaemia, infection, bleeding)
Extranodal disease
Bowel obstruction (GI tract)
Fatigue, easy bruising, recurrent infections (bone marrow)
motor/sensory deficits (spinal cord)
164
investigations in NHL
Bloods
- FBC (may show anaemia, high WCC and low platelets)
- LFTs can show liver involvement
- U&Es
Bone marrow/lymph node biopsy
- NO Reed Sternberg Cells
165
what is the treatment for indolent NHL
If symptomless - do nothing and monitor
Combination chemotherapy
Monoclonal antibodies: rituximab maintains remission. Kills CD20 positive cells.
Radiotherapy may be curative in localised disease
166
what is the treatment for aggressive NHL
R-CHOP regimen chemotherapy
early - R-CHOP + radiotherapy
late - R-CHOP + monoclonal antibodies
167
what is myeloma?
neoplasm of plasma cells in the bone marrow
168
what is the aetiology of myeloma?
Abnormal proliferation of a single clone of plasma or lymphoplasmacytic cells leading to secretion of Ig or an Ig fragment causing the dysfunction of many organs.
169
what are the clinical features of myeloma?
```
CRAB
Calcium high (hypercalcaemia)
Renal impairment
Anaemia (tiredness and malaise)
Bone pain (osteolytic bone lesions +/- fractures)
```
170
investigations in myeloma?
```
1. Bloods
FBC
- normocytic normochromic anaemia
Blood film
- U&Es: Hypercalcaemia, high urea and creatinine
- Raised ESR
- Rouleaux cells
```
2. Bone marrow biopsy: myeloma bone marrow, many plasma cells with abnormal forms
3. Imaging: X-ray of spine, chest and pelvis may show punched out lesions, vertebral collapse and fractures
4. Electrophoresis : Ig paraprotein monoclonal bands in serum or urine
171
what are the key features in order to make a diagnosis of myeloma?
need to have a high index of suspicion!
- monoclonal paraprotein band in serum or urine electrophoresis
- increased plasma cells on bone marrow biopsy
- evidence of end organ damage from myeloma (hypercalcaemia, anaemia)
- bone lesions
172
What is the treatment for myeloma?
```
Supportive:
Analgesia for bone pain
Bisphosphonate
Transfusion and erythropoietin (anaemia)
Hydrate (renal insufficiency)
Isolation and handwashing (better hygiene to reduce infection risk)
```
Chemotherapy
Stem Cell Transplant if suitable
173
what is the most prevalent malaria parasite?
Plasmodium falciparum
174
in what two species of malaria parasite is there a dormant stage? what is a dormant stage?
Plasmodium ovale and Plasmodium vivax
Dormant stage means that if the infection is inadequately treated the merozoites can be released from the liver weeks or years later after the initial infection causing recurrent disease
175
where in the world has the majority of cases of malaria?
Sub-Saharan Africa
176
what is the vector for malaria parasites?
female anopheles mosquito
177
name two other routes of transmission of malaria (rare with no mosquito involvement)
transfusion
needle sharing
organ transplantation
178
pathophysiology of malaria and the life cycle ?
1. Infected female mosquito bites human and injects sporozoite into the blood which travels to the liver.
2. Sporozoite enters hepatocytes and replicates : sporozoite → merozoites → schizont.
3. Hepatocyte ruptures releasing the merozoites into the blood.
4. Merozoites invade RBC and multiply until the cell bursts releasing the merozoites into the blood.
5. Merozoite forms a trophozoite in a RBC which replicates to form many more merozoites.
6. RBC bursts releasing into the blood. This repeats.
7. after several asexual cycles merozoites can invade RBC and develop into plasmodium gametocytes
8. if an unaffected mosquito then bites the infected human it ingests the male and female gametocytes and they develop into mature gametes in the vector stage.
179
what gives rise to the clinical symptoms of malaria and why?
the blood stage
when the parasite is developing in the RBC it produces waste products and toxic factors. when the infected cells lyse they release these toxic factors into the blood
this stimulates the macrophages to produce pro inflammatory cytokines which causes symptoms
180
what are the signs and symptoms of malaria?
```
Fever and chills
Headache
Myalgia
Fatigue
Diarrhoea
Cough
```
If diagnosis is delayed or it is severe disease, then patients may present with haematological changes.
Haemolysis: haemolytic anaemia (breathless, fatigue, pre-hepatic jaundice, haemoglobinuria)
Monocytosis and lymphopenia : loss of WBC → infection
Triggering of the coagulation cascade : thrombocytopenia
181
what is cytoadherance?
when is it observed?
what complications can it cause?
- infected RBCs display specific membrane proteins on their surface which adhere to microvascular endothelium
- characteristic of P. falciparum malaria
- accumulate in capillaries, block blood flow and can get cerebral malaria due to haemorrhage
182
what is rosetting in malaria?
infected RBCs can adhere to other non-infected RBCs in rosettes
183
what is complicated malaria?
| what complications can arise?
infections are complicated by serious organ failures
```
Cerebral malaria
Renal failure
Acute respiratory distress syndrome (rapid widespread inflammation across the lungs)
Bleeding
Shock
```
184
investigations in malaria
Immediate blood test
Microscopy of thick and thin blood smear.
Thick: looking for number of little black dots per 100 RBCs (severity)
Thin: looking morphologically at the shape of the RBCs to decide which species of plasmodium it is. 3 in 24 hrs.
Rapid diagnostic test of the parasite antigen
```
FBC (anaemia and thrombocytopenia)
U&Es (AKI)
Clotting (DIC)
Glucose
ABG (acidosis)
Urinalysis (haemoglobinuria)
```
185
what is the treatment for complicated malaria?
IV artesunate
186
what is the treatment for uncomplicated malaria?
artemisinin combination therapies
187
what drug would you use to eliminate hypnozoites in the liver stage for dormant stage P.ovale and P.vivax
Primaquine
188
what treatments would you use to treat complications arising due to malaria?
Cerebral = anti-epileptics
ARDS = ventilation support, oxygen
Renal failure = hydration (dialysis if severe)
Sepsis = broad spectrum antibiotics
Bleeding/anaemia = blood products
189
name some prevention methods used to stop the spread of malaria?
Vector control
- destruction of mosquito breeding sites
- long-lasting insecticidal nets
- sterile male mosquito release
Chemoprophylaxis
- antimalarial drugs to prevent clinical disease
190
what is polycythaemia?
disease state in which the haematocrit is raised
191
how is polycythaemia divided?
Relative Polycythaemia: decreased plasma volume and normal RBC mass
Absolute Polycythaemia:
Increased RBC mass
192
aetiology of acute and chronic relative polycythaemia?
acute : dehydration
| chronic : associated with obesity, hypertension and a high alcohol and tobacco intake
193
aetiology of primary and secondary absolute polycythaemia?
Primary
Polycythaemia vera
Secondary
- due to hypoxia
- High altitude
- Chronic lung disease
- Cyanotic congenital heart disease
- Heavy smoking
- Inappropriately increased erythopoietin secretion (renal carcinoma)
194
what is polycythaemia vera?
malignant proliferation of a clone derived from one pluripotent stem cell causing an excess proliferation of RBCs, WBCs and platelets leading to hyperviscosity and thrombosis
195
presentation of polycythaemia vera?
May be asymptomatic and only detected on FBC.
May present with vague symptoms due to hyperviscosity: headache, dizziness, tinnitus, visual disturbance
Characteristic:
Itching after a hot bath
Erythromelalgia (burning sensation in fingers and toes)
196
signs of polycythaemia vera
Facial plethora
Splenomegaly
Gout may occur due to increased urate from RBC turnover
197
investigations in polycythaemia vera
FBC
- Increased red cell count
- Increased haemoglobin
- Increased hematocrit
- Increased packed cell volume
Increased B12
Marrow shows hypercellularity with erythroid hyperplasia
Decreased serum erythropoietin
Raised red cell mass
198
what is the treatment for polycythaemia vera?
Aim is to keep haematocrit < 0.45 to decrease the risk of thrombosis
Younger patients: venesection (remove blood from circulatory system)
Higher risk (over 60 and previous thrombosis) - hydroxycarbamide
Aspirin 75mg given daily
199
outline the normal physiology of platelets?
- produced in bone marrow
- arise from megakaryocytes
- regulated by thrombopoietin (produced by the liver)
- play an important role in primary homeostasis
- annulcleate cell fragment with lifespan of 7-10 days
- old platelets are removed by the spleen
200
what is the normal platelet count ?
150-400 x 10^9/L
201
what is thrombocytopenia
deficiency of platelets in the blood
202
what is the pathophysiology of immune thrombocytopenia purpura ?
IgG antibodies form against platelet and megakaryocyte surface glycoproteins
increased destruction of platelets
203
aetiology of immune thrombocytopenia purpura ?
Thrombocytopenia caused by antiplatelet autoantibodies
Primary : may follow viral infection/immunisation in children
Secondary: occurs in association with some malignancies (CLL) and infections (HIV, Hep C)
204
presentation of primary immune thrombocytopenia purpura?
Acute onset with sudden self limiting purpura (purple spots on the skin caused by bleeding underneath the skin)
Muco-cutaneous bleeding
205
presentation of secondary immune thrombocytopenia purpura ?
```
chronic presentation
fluctuating course of :
- bleeding
- purpura
- epistaxis
- menorrhagia
```
206
investigations in suspected immune thrombocytopenia purpura
Bone marrow biopsy shows increased megakaryocytes
Antiplatelet autoantibodies often present but are not needed for diagnosis
207
what is the treatment for immune thrombocytopenia purpura ?
None if mild
Symptomatic :
Prednisolone
IV immunoglobulin may raise platelet count temporarily
If relapse:
Splenectomy
B cell depletion with rituximab
208
what is the pathology of thrombotic thrombocytopenia purpura?
Large multimers of vWF form resulting in platelet aggregation and fibrin deposits in small vessels leading to microthrombi.
Large consumption of platelets leads to profound thrombocytopenia
209
aetiology of thrombotic thrombocytopenic purpura
occurs due to a reduction in the protease enzyme
```
Idiopathic
Autoimmune
Cancer
Pregnancy
Drug association
```
210
clinical presentation of TTP
Purpura
Fever
Fluctuating cerebral dysfunction
Haemolytic anaemia with red cell fragmentation often accompanied by AKI
211
Investigations for diagnosis of thrombotic thrombocytopenia purpura
Normal coagulation screen
Lactate dehydrogenase is raised
Blood film: Schistocytes
212
treatment for TTP
Urgent plasma exchange to remove antibody and replace ADAMST-13
IV methylprednisolone
IV rituximab
213
pathology of disseminated intravascular coagulation
Cytokine release in response to systemic inflammatory response syndrome
Widespread systemic generation of fibrin within blood vessels caused by the initiation of the coagulation pathway (MASSIVE ACTIVATION OF COAGULATION CASCADE)
Will either cause microvascular thrombosis and organ failure OR the consumption of platelets and coagulation factors leading to bleeding
214
aetiology of disseminated intravascular coagulation
| - include initiating factors
Never occurs in isolation
Severe infection activates the clotting cascade and consumes platelets.
Initiating factors:
1) Extensive damage to vascular endothelium exposing tissue factor e.g major trauma and tissue destruction
2) Enhanced expression of tissue factor by monocytes in response to cytokines
- Sepsis
- Advanced cancer
- Obstetric complications
- Major trauma
215
clinical presentation of disseminated intravascular coagulation
Often acutely ill and shocked
Bleeding may occur from the mouth, nose and venepuncture sites.
Widespread bruising
Confusion
Thrombotic events may occur as a result of vessel occlusion by fibrin and platelets (skin, brain and kidneys are most affected)
216
Investigation and diagnosis of disseminated intravascular coagulation
Diagnosis can be suggested from history from underlying cause (sepsis, malignancy or obstetric causes)
Decreased fibrinogen
Elevated fibrin degradation products (high D-dimer)
Blood film shows fragmented RBCs
Prolonged prothrombin time
217
Treatment of disseminated intravascular coagulation
Treat the underlying condition - antibiotics
Replace platelets if very low via transfusion if patient is actively bleeding
Fresh frozen plasma to replace coagulation factors
Red cell transfusion in patients that are still bleeding
218
epidemiology of HIV
- 5000 new infections per day
- majority in Sub-Saharan Africa
- 50% of all new infections occur in 15-24 year olds
- 1 in 4 people do not know they have HIV
219
what are the modes of transmission of HIV?
- sexual intercourse
- sharing of contaminated needles
- receipt of infected blood/blood products/donated organs
- vertical transmission (mother to baby during labour and breast feeding)
220
what does U= U mean?
undetectable = untransmittable
| having an undetectable viral load when taking HIV treatment also stops transmission
221
name 5 risk factors that increase your likelihood of getting HIV
- sexual contact with people with high prevalence groups (MSM)
- having multiple sexual partners
- IVDU
- Commercial sex workers
- Vertical transmission (baby more likely to contract if mum has HIV)
222
what type of virus is HIV?
| What does this mean?
retrovirus
| genetic material is RNA so has to undergo reverse transcription into DNA to be incorporated into the host cell
223
what immune cell is HIV trophic to?
CD4+ T cells
224
how does HIV infect a CD4+ T cell ?
1. HIV free in plasma
2. HIV recognises and fuses to CD4 and CCR5 receptors on the the CD4+ T cell
3. virus fuses to the cell membrane and enters the cell
4. caspid enters the cell
5. enzymes reverse transcriptase and integrase enzyme both enable viral DNA to be integrated into the host cells DNA
6. when the host cell replicates the viral DNA also replicates
7. Viral proteins made
8. Virus matures and buds out of the host cell
225
what is the natural history of HIV
1. initially get an acute primary infection when first acquire HIV
- huge spike in viral replication
- transient immunosuppression and fall in CD4 count
- abrupt onset of non-specific viral/flu symptoms (can be severe) significant weight loss, fever, rash
2. Body develops antibodies to HIV and is able to partially control the infection leading to a period of CLINICAL LATENCY (approx 7 years)
3. Progresses to AIDS and get signs and symptoms
226
What potential findings are there in the asymptomatic phase of HIV?
- persistent generalised lymphadenopathy
- shingles
- cervical abnormalities
- may be a high protein count on blood test (high immunoglobulins and normal albumin)
227
what cells serve as a marker for HIV infection?
CD4 T cells
228
what are 2 important prognostic factors for progression to AIDS?
- conc of HIV RNA in the blood (viral load) at the time of diagnosis
- CD4+ helper T cell count
229
symptoms of early symptomatic HIV (AIDS related complex)
- RECURRENT SHINGLES
- Candidiasis
- Diarrhoea
- Night sweats
- Weight loss
230
symptoms of AIDS
the dominant clinical manifestations of AIDS are opportunistic infections and tumours.
Typical infections :
- Oesophageal candida
- Pneumocystis jirovecii pneumonia
- TB
- Chronic Herpes Simplex Virus Infection
AIDS defining conditions
- Oesophageal candida
- Pneumocystis jirovecii pneumonia
- Kaposi's carcinoma
- Non-Hodgkin's Lymphoma (caused by EBV)
Direct HIV effect :
- HIV dementia
- HIV wasting
231
3 factors that the development of AIDS depends on
- genetic background
- repeated immune stimulation
pregnancy
232
at what CD4 T cell level do opportunistic infections occur?
less than 200
233
What test to do in suspected HIV?
Blood test
| tests for HIV antibody and antigen
234
What is the treatment for HIV?
Antiretroviral treatment (HAART)
- entry inhibitor drugs
- fusion inhibitors
- inhibition of viral replication
- protease inhibitors
235
Prevention of HIV spread
1. PreP - take tablets before sex to protect
2. Circumcision reduces risk of transmission
3. PEP - take drugs after sex
4. STI control - condoms!
236
what is UNAIDS 90/90/90
to be achieved by 2020
- 90% of people living with HIV are diagnosed
- 90% of those diagnosed to be on ART therapy
- 90% of those on ART to have viral suppression
