Haematology Flashcards
1
Q
What is haemopoiesis
A
The physiological developmental process that gives rise to the cellular components of blood
2
Q
What are the characteristics of haemopoietic stem cells
A
Self renewal
High proliferative potential
Differentiation potential for all lineages
Long term activity throughout the lifespan of the individual
3
Q
What are the two types of haemopoietic lineages
A
Myeloid
Lymphoid
4
Q
When and where does haemopoiesis happen in utero
A
Day 27 in the aorta mesonephros region, expands rapidly at day 35, then disappear at day 40 when the haemopoietic stem cells migrate to the foetal liver which becomes the subsequent site of haemopoiesis
5
Q
What are the functions of blood cells
A
Oxygen transport
Coagulation (haemostasis)
Immune response to infection
Immune response to abnormal cells (senescent, malignant etc)
6
Q
What is anaemia
A
Reduced red cells
7
Q
What is polycythaemia
A
Raised red blood cells
8
Q
What are the functions of white blood cells (leukocytes)
A
Immunity and host defence
9
Q
What are the types of white blood cells
A
Granulocytes: -Neutrophils -Eosinophils -Basophils Moncytes Lymphocytes
10
Q
What is neutropenia
A
Decrease numbers of neutrophils
11
Q
What is eosinophilia
A
Increased numbers of eosinophils
12
Q
What is basophilia
A
Increased numbers of basophils
13
Q
What is monocytosis
A
Increased numbers of monocytes
14
Q
What is lymphocytosis
A
Increased numbers of lymphocytes
15
Q
What is lymphopenia
A
Decreased numbers of lymphocytes
16
Q
What are the four main subdivisions of haematology clinical practice
A
Coagulation
Malignant
Non-malignant
Transfusion
17
Q
What are the diagnostic tests in haematology
A
Full blood count
Blood film (or smear)
Coagulation screen
18
Q
What does the full blood count test
A
Haemoglobin conc Red cell parameters -MCV (mean cell volume) -MCH (mean cell Hb) White cell count (WCC) Platelet count
19
Q
What does a coagulation screen do?
A
Tests measure the time taken for a clot to form when plasma is mixed with specified reagents
20
Q
What parts of coagulation cascade can be assayed
A
- Prothrombin time
- Activated partial thromboplastin time
- Thrombin time
21
Q
How is bone marrow aspirated
A
Under local anaesthetic, liquid marrow is aspirated from the posterior iliac crest of the pelvis and a trephine core biopsy is then taken with a hollow needle
22
Q
What is the sensitivity of a test
A
Defined as the proportion of abnormal results correctly classified by the test
Expresses the ability to detect a true abnormality
23
Q
What is the specificity of a test
A
Defined as the proportion of normal results correctly classified by the test
Expresses the ability to exclude an abnormal result in a healthy person
24
Q
How do the cells in iron deficiency anaemia present
A
Small, pale red cells
Low MCV and MCH
Variable size and shape- long thin pencil cells
25
What is leucodepletion
When whole blood is filtered before further processing to remove white cells
26
How is a unit of red blood cells kept healthy during storage
Plasma is replaced by a solution of electrolytes, glucose and adenine
27
What is the raise in a patients Hb expected to be after a unit of RBC transfusion
10g/L
28
How much iron is in one unit of packed RBC
200-250 mg of iron
29
How is a unit of RBC stored
At 4 degrees C for up to 35 days from collection
30
What is the therapeutic dose of RBC
10-20ml/kg of recipient
31
What is the usual transfusion time
1.5-3 hours
32
Why are red blood cells transfused
Significant bleeding
Acute anaemia
Chronic anaemia
To restore oxygen carrying capacity
33
What types of anaemia can be treated without blood transfusion
```
Iron deficiency
B12 and folate deficiency
Renal disease (erythropoietin treatment)
```
34
How many units of pooled platelets are in a single pack
4-6 units which each come from different donors as one unit of platelet comes form one unit of whole blood
35
What are aphaeresis platelets
Platelets that have been removed through an apheresis machine that collects platelets and returns all other blood constituents to the donor
The amount of platelets collected this way is equivalent to 4-6 units of pooled platelets
36
How much will a therapeutic dose of platelets raise patients platelets
20-60x 10^9/L
37
What is the platelet count per therapeutic dose
3 x 10^11
38
How are platelets stored
```
Room temperature (22 degrees C) on an agitator
Shelf-life 5 days from collection
```
39
What is the usual transfusion time
30 mins/unit
40
What is the limiting factor for the shelf life of platelets
The risk of contamination by bacteria from the donor's arm that grow at the conditions of storage and can be transmitted to the recipient
41
Why are platelets transfused
To treat bleeding due to severe thrombocytopenia (low platelets) or platelet dysfunction
To prevent bleeding in patients with thrombocytopenia or platelet dysfunction
42
What is fresh frozen plasma
Contains all clotting factors at physiological levels
43
What is the therapeutic dose of fresh frozen plasma
12-15 ml/kg (4-6 units for average adults)
44
How is fresh frozen plasma stored
-30 degrees C for up to 36 months
45
What is the volume of 1 unit of fresh frozen plasma
300ml
46
What is the usual transfusion time of fresh frozen plasma
30 mins/unit
47
Why is fresh frozen plasma transfused
To replace clotting factors in patients with multiple factor deficiencies:
- to treat significant bleeding in patients with abnormal clotting results
- to correct abnormal clotting results prior to invasive procedures
48
When should you not transfuse FFP
To treat single factor deficiencies
To correct abnormal clotting results in patients that are not bleeding
To reverse warfarin
49
What are some acquired coagulopathies
Liver disease
Disseminated intravascular coagulation
Massive haemorrhage
50
How is warfarin anticoagulation reversed
Prothrombin complex concentrate (factor IX complex)
51
What is cryoprecipitate
Extracted from FFP during thawing
Contains fibrinogen, von Willebrand, factor VIII, factor XIII
Therapeutic dose: 10-15ml/kg (6-10 units)
Used as a concentrated source of fibrinogen in acquired coagulopathies
52
What are causes of anaemia
```
Haematinic deficiencies
Secondary to chronic disease
Haemolysis
Alcohol, drugs, toxins
Renal impairment - EPO
Primary haematological/ marrow disease:
-Malignant
-Haemoglobin disorders (sickle etc)
-Aplasia
-Congenital
```
53
What are the classifications of anaemia based on MCV
Macrocytic
Normocytic
Microcytic
54
What types of anaemia fall in to Macrocytic
- B12, Folate, metabolic (thyroid/liver disease)
- Marrow damage (booze, drugs, marrow disease)
- Haemolysis (due to reticulocytosis)
55
What types of anaemia fall in to normocytic
Anaemia of chronic disease/inflammatory
56
What types of anaemia fall in to microcytic
Iron deficiency
Haemoglobin disorders
Sometimes chronic disease
57
How is iron balanced
```
No excretion - limited absorption
Controlled at the level of the gut mucosa
Most iron is thus re-cycled
Absorbed in duodenum
Transported by transferrin
Stored in ferritin/ haemosiderin
```
58
Where can iron be found in diet
Pretty much everything
| Should not be iron deficiently anaemic if eating a balanced diet
59
What is the management of iron deficiency disorder
Establish that there is low iron
Establish the cause
Treat the iron and the cause
60
How is low iron established
```
FBC, indices and film
Ferritin levels tell if iron deficient
% hypochromic cells
Serum iron/ TIBC
Marrow
```
61
What are the main causes of iron deficiency
Blood loss from anywhere (gut/ PV/ PU/ respiratory tract etc)
Malignancy
Increased demand (pregnancy/ growth)
Reduced intake (diet/ malabsorption)
62
How is iron deficiency treated
Oral iron
IM iron
IV iron
63
What is megaloblastic anaemia
A characteristic cell morphology caused by impaired DNA synthesis
64
What are the most common causes of thrombocytopenia
```
Drugs, alcohol, toxins
ITP
Autoimmune disease
Liver disease and/or hyperslenism
Pregnancy
Haematological/ marrow disease
Infections acute or otherwise:
-HIV
-Acute sepsis
-Viral infection (EBV)
Disseminated intravascular coagulation
Range of congenital conditions
Many others
```
65
What is ITP
```
Common
Immune thrombocytopenic purport
Immune disorder
Occurs on its own or as part of:
-Other autoimmune disease
-Lymphomas/ CLL
-HIV
Can be acute/ chronic/ relapsing
```
66
How does ITP present
```
Bruising or petechiae or bleeding
Platelet count:
<10 urgent/ might be bleeding
<20 a worry
<30 need treatment especially if having surgery
No definitive test
```
67
How is ITP treated
```
Steroid is first line
IV immunoglobulin
Immunosuppressives or splectomy
Thrombosis-mimetics:
-Eltrombopag
-Romiplostin
```
68
What is the outcome of ITP therapy
```
Usually rapid response
Can relapse after therapy
Rarely life-threathening
Commonly recurrent
Some difficult refractory causes
```
69
What is TTP
```
Thrombotic thrombocytopenia purpura
Rare but urgent diagnosis
Most are immune ADAMTS-13/VWD
Suspect if thrombocytopenia and:
-Fever
-Neurological symptoms
-Haemolysis (retics/ LDH)
Seek evidence of microangiopathy:
-Blood film fragments
```
70
How is TTP treated
Plasma exchange with FFP/plasma
Steroids
(Vincristine)
(Rituximab)
71
What are the causes of megaloblastic change
```
B12 and/ or folic acid deficiency
Alcohol
Drugs:
-cytotoxics
-folate antagonists
-N20
Haematological malignancy
Congenital rarities:
-Transcobalamin deficiency
-Orotic aciduria
```
72
How do B12 and Folate cause anaemia
DNA consists of purine/pyrimidine bases
Folates are required for their synthesis
B12 is essential for cell folate generation
So low folate or B12 starves DNA of bases
73
Where can vitamin B12 be found in the diet and how is it absorbed
```
Loads in most diets but only from animal sources
Absorption:
-gastric parietal cells
-intrinsic factor
-receptors in terminal ileum
Stores sufficient for some years
```
74
Who has b12 deficiency
```
Nutritional: vegans
Gastric problems:
-pernicious anaemia (autoimmune)
-Gastrectomy
Small bowel problems
-terminal ileum resection/ Chrons
-Stagnant loops/ jejunal diverticulosis
-Tropical sprue/ Fish tapeworm
```
75
Where can folic acid be found and absorbed
Mainly in green vegetables, beans, peas, nuts and liver
Required intake needs decent daily diet
Absorbed in upper small bowel
4 months body stores
76
Why do patients have folic acid deficiency
```
Mainly dietary/ malnutrition
Malabsorption/ small bowel disease
Increased usage:
-pregnancy
-haemolysis
-inflammatory disorders
Drugs/ alcohol/ ITU
```
77
What are the features common to B12 or folate deficiency
```
Megaloblastic anaemia
Can have pancytopenia if more severe
Mild jaundice
Glossitis/ angular stomatitis
Anorexia/ weight loss
Sterility
```
78
What is haemolysis and the causes
```
Shortened red cell life
Causes:
-Things wrong inside the red cell
-Things wrong with the red -cell membrane
-Things wrong external to the red cell
```
79
Why are anticoagulants used
```
Prevention of venous thromboembolism
Prevention of stroke in AF
Treatment of DVT/PE etc
Mechanical valve patients
Arterial thrombosis/ limb ischaemia
```
80
What are the common anticoagulants
```
Heparin
Fondaparinux
Vitamin K antagonists:
Warfarin
Sinthrome ( Acenocoumoral)
DOACs ( Direct Oral Anticoagulants):
-Rivaraoxaban
-Apixaban
-Edoxaban
-Dabigatran
```
81
What is heparin
Derived from pigs
Mode of action:
Increases ability of antithrombin to bind to and irreversibly switch off thrombin (IIa) and Factor Xa
82
What are the potential complications of heparin
Skin/allergic reactions
Osteoporosis
Heparin induced thrombocytopenia
83
How does heparin induced thrombocytopenia present
```
drop in platelet count
>50% from baseline
usually 5-10 days after starting heparin
can be associated with thrombosis
Calculate 4Ts score (timing, level, thrombosis, other causes) and if > 3 send HIT screen, stop heparin, start argatroban
```
84
What is fondaparinux
Synthetic pentasaccharide, given subcutaneously
Binds to antithrombin and inhibits Xa activity
Half life 17-20 hours if normal renal function
Bleeding- stop treatment and general haemostatic measures
No specific antidote
Critical bleeding- consider rFVIIa
85
How is warfarin monitored
By INR
86
What is INR
Prothrombin ratio
| Prothrombin ratio = Patient's prothrombin time/ mean normal prothrombin time
87
What are the problems with oral anticoagulants
React with many drugs
Food interactions- vitamin K containing
Alcohol
88
What are the characteristics of the ideal anticoagulant
- Oral administration
- No requirement for routine coagulation monitoring and dose adjustment
- Wide therapeutic window: high efficacy in preventing thrombosis; low bleeding risk
- Rapid onset of action
- Predictable pharmacokinetics and pharmacodynamics
- Minimal interactions with foods and other drugs
- Ability to inhibit free and clot-bound coagulation factors
- Low non-specific binding
- Availability of an antidote
- No unexpected toxicities
- Acceptable costs
89
What are the benefits of DOACs
Uniform dose in most patients
No need for routine monitoring
Minimal interactions with drugs and foodstuffs
90
What are the cons of DOACs
```
Contraindications:
-Renal impairment
-Women of child bearing age
-Extremes of body weight >120 kg
Management of bleeding
Lab issues
Adherence
Special populations:
-Mechanical valves
-antiphospholipid syndrome
Peri-operative management
```
91
What are the indications for measuring anticoagulant drug levels
```
Bleeding
Need for emergency surgery/procedure
Question of adherence
Recurrent thrombosis
Renal impairment
Potential drug interactions
Extremes of weight
```
92
What is aspirin
Inactivates platelet cyclooxygenase reducing thromboxane A2
Irreversible effect, lasts 4-5 days
No reversal agents
Give 2-3 adult doses of platelets in critical bleeding
93
What are the acquired bleeding disorders
```
Vitamin K deficiency
Liver disease
Renal disease
Major haemorrhage
DIC
```
94
What are the causes of vitamin K deficiency
Obstructive jaundice
Prolonged nutritional deficiency
Broad spectrum antibiotics
Neonates (classical 1-7 days)
95
How is vitamin K deficiency treated
IV/Oral Vitamin K 10mg for 3-5 days
96
How is haemostasis impaired in liver disease
- Thrombocytopenia (production or hypersplenism)
- Platelet dysfunction (plasmin induced cleavage of surface glycoproteins)
- Reduced plasma concentration of all coagulation factors (reduced synthesis) except FVIII
- Delayed fibrin monomer polymerisation due to altered fibrinogen glycosylation (xs sialic acid)
- Excessive plasmin activity
97
How is bleeding in liver disease treated
Platelet transfusions
FFP or prothrombin complex concentrate
Cryoprecipitate or fibrinogen concentrate
Endoscopy if GI bleed
NB above transfusions may not correct clotting tests completely.
98
How does bleeding in renal disease present
Symptoms: (30-50% of CRF patients)
Easy bruising, petechia, gum bleeding, nosebleeds, excessive bleeding from venepuncture/lines
ICH bleeds, retroperitoneal bleed, pericardial tamponade, GI bleeds
Patients with uncontrolled high BP and on dialysis Increased risk of ICH
99
What are the causes of bleeding in renal disease
Anaemia
Drugs accumulating in renal failure can bind to platelets and block their receptors
Uremia
100
How is bleeding prevented in renal disease
Correction of anaemia- EPO and transfusions
Avoidance of antiplatelet drugs for at least 7 days prior to procedures
Dialysis
DDAVP pre procedures
Tranexamic acid pre procedures (not if urinary tract and risk of haematuria)
101
How is bleeding treated in renal disease
DDAVP
Tranexamic acid
Cryoprecipitate used in cases not responsive to DDAVP ( rich in FVIII, VWF, fibrinogen, FXIII)
102
What is the definition of a major haemorrhage
```
HR >110, systolic BP <90 mmHg
And/ or
Transfusion of a volume equal to the patient’s total blood volume in less than 24 hours or
50% blood volume loss within 3 hours
Loss of > 150ml/min
```
103
What is DIC
Disseminated intravascular Coagulation
It is characterised by systemic activation of pathways leading to and regulating coagulation, which can result in the generation of fibrin clots that may cause organ failure with concomitant consumption of platelets and coagulation factors that may result in clinical bleeding.
104
What is the pathogenesis of DIC
Excess thrombin generation
Reduced natural anticoagulant activity
Decreased fibrinolysis
105
What are the causes of DIC
Acute DIC:
Sepsis (any organism)
Obstetric complications- amniotic fluid embolism, abruption
Trauma/Tissue necrosis/Fat embolism
Acute intravascular haemolysis eg ABO incompatible blood transfusion
Fulminant liver disease
Organ destruction ( e.g. severe pancreatitis)
Massive blood loss
Severe toxic or immunological reactions (e.g. recreational drugs, transfusion reactions, transplant rejection, snake bites)
Chronic DIC
Malignancy
End stage liver Disease
Vascular abnormalities (e.g. Kassbach-Merrit syndrome)
106
What are the clinical features of DIC
Mucosal oozing, bleeding from surgical wounds or indwelling canulae
Multi organ failure secondary to microthrombi (and hypovolaemia)
Skin necrosis
Thrombus
107
What are the common causes of Haemolysis
Inside:
- Haemoglobinopathy (sickle)
- Enzyme defects (G6PD)
Membrane:
-Hereditary spherocytosis/ elliptocytosis
External:
- Antibodies (warm/cold)
- Drugs, toxins
- Heart valves
- Vascular/ vasculitis/ microangiopathy
108
How can the presence of Haemolysis be tested
```
Anaemia
High MCV, microcytic
High reticulocytes
Blood fil (fragments/ spherocytes)
Raised bilirubin, LDH
Low haptoglobins
Urinary haemosiderin
```
109
When do acute and delayed reactions to transfusion occur
Acute: <24 hours post transfusion
Delayed: >24 hours post transfusion
110
What are the complications of transfusion which are non immunological
Transfusion transmitted infections
Transfusion associated circulatory overload (TACO)
Febrile non-haemolytic transfusion reaction (FNHTR)
Iron overload
111
How are viral transfusion transmitted infections prevented
```
Donor questionnaire
Mandatory testing:
-Hep B
-HIV
-Hep C
-Hep E
-Human T-cell lymphotropic virus
-Syphilis
```
112
What are the symptoms of a transfusion of bacterial contaminated components
```
Rigors
High fever
Severe chills
Hypotension
Nausea
Vomiting
Dyspnoea
Circulatory collapse
```
113
How may blood components for transfusion become contaminated
By bacteria from the donor's skin during collection
By unrecognised bacteraemia in the donor
Contamination from the environment
Increase risk with storage after donation
114
What is FNHTR
Febrile non-haemolytic transfusion reaction
| Due to cytokines or other biologically active molecules accumulating during storage of blood components
115
What are the clinical features of FNHTR
```
Rise of temp >1 degree C from baseline
±rigors
±tachycardia
Unpleasant but not life-threatening
Resolves after discontinuation of transfusion
```
116
What are the symptoms of transfusion associated circulatory overload
```
Starts up to 24 hours after transfusion
Sudden dyspnoea
Orthopnoea
Tachycardia
Hypertension
Hypoxemia
Raised BP
Elevated JVP
```
117
What are the risk factors for transfusion associated circulatory overload
```
Elderly patients
Small children
Patients with compromised left ventricular function
Large transfusion volume
Increased rate of transfusion
```
118
How is transfusion associated circulatory overload prevented
Follow guidance on volume and rate of transfusion for each component
119
What are the immunological complications related to transfusions
Acute haemolytic transfusion reaction due to incompatibility
Delayed haemolytic reaction
Post transfusion purpura
Allergic/ anaphylactic reaction
Transfusion related acute lung injury (TRALI)
Transfusion-associated graft-versus-host disease (TA-GvHD)
120
What causes acute haemolytic reaction
Transfusion of red blood cells to a recipient that has preformed antibodies against antigens that are expressed on the transfused red blood cell causing free haemoglobin to be released into the circulation
121
What are the possible results of acute haemolytic reaction due to free haemoglobin
Vasoconstriction, hypertension, angina
Fever, riggers, hypotension
Bleeding
Acute kidney injury
Death
122
What are the signs and symptoms of acute haemolytic reaction due to incompatibility
```
Fever and chills
Back pain
Infusion pain
Hypotension/shock
Haemoglobinuria
Increased bleeding (DIC)
Chest pain
Sense of impending death
```
123
What is a group and screen
Determination of ABO and Rh(D) group
Test patient's plasma to screen for antibodies against other clinically significant blood group antigens:
-Positive: antibody identification by testing the patient's plasma against a panel of red cells containing all the clinically significant blood groups
-Negative: no further testing
124
What is crossmatching testing
Final test before transfusion of RBC
Donor RBC of correct ABO and Rh group and antigen negative for the antibodies detected in the green are selected from blood bank
Crossmatching is when patient's plasma is mixed with aliquots of donor RBC to see if there is a reaction
-No: RBS units compatible, no risk of acute haemolysis
Yes: RBC incompatible, risk of acute haemolysis
125
What causes delayed haemolytic reaction to transfusion
Post transfusion formation of new immune IgG antibodies against RBC antigens other than ABO
126
What are the clinical features of delayed haemolytic reaction
```
Onset 3-14 days after transfusion of RBC
Fatigue
Jaundice
± Fever
Lab findings:
-Drop in Hb
-Increased LDH
-Increased indirect bilirubin
-Direct and indirect antiglobulin test positive
```
127
What are the other names given to direct anti-globulin test
Coomb's test
Anti-human globulin test (AHG)
Direct anti-globulin test (DAT)
128
What causes allergic reactions to transfusions
Hypersensitivity of recipient to transfused random proteins
| Usually after transfusion of components that contain plasma (FFP, Cryoprecipitate, platelets)
129
What are the clinical features of allergic reactions to transfusions
```
Rash
Urticaria
Pruritus
±fever
±rigors
Periorbital oedema
```
130
What are the symptoms of anaphylactic reaction to transfusions and who is at higher risk
Laryngeal oedema
Bronchospasm
Hypotension
Swelling
Risk:
Patients with IgA deficiency and anti-IgA antibodies
131
How are newborns screened for haemoglobinopathy and why
At 5 days
Mid wife, heel prick test
Analysis of dried blood spot (multiple conditions tested for)
Early detection of sickle cell disease (parent education, starting antibiotic prophylaxis
132
What is a normal red blood cell
Bi-concave disks
No nucleus
Function is to transport oxygen bound to haemoglobin
Production controlled by erythropoietin produced in kidneys in response to tissue oxygen concentration
133
What is haemoglobin
Tetramer of globin chains, each non-covalently bound to a haem
2 alpha and 2 non-alpha chains
134
What is the function of globin
Protects haem from oxidation
Renders the molecule soluble
Permits variation in oxygen affinity
135
What is a haemoglobinopathy
Changes in globing genes or their expression Leeds to disease
136
What is thalassaemia
Change in globing gene expression leading to reduced rate of synthesis of normal globing chains. Pathology is due to imbalance of alpha and beta chain production (free globing chains damage red cell membrane)
137
What are structural Hb variant haemoglobinopathies
Usually a single base substitution in globin gene causes altered structure/ function
Eg sickle cell
138
How are Haemoglobinopathies inherited
Autosomal recessive
139
What is the clinical picture for sickle cell trait (Heterozygous)
Blood count normal
| No problems except when extreme hypoxia/ dehydration
140
What happens in sickle cell disease
Sickle Hb polymerises to form long liberals which distort the red cell membrane and produce the classic sickle shape
141
What is the clinical picture for sickle cell disease (homozygote)
Blood count: anaemia
| Blood film: sickle cells
142
What are acute complications of sickle cell disease
Vaso-occlusive crisis
Septicaemia
Aplastic crisis
Sequestration crisis
143
What are chronic complications of sickle cell disease
Hyposplenism: due to infarction and atrophy of spleen
Renal disease: medullary infarction with papillary necrosis.
- tubular damage then can't concentrate urine resulting in bed-wedding
- Glomerular damage results in chronic renal failure/ dialysis
Avascular necrosis: femoral/humeral heads
Leg ulcers, osteomyelitis, gall stones, retinopathy, cardiac, respiratory
144
How is sickle cell disease treated in neonatal
Penicillin from 6 months (neonatal screening)
145
How is sickle cell disease treated in acute crisis
Vaso-occlusive - analgesia (opiates), hydration (to maintain red cell water), treatment of precipitants
-Priapism- education
146
How are thalassaemias categorised
α, β, δβ and γδβ
according to which globing chain is reduced
In some, no globing chain is produced and in others they are produced at reduced rate
147
What is the blood picture in β-Thalassaemia and how does it present clinically
resembles iron deficiency by being small pale red cells
Total Hb level normal or slightly reduced
No clinical problems
148
How do those with β-Thalassaemia major present
Short stature and distorted limb growth due to premature closure of epiphyses in long bones
Enlarged liver and spleen
149
What are the three top causes of death in patients with thalassaemia
60. 2%
6. 8%
6. 8%
150
How is iron overload prevented in patients with β-Thalassaemia major
To prevent death patients are started on Iron chelation therapy from 2nd year of life to promote excretion of iron in urine and faeces
151
How is desferrioxamine given
8-12 hourly subcutaneous infusion via a syringe-pump as home-treatment on at least 5 nights a week to prevent the accumulation of iron in β-Thalassaemia major patients
152
What are new oral iron chelators
Deferiprone
| Deferasirox
153
What is the target Ferritin
~1000-1500µg/L
154
What are the physiological changes which may occur in pregnancy
Anaemia (macrocytosis), thrombocytopenia
Neutrophilia (and left shift)
Increased pro-coagulant factor and decrease in fibrinolysis
155
What are the fundamental factors which contribute to thrombogenesis
Alterations in blood flow producing stasis, damage to the vascular endothelium and changes in blood constituents resulting in hypercoagulability
156
What is arterial thrombosis
Cause by atherosclerosis of vessel wall.
Rupture of atheromatous plaque
Endothelial injury
Platelet aggregation and platelet thrombi play an important role in final vessel occlusion
157
What are the risk factors for arterial thrombosis
Smoking, hypertension, hypercholesterolaemia, diabetes, family history, obesity, physical inactivity, age, male sex
158
What is venous thrombosis
Pathogenesis mainly involves:
- venous stasis
- hypercoagulable states
159
What makes up venous thrombi
Predominantly composed of fibrin with a lesser role for platelet accumulation and aggregation
160
What is the care pathway for hospital admission in relation to VTE
Patient admitted to hospital
Assess VTE risk
Assess bleeding risk
Balance risks of VTE and bleeding
Offer VTE prophylaxis if appropriate
Do not offer pharmacological VTE prophylaxis if patient has any risk factor for bleeding and risk of bleeding outweighs risk of VTE
Reassess risks of VTE and bleeding within 24 hours of admission and whenever clinical situation changes
161
What are the risk factors for VTE
- Active cancer or cancer treatment
- >60 yo
- Critical care admission
- Dehydration
- Known thrombophilias
- One or more significant medical comorbidities
- Surgery
- Major trauma
- Personal history of VTE
- Use of hormone replacement therapy
- Use of oestrogen-containing contraceptive therapy
- Varicose veins with phlebitis
- Obesity (BMI over 30)
- Pregnancy and postnatal period
- Immobility
- First degree relative with VTE
162
What is the general advice for those at risk of VTE in hospital
Do not allow patients to become dehydrated unless clinically indicated
Encourage patients to mobilise as soon as possible
Do not regard aspirin or other anti-platelet drugs as adequate prophylaxis for VTE
163
What meds are used in pharmacological prophylaxis
```
Low dose low molecular weight heparin
Fondaparinux (synthetic pentasaccharide)
Newer anticoagulants:
-direct inhibitors of factor Xa:
-- rivaroxaban
-- apixaban
-direct thrombin inhibitors:
-- dabigatran
```
164
What is the Wells score
Reflects the risk of developing DVT
Validated numerical clinical probability score
Sensitive quantitative D-dimer with high negative predictive value
Used in an agreed algorithm
165
How can DVTs be diagnosed with imaging
Ultrasound
Duplex scanning with compression will aid to detect any thrombus
Highly sensitive and specific
Look for loss of flow signal, intravascular defects or non collapsing vessels in the venous system
166
How is low molecular weight heparin used in VTE treatment
Doses are fixed by body weight
Once daily by sub cut injection
Treat for at least 5 days
Overlap with warfarin until INR >2.0 for two consecutive days
167
How are VTEs managed
First episode of proximal vein DVT or PE:
- treat for 3-6 months
- warfarin target INR= 2.5
Recurrent VTE:
- treat with long term anticoagulation
Proximal DVT or PE which has occurred in absence of reversible risk factor:
-consider long term anticoagulation
Recurrent VTE on therapeutic anticoagulation:
-increase target INR to 3.5 for warfarin
168
What are the definitions of thrombophilia
Familial or acquired disorders of the haemostat mechanism which are likely to predispose to thrombosis
Patients who develop VTE:
- spontaneously
- of disproportionate severity
- recurrently
- at an early age
169
What are heritable thrombophilias
```
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Activated Protein C resistance/ Factor V Leiden
Dysfibrinogenaemia
Prothrombin 20210A
```
170
What is the acquired thrombophilia
Antiphospholipid syndrome
171
What are the clinical features of thrombophilia
DVT
PE
Superficial thrombophlebitis
Thrombosis of cerebral, axillary, portal, mesenteric veins
Arterial thrombosis |(APS, only)
Coumarin induced skin necrosis (PC deficiency)
Obstetric complication: foetal wastage (APS)
172
What is antiphospholipid syndrome
Antiphospholipid antibodies on at least 2 occasions, 8 weeks apart in association with venous thrombosis or arterial thrombosis or >2 foetal loss
May be primary or secondary
173
When should a patient be tested for thrombophilia
Not unselected patient who just have a VTE
After counselling re pros and cons and discussion of management
Asymptomatic relatives not usually tested
174
What are some haematological emergencies on a haematology ward
- Neutropenic sepsis
- Pneumonia
- Hypercalcaemia and hyper-viscosity
- Spinal cord compression
- Acute kidney failure
- Tumour lysis syndrome
- Sickle cell crisis
- Acute haemolysis
- Acute haemorrhage in haemophilia A or B
- New acute leukaemia
- Mediastinal mass
175
What are some haematological emergencies on a general ward
- PE
- DVT
- Transfusion reactions (haemolysis, febrile non-haemolytic, TRALI, Massive transfusion)
- Heparin induced thrombocytopenia
- Immune thrombocytopenia purpura
- Disseminated intravascular coagulation (DIC)
- Over anti-coagulated patient
- Management of the anti-coagulated patient undergoing acute surgery
- Thrombotic thrombocytopenia purpura
- HELLP syndrome
176
What is HELLP syndrome
Haemolysis
Elevated liver enzymes
Low platelet count
177
What are chronic myeloproliferative disorders
CMPD
Clonal stem cell disorders of the bone marrow
Malignant
178
What are the three types of CMPD
Polycythaemia Vera
Essential thrombocytosis
Idiopathic Myelofibrosis
179
What is polycythaemia vera
Increased red cells
±neutrophils
±platelets
Distinguish from secondary polycythaemias and relative polycythaemia
180
What is essential thrombocythaemia
Increased platelets
| Distinguish from reactive thrombocytosis
181
What is myelofibrosis
Variable cytopenias with a large spleen
| Distinguish from other causes of splenomegaly
182
What are the signs and symptoms of polycythaemia vera
```
Symptoms:
Insidious itching
Plethoric face (red)
Headache
Muzziness
General malaise
Tinnitus
Peptic ulcer
Gout
Gangrene of the toes
```
Signs:
Plethora
Engorged retinal veins
Splenomegaly
183
How is PV diagnosed
```
Persistent increased Hb/hct > 0.5
Relative vs absolute
Primary vs secondary
History and exam
FBC
Ferritn
Epo level
U and E/ LFT
```
184
What are causes of secondary polycthaemia
```
Central hypoxic process
Renal disease
EPO producing tumours
Drug associated
Congenital
Idiopathic erythrocytosis
```
185
What does the presence of JAK2 V617F mutation show
In peripheral blood DNA it is diagnostic of a myeloproliferative disorder
186
How is PV treated
Aspirin 75mg daily
| Aim for HCT<0.45
187
What is the prognosis for PV
Good- 15 year median survival
| Risk of developing AML and/or myelofibrosis
188
How is thrombocytosis investigated
```
History and exam
Recent normal count prior to surgery
Persistent platelets >450 x 109/L
1st line:
-FBC and film
-Ferritin
-CRP
-CXR
-ESR
2nd line:
-JAK2
-CALR
-Bone marrow biopsy
-Extensive search for secondary cause
```
189
What is CALR mutation
Calreticulin mutation
Cell signalling protein produced in endoplasmic reticulin
Mutation in EXON 9 of gene
Found in Myeloid progenitors in essential thrombocythaemia
190
How is ET diagnosed
JAK2 mutation- approx 50%
CALR mutation- approx 45%
Bone marrow
191
How is ET treated
Assess thrombotic risk
Antiplatelet treatment (aspirin 75mg daily)
Cytoreduction (if high risk)
192
What performs cytoreduction
Hydroxycarbamide
Interferon
Anagrelide
P32
193
What is the prognosis of ET
Excellent- 20 year median survival
Risk of AML or myelofibrosis
CALR mutated have lower thrombosis risk
194
How does myelofibrosis present
Pancytopenia
B symptoms
Massive splenomegaly
195
How is myelofibrosis investigated
FBC and film
| Haematinics
196
How is myelofibrosis diagnosed
Blood film
Bone marrow results
JAK2 mutation 50%
CALR mutation 30%
197
What are the causes of splenomegaly
```
CHICAGO
Cancer
Haematological (myelofibrosis, CML, CLL, hairy cell leukaemia)
Infection (schistosomiasis, malaria, leishmaniasis, EBV)
Congestion (liver disease/portal)
Autoimmune (haemolysis, SLE)
Glycogen storage disorders
Other - Amyloid, sarcoid
```
198
What are the treatments of splenomegaly
Supportive care
JAK2 inhibitors
Bone marrow transplant
199
What is the prognosis of splenomegaly
Poor with median survival of 5 years
200
How is chronic myeloid leukaemia characterised
Leucocytosis
Leucoerythroblastic blood picture
Anaemia
Splenomegaly
201
What are the symptoms of chronic myeloid leukaemia
```
Abdominal discomfort (splenomegaly)
Abdominal pain (splenic infarction)
Fatigue (anaemia, catabolic state)
Venous occlusion (retinal vein, DVT, priapism)
Gout (hyperuricaemia)
```
202
What are the causes of acute leukaemia
Result of accumulation of early myeloid (AML) or lymphoid (ALL) precursors in bone marrow, blood and other tissues
Probably occurs by somatic mutation in a single cell within a population of early progenitor cells
May arise de novo or secondary to prior chemotherapy/radiotherapy or develop from another haematological condition
203
What is the median age at presentation of AML
69 years
204
What are the clinical features of AML
```
Presents with features of bone marrow failure:
-anaemia
-infections
-early bruising and haemorrhage
Organ infiltration by leukaemia cells may occur in:
-spleen
-liver
-meninges
-testes
-skin
```
205
What does AML mean
Acute monocytic leukaemia
206
What are the haematological features of AML
- Anaemia
- Low or high white cell count with circulating leukaemia cells
- Low platelets
207
How is AML diagnosed
Morphology
Immunological markers
Cytogenetics (chromosomes) (certain abnormalities correlate with prognosis eg t(8;21) inv(16) and t(15:17))
208
What is important for prognosis in AML
```
Age
Chromosomes
Molecular features (NPM1 and FLT3-ITD)
Extramedullary disease
Disease that doesn't respond to treatment
```
209
Up to what age should AML patients be considered for intensive treatment
Up to age 80 yo
210
What is the intensive chemotherapy regime for AML and the risks
```
3-4 cycles of intravenous cytotoxic drugs given centrally
80-85% complete remission after cycle 1
Disease assessment after 1st cycle
High risk patients go on to have a bone marrow transplant
Risk:
-death
-sepsis
-alopecia
-infertility
-tumor lysis
```
211
How factors determine who to target with intensive vs non-intensive chemo
```
Age
Co-morbidity
Body habits
Lifestyle decisions
Cytogenetics
Molecular information
```
212
When should patients be given immediate intensive chemotherapy treatment
Critically ill patients with rapidly progressive disease (such as WCC>100 x 10^9/L) with respiratory/ neurological/ other organ compromise
All other patients: no proven benefit to early initiation of treatment, wait for cytogenetics and mutational status prior to deciding on definitive therapy
213
What are the options for non-intensive treatment in AML
Low dose chemotherapy (cytarabine)
Hypomethylating agents
New treatments
214
What do the newer treatments available to patients with AML do
Target specific abnormalities expressed on leukaemia cells
Provide individualised treatments
Used in combination with chemo or on their own
215
What does ALL mean
Acute lymphoblastic leukaemia
216
How does ALL present
```
Fatigue
Bruising/bleeding
Weight loss
Weight sweats
Hepatosplenomegaly
Lymphadenopathy
Mediastinal mass
```
217
What is the general course of treatment for ALL patients
4 components:
- Induction (8 weeks)
- Intensification/ CNS prophylaxis (4 weeks)
- Consolidation (20 weeks)
- Maintenance (2 years)
If high risk proceed to bone marrow transplant after intensification
218
What are the treatment options for relapse disease of ALL
```
Further intensive chemo
Blinatumomab
Inotuzumab
CAR-T cells
BMT- sib/MUD/Cord/Haplo
```
219
What are immunotoxins/ immunoconjugates
Monoclonal antibodies/ cell antigen binding fragment and a toxin moiety which induces cell death
Markedly increases activity of the antibody
CD22 most attractive target
220
What is neutropenic sepsis and how is it treated
Life threatening complication of chemotherapy
Time critical medical emergency
Symptoms:
-fever
-hypotension
-organ impairment
Treat with broad spectrum IV antibiotics as soon as suspected
221
What is MDS
Myelodysplasia
Represents several related disorders with common features
A heterogeneous group of clonal bone marrow stem cell disorders that result in ineffective haematopoiesis with reduced production of one or more of the peripheral blood cell lineages
Incidence of MDS increases with age
222
What are the features of MDS
Dysplasia
Inefficient haematopoiesis
Cytopenias
Increased risk of transformation to AML
223
What should be the procedure for low risk MDS
May only need to monitor the patient
Only treat if symptomatic
Erythropoietin for anaemia
Blood product support as necessary
224
What should be the procedure for high risk MDS
Treatment aimed at altering natural history of the disease
If fit enough treat as per AML with intensive chemotherapy and bone marrow transplant
If not fit or complex cytogenetics consider azacytidine
225
What are immunoglobulins
Glycoprotein molecules
Produced by plasma cells in response to an immunogen
Composed of two light chains and two heavy chains held together by covalent disulphide bonds
Each chain has one variable and one constant region
226
How are immunoglobulins classified
According to amino acid sequences in the constant region of the:
Heavy chains: IgG, IgM, IgA, IgD, IgE
Light chains: kappa or lambda
227
What is protein electrophoresis
The lab technique whereby serum is placed in a gel and exposed to an electric current
Five major fractions are normally identified:
-Serum albumin
-Alpha-1 globulins
-Alpha-2 globulins
-Beta globulins
-Gamma globulins
228
What is immunofixation
Enables the detection and identification of monoclonal immunoglobulins
Performed when M spike seen on electrophoresis
Serum or urine is placed on a gel and electric current applied to separate the proteins
Anti-immunoglobulin antisera is added to each migration lane
If the immunoglobulin is present, a complex precipitates
229
What is myeloma
An incurable malignant disorder of clonal plasma cells
230
What is diagnostic of myeloma
IMWG diagnostic criteria:
Clonal BM plasma cells >/= 10% or biopsy-proven boney or extra medullary plasmacytoma and any one or more of:
-CRAB features
-MDEs
231
What are the CRAB features
C- hypercalcamia (>2.75mmol/L)
R- renal insufficiency (creat clearance <40ml/min or serum creat >177micromol/L)
A- anaemia (Hb<100g/L)
B- bone lesions (one or more osteolytic lesions on skeletal radiography, CT, or PET/CT
232
What are MDEs
Myeloma-defining events:
- >/= 60% clonal plasma cells on bone marrow biopsy
- SFLC ratio >100mg/L provided the absolute level of the involved LC is >100mg/L
- >1 focal lesion on MRI measuring >5mm
233
What are the clinical features of myeloma
```
Confusion
Poor appetite
Thirst
Chest infections
Breathlessness
Polyuria or oliguria/ anuria
Peripheral oedema
Constipation
Pathological fractures
Nausea
Bone pains
```
234
What is the normal range of Hb
130-180g/dL
235
What is the normal range of creatine
40-90mmol/L
236
What is the normal range of Ca2+
2.2-2.6mmol/L
237
What is MGUS
Serum M-protein <30g/L
<10% clonal plasma cells in the bone marrow
Absence of end organ damage (CRAB)
Majority progress to myeloma
238
What is the normal range for albumin
30-40 g/L
239
What are lymphomas
Caused by malignant proliferation of lymphocytes
Lymph nodes are predominantly affected though in advanced stages, there may be bone marrow involvement and other organ involvement
Classified according to the presence of Redd-Sternberg cells
240
What are important factors to consider is a patient presents with a neck lump
```
Nature of lump (size, rate of change, tenderness, skin changes, history of trauma)
Additional lumps elsewhere
Weight loss
Night sweats
Breathlessness, cough, haemoptysis
PMH (malignancies)
SH (smoking)
FH (bone marrow disorders or malignancies)
```
241
What will clinical examination of patient with neck lump focus on
Nature of the lump – size, location, skin changes, contour, whether fixed to underlying structures
Evidence of additional neck masses
Presence of palpable lymphadenopathy
Presence of hepatosplenomegaly
Presence of breast lumps
Chest examination – insection, auscultation and percussion
242
What are the possible causes of a neck mass
Malignant:
- lymphoma
- chronic lymphocytic leukaemia
- metastatic cancer of the lung/ breast/ cervix
Non-malignant:
- Infection (bacterial, viral, mycobacterial)
- Inflammation (sarcoidosis)
- Lipoma
- Fibroma
- Haemangioma
243
What investigations should be done on a patient with neck lump
Bloods:
- FBC
- U&Es
- LFTs
- Ca2+
- LDH
- Immunoglobulins and protein electrophoresis
Imaging:
- Chest X-ray
- Ultrasound scan of the neck lump
- Fine needle aspirate and/or core needle biopsy
244
What is follicular lymphoma
Neoplastic disorder of lymphoid tissue
| Type of non-Hodgkin lymphoma characterised by slowly enlarging lymph nodes
245
What are the important factors in the history of a patient presenting with breathlessness
Nature of the breathlessness – rate and duration of onset, variability with activities, exacerbating and relieving factors
Additional symptoms – cough, sputum production, ankle swelling, orthopnoea, PND, weight loss, night sweats
Past medical history – childhood illnesses
Social history – smoking, occupational and animal exposure
Family history – any history of respiratory/cardiac problems
246
What are the important factors clinical examination features of a patient presenting with breathlessness
Chest and cardiovascular examination
| Lymphadenopathy
247
What are the investigations done on a patient presenting with breathlessness
Bloods:
- FBC
- U&Es
- LFTs
- LDH
- ACE level
- ESR
Imaging:
- Chest -ray
- PET-CT
248
What are the characteristic of Hodgkin lymphoma
Presence of Hodgkin Reed-Sternberg (HRS) cells within a cellular infiltrate of non-malignant inflammatory cells eg: eosinophils
HRS fail to express surface immunoglobulin and evade apoptosis through several mechanisms – eg: activation of NFkB, incorporation of EBV and latent membrane proteins (LMP1 and LMP2)
249
How is Hodgkin lymphoma managed
Chemotherapy
Radiotherapy
Doses/number of courses depends on stage
250
What is the prognosis of Hodgkin lymphoma
High proportion are cured – 86% 5 year survival
Long-term effects of therapy are important:
- Increased mortality is still seen at >20 years post therapy
- Pulmonary toxicity
- Cardiovascular disease
- Secondary malignancies
251
What is CLL
Chronic lymphocytic leukaemia
A malignant disorder of mature B cells
Most common type of leukaemia in UK
252
What is the treatment for CLL
Chemo-immunotherapy (bendamustine and rituximab)
| Bone marrow treatment
