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MBChB Year 3 > Week 3 - Haematology > Flashcards

Week 3 - Haematology Flashcards

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1
Q

Describe the different sites of haematopoiesis in the growing foetus?

A
  • 0-2months: Yolk sac
  • 2-7months: liver & spleen
  • 5-9months: bone marrow
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2
Q

What is the site of haemopoiesis in infants?

A

Bone marrow (all bones)

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3
Q

What is the site of haemopoiesis in adults?

A

Bone marrow (vertebrae, ribs, sternum, skull, sacrum, pelvis, ends of femurs)

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4
Q

List the 5 haemopoietic stem cell characteristics?

A
  1. Self renewal capacity
  2. Unspecialised
  3. Ability to differentiate (mature)
  4. Rare (1 in 10,000 to 1 in 1 million in bone marrow)
  5. Quiescent (i.e. not under going cell cycle)
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5
Q

What are 3 locations for haemopoietic stem cells?

A
  1. Bone marrow
  2. Peripheral blood after treatment with G-CSF
  3. Umbilical cord blood
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6
Q

What are 3 things which can happen to haemopoietic stem cells?

A
  1. Self-renewal
  2. Apoptosis
  3. Differentiation
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7
Q

What controls stem cell fate?

A
  • A complex interplay of micro- environmental signals (the niche) & internal cues
  • Selected Embryonic Patterning Pathways
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8
Q

What is the definition of stroma?

A

Bone marrow microenvironment that supports the developing haemopoietic cell

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9
Q

What are stromal cells supported by?

A

Extracellular matrix

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10
Q

Give 5 examples of stromal cells?

A
  1. Macrophages
  2. Fibroblasts
  3. Endothelial cells
  4. Fat cells
  5. Reticulum cells
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11
Q

What are the 2 outcomes for symmetrical division of stem cells?

A
  1. Contraction of stem cell numbers

2. Expansion of stem cell numbers

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12
Q

What is the outcome of asymmetrical division of stem cells?

A

Maintenance of stem cell numbers

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13
Q

List 5 hereditary conditions which impair bone marrow function?

A
  1. Thalassaemia
  2. Sickle cell anaemia
  3. Fanconi anaemia
  4. Thrombocytopenia with absent radii
  5. Hereditary leukaemia (v. rare)
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14
Q

List 10 acquired conditions which impair bone marrow function?

A
  1. Aplastic anaemia
  2. Leukaemia
  3. Myelodysplasia
  4. Myeloproliferative disorders
  5. Lymphoproliferative disorders
  6. Myelofibrosis
  7. Metastatic malignancy e.g. breast, prostate
  8. Infections e.g. TB / HIV
  9. Drugs and toxins
  10. Chemotherapy
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15
Q

List the 4 principles of leukaemogenesis?

A
  • Multi-step process
  • Neoplastic cell is a haemopoietic stem cell/early myeloid/lymphoid cell
  • Dysregulation of cell growth & differentiation
  • Proliferation of the leukaemic clone with differentiation blocked at an early stage
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16
Q

What is the definition of leukaemogenesis?

A

Induction or production of leukemia

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17
Q

Describe the process of leukaemogenesis?

A

Human stem cell –> (leukaemogenic event) Leukaemia stem cell –> clonogenic leukaemia cells –> Non-clonogenic leukaemia blast cells

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18
Q

When are haematological malignancies & pre-malignant conditions termed “clonal”?

A

If they arise from a single ancestral cell

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19
Q

What are non malignant lymphoid proliferations?

A

Polyclonal

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20
Q

Regarding clonal haemopoietic stem cell disorders, what do X chromosome inactivation studies in women with leukaemia show?

A

Clonal proliferation carries either an active maternal or paternal X chromosome

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21
Q

What are Myeloproliferative Disorders?

A

Clonal disorders of haemopoiesis leading to increased numbers of one or more mature blood progeny

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22
Q

Give 6 examples of Myeloproliferative Disorders?

A
  1. Polycythaemia rubra vera
  2. Essential thrombocytosis
  3. Myelofibrosis
  4. Mastocytosis
  5. Clonal hypereosinophilic syndromes
  6. Chronic neutrophilic leukaemia
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23
Q

What mutations are Myeloproliferative Disorders variably associated with?

A

JAK2V617F & calreticulin mutation

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24
Q

What do Myeloproliferative Disorders have the potential to transform into?

A

Acute Myeloid leukaemia (AML)

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25
What is the platelet cost for essential thrombocytosis?
>600x10*9 /L persistently
26
List 6 clinical features of essential thrombocytosis?
1. Continuum with polycythemia rubra vera (PRV) 2. Thrombotic complications 3. Haemorrhagic complications 4. Splenomegaly 5. Transformation to PRV/myelofibrosis 6. Leukaemic transformation in ~3%
27
Describe people at low risk of essential thrombocytosis?
Age <40 with no high risk features
28
How would you treat people at low risk of essential thrombocytosis?
Aspirin or anti-platelet agent
29
Describe people at intermediate risk of essential thrombocytosis?
Aged 40-60 with no high risk features
30
How would you treat people at intermediate risk of essential thrombocytosis?
Aspirin ± hydroxycarbamide
31
Describe people at high risk of essential thrombocytosis?
- Aged >60 - 1 or more high risk features (plt >1500x109/L, previous thrombosis or thrombotic risk factors e.g. diabetes or hypertension)
32
How would you manage people at high risk of essential thrombocytosis?
- 1st line: hydroxycarbamide + aspirin | - 2nd line: anagrelide + aspirin
33
What drug is useful in managing high risk essential thrombocytosis in pregnancy?
IFNα
34
What are 4 other management options for high risk essential thrombocytosis?
1. Busulphan 2. 32P 3. Combination therapy 4. JAK2 inhibitors e.g. ruxolitinib
35
What do JAK2 mutations result in?
Continuous activation of JAK receptor regardless of ligand binding
36
What is the JAK2 inhibitors Ruxolitinib now approved for?
Use in patients with myelofibrosis with trials ongoing in essential thrombocytosis & Polycythaemia rubra vera
37
What does Ruxolitinib do?
Inhibits JAK1 & 2
38
What does Ruxolitinib show in 70-80% of patients?
Reduced splenomegaly & functional improvement
39
What is the main side effect of Ruxolitinib?
Thrombocytopenia
40
What are Myelodysplastic syndromes (MDS) characterised by?
Dysplasia & ineffective haemopoiesis in ≥1 of the myeloid series
41
What may Myelodysplastic syndromes (MDS) be secondary to?
Previous chemotherapy or radiotherapy
42
Describe Myelodysplastic syndromes (MDS)?
- May have increased myeloblasts | - Multiple sub-types based on morphology and % blasts (WHO classification)
43
What do the majority of Myelodysplastic syndromes (MDS) result in?
Progressive bone marrow failure
44
What can some Myelodysplastic syndromes (MDS) progress to?
Acute myeloid leukaemia
45
Describe Myelodysplastic syndromes (MDS) clinical features?
- Predominantly affects the elderly - 20% incidental finding on FBC - 20% present with infections or bleeding - Majority (70-80%) present with fatigue due to anaemia
46
What 3 things are Myelodysplastic syndromes (MDS) IPSS risk scores based on?
1. BM blasts (%) 2. Karyotype 3. Cytopenias
47
List ways to manage Myelodysplastic syndromes (MDS)?
1. Blood & platelet transfusion 2. Erythropoietin ± granulocyte colony stimulating factor (G-CSF) 3. Immunosuppression: anti-thymocyte globulin (ATG) 4. Low dose chemotherapy: hydroxycarbamide, low dose cytarabine 5. Demethylating agents: azacytidine, an epigenetic therapy 6. Intensive chemotherapy 7. Allogeneic stem cell transplantation
48
What may you need to consider when managing Myelodysplastic syndromes (MDS) in younger patients?
Iron chelation
49
Describe Fanconi anaemia?
- Bone marrow failure may present from birth into adulthood - Autosomal recessive inheritance - Currently 7 genetic sub-types FANCA-G
50
List the 5 characteristics of Fanconi anaemia?
1. Somatic abnormalities 2. Bone marrow failure 3. Short telomeres 4. Malignancy 5. Chromosome instability
51
List 6 abnormalities which can stem from Fanconi anaemia?
1. Microphthalmia 2. GU malformations 3. GI malformations 4. Mental retardation 5. Hearing loss 6. CNS e.g. hydrocephalus
52
What is the main cause of mortality in people with Fanconi anaemia?
Premature bone marrow failure
53
What is the gold standard therapy for Fanconi anaemia?
Allogeneic stem cell transplant
54
What are the 3 other options for treatment of Fanconi anaemia?
1. Supportive care 2. Corticosteroids 3. Androgens (oxymethalone)
55
What do people with Fanconi anaemia need life time surveillance for?
Secondary tumours
56
What is the future treatment possibilities for Fanconi anaemia?
Gene therapy in future where faulty FANC gene is replaced
57
What are the 2 different types of stem cell transplants?
1. Autologous transplant (“autograft”)- the patients own blood stem cells 2. Allogeneic transplant (“allograft”)- any transplant in which the stem cells come from a donor
58
List the 5 different types of stem cell donors for Allogeneic transplants?
1. Syngeneic Transplant (between identical twins) 2. Allogeneic Sibling (HLA identical) 3. Haplotype identical (half matched family member, usually parent/half matched sibling) 4. Volunteer Unrelated (VUD)/Matched Unrelated (MUD) 5. Umbilical cord blood
59
What are the 4 main indications for autologous stem cell transplant?
1. Relapsed Hodgkin’s disease 2. Non Hodgkin’s lymphoma 3. Myeloma 4. Leukaemia
60
What do almost all autografts (autologous stem cell transplant) use?
Mobilised peripheral blood stem cells harvested by apheresis
61
What do patients receive when getting an autologous stem cell transplant?
- Growth factor (G-CSF) +/- chemotherapy to make stem cells leave the bone marrow - Mozobil to collect stem cells in patients that failed to mobilise
62
What 3 things can you use for allogeneic stem cell transplant?
1. Peripheral blood stem cells 2. Bone marrow 3. Umbilical cord blood
63
What are the 4 main indications for allogeneic stem cell transplant?
1. Acute & chronic leukaemias 2. Relapsed lymphoma 3. Aplastic anaemia 4. Hereditary disorders
64
What does an allograft have the benefit of in malignant disease?
Graft versus leukaemia but at the expense of graft versus host disease
65
What is the donor registry within the UK called?
The Anthony Nolan Trust donor registry
66
What are the 2 problems with volunteer unrelated donor (VUD) transplant?
1. Increased risk of graft vs host disease compared to family donor (prefer young, male donors) 2. Shortage of donors from other ethnic groups apart from caucasian
67
Describe non-myeloablative stem cell transplant (SCT)?
- Low-dose, less toxic preparative regimens - Immunosuppression to allow donor cells to engraft, while graft-versus-leukaemia effect eradicates tumour - Permits use in patients not eligible for conventional SCT
68
What are the 3 other advances in stem cell transplant (SCT)?
1. Non-myeloablative SCT 2. Cord blood transplant 3. Donor lymphocyte infusion (DLI) after SCT
69
Describe Donor lymphocyte infusion (DLI) after stem cell transplant (SCT)?
- To prevent/treat relapse after SCT - Can induce a graft-versus-leukaemia effect - High rate of graft-versus-host disease (GVHD)
70
Describe the process of umbilical cord blood transplant?
- Blood stem cells collected from umbilical cord & placenta - Cells are tissue typed & frozen in liquid nitrogen in cord blood banks for future use
71
What are the 2 advantages of umbilical cord blood transplant?
- More rapidly available than volunteers unrelated donor | - Less rigorous matching to patient type of patient as immune system naive
72
What are the 3 disadvantages of umbilical cord blood transplant?
- Small amount (adults often require double cord transplant) - Slower engraftment - If relapse, cannot go back for donor lymphocyte infusion
73
How does graft versus host disease (GvHD) occur?
- Can happen in patients who have received an allogeneic transplant - New donor’s immune system recognises the host’s body as ‘foreign’ & starts to attack it
74
What are the 3 most common manifestations of graft versus host disease (GvHD)?
1. Skin rash 2. Jaundice 3. Diarrhoea
75
Describe the 2 different forms of graft versus host disease (GvHD)?
1. ACUTE graft vs host disease: occurs WITHIN the first 100 days of the transplant 2. CHRONIC graft vs host disease: occurs AFTER the first 100 days of the transplant.
76
What is graft versus host disease (GvHD) usually treated with?
Immunosuppressive agents
77
Describe graft vs leukaemia (GvL)?
- The same cells which cause GvHD, also attack remaining leukaemia cells - Very effective, esp in patients where a good remission has been difficult to maintain
78
What 2 other clinical disorders can graft vs leukaemia (GvL) also work in?
1. Lymphoma | 2. Myeloma
79
Is there graft vs leukaemia (GvL) in autologous transplant?
NO GvHD & therefore NO GvL resulting in a greater risk of relapse
80
List the 10 problems with stem cell transplant?
1. Limited donor availability (age limit <65 years) 2. Mortality 10-50% 3. Graft versus Host Disease (GVHD) 4. Immunosuppression 5. Infertility in both sexes 6. Risk of cataract formation 7. Hypothyroidism 8. Risk of secondary malignancy 9. Risk of osteoporosis / avascular necrosis 10. Relapse
81
What is polycythaemia in simple terms?
Too much blood!
82
What are the 2 major roles of red blood cells?
1. CO2 removal | 2. O2 delivery from lungs to tissues
83
What are the 3 locations for CO2 removal?
1. Renal tubules 2. Lungs 3. Red blood cells
84
Describe the structure of 1 molecule of haemoglobin?
- 4 globin chains (2 alpha, 2 beta) | - 4 Haem groups
85
What is haemoglobin able to do?
Reversibly bind O2 without undergoing oxidation or reduction
86
What is another name for oxidised haemoglobin?
Methemoglobin
87
What is the total body content of iron?
4G
88
How much iron is stored in bone marrow & red blood cells?
3G
89
What transports iron in the plasma?
Transferrin (glycoprotein)
90
Where is Transferrin synthesised?
In hepatocytes
91
Describe the structure of Transferrin?
- 2 iron binding domains | - 30% saturated with iron
92
What 4 places does Transferrin delivery iron to?
1. All tissues 2. Erythroblasts 3. Hepatocytes 4. Muscle
93
What is serum ferritin levels directly proportional to?
Reticuloendothelial system (RES) iron
94
What is 1mmol/l serum ferritin also equal to?
8mg RES Iron
95
What is the problem with measuring serum ferritin?
Its an acute phase protein (will increase during infection/inflammation) so isn't always an accurate measure of iron levels
96
Describe iron loss in males?
1-2mg/day through GI system
97
Describe iron loss in females?
1-2mg/day through menstrual loss
98
What is the amount of iron needed daily?
1-2mg/day
99
Iron homeostasis has no ___________?
Regulated excretory pathway
100
What hormone controls the release of iron from the gut cell into the plasma?
Hepcidin
101
Is haem or non-haem iron easier to absorb from gut lumen into the gut cell?
Haem iron is easier
102
Describe the reticuloendothelial system (RES) storage of iron?
~500mg of iron stored in ferritin/haemosiderin
103
What is the lifespan of red blood cells?
120 days
104
How is iron released & recycled from the reticuloendothelial system (RES)?
- Releases iron to transferrin in plasma | - Transferrin-iron taken up via transferrin receptors on erythroblasts, hepatocytes etc.
105
Describe hepcidin?
- ‘Low iron’ hormone - Reduces the levels of iron in plasma - Binds ferroportin & degrades it, reducing iron absorption & decreasing iron release from the RES
106
What is the likely cause of most Hereditary Haemochromatosis diseases?
Loss of hepcidin
107
Where is hepcidin synthesised & what does it require?
Synthesised in the liver (this requires expression of HFE)
108
What is the most common anaemia in the world?
Iron deficiency anaemia (IDA)
109
Describe the RBC laboratory features of iron deficiency anaemia?
Hypochromic & Microcytic
110
What are 4 examples of when you would see hypochromic microcytic red blood cells?
1. Iron deficiency anaemia 2. Thalassaemia 3. Anaemia of chronic disease 4. Sideroblastic Anaemia (particularly congenital)
111
What % of transferrin are saturated with iron in iron deficiency anaemia?
<15%
112
What does a low serum ferritin always indicate?
Low RED iron stores
113
Describe iron deficiency anaemia in the presence of tissue inflammation?
IDA can occur with normal serum ferritin levels (rheumatoid arthritis & IBD)
114
List 4 clinical features of iron deficiency anaemia?
1. Koilonychia 2. Atrophic glossitis (painless) 3. Angular stomatitis 4. Oesophageal web (plummer vinson syndrome --> dysphagia)
115
What are 3 causes of iron deficiency anaemia?
1. Dietary (premature neonates, adolescent females) 2. Malabsorption (coeliacs) 3. Blood loss (mensuration)
116
How do you confirm a diagnosis of iron deficiency anaemia?
Serum ferritin levels
117
How much blood is lost during menorrhagia (abnormally heavy period)?
>80mls blood/period
118
How much blood is lost during pregnancy?
500mg/ baby
119
What is the golden rule regarding iron deficiency anaemia in males & post menopausal females?
Due to GI blood loss until proven otherwise
120
When would be the only 2 times that you would do GI investigations in iron deficiency anaemia?
1. GI symptoms | 2. Blood in stools
121
What are the 4 different treatment options for iron deficiency anaemia?
1. Ferrous sulphate (200mg tablets) 2. Ferrous gluconate (300mg tablets) 3. IV iron (1G over 2-3hrs) 4. Discover cause
122
What are the 3 main uses for IV iron to treat iron deficiency anaemia?
1. Intolerant of oral iron 2. Compliance 3. Renal anaemia & Erythropoietin replacement
123
Describe anaemia of chronic disease (ACD)?
- Failure of iron utilisation - Iron trapped in RES - Common
124
What are 3 causes of anaemia of chronic disease (ACD)?
1. Infection 2. Inflammation 3. Neoplasia
125
What 2 things does chronic renal failure give?
1. Anaemia of chronic disease | 2. Decreased Erythropoietin
126
Describe the RBC laboratory features of anaemia of chronic disease (ACD)?
Normochromic normocytic OR hypochromic microcytic
127
Describe the blood test results for anaemia of chronic disease (ACD)?
- MCV/MCH normal or raised - ESR raised - Ferritin normal or raised - Iron decreased - TIBC decreased
128
What does the blood test TIBC stand for?
Total iron-binding capacity
129
What does the blood test ESR stand for?
Erythrocyte Sedimentation Rate
130
What does RBC rouleaux mean?
Stacks or aggregations of red blood cells (RBCs) which can occur when the ESR is raised and is a non-specific indicator of the presence of disease
131
What are the 3 possible causes of anaemia of chronic disease (ACD)?
1. RES Iron blockade, iron trapped in macrophages, raised levels Hepcidin 2. Reduced Erythropoietin response 3. Depressed marrow activity, cytokine marrow depression
132
What is the treatment for anaemia of chronic disease (ACD)?
Treat underlying disorder
133
What is B12/Folate needed for?
- DNA synthesis & nuclear maturation | - Required for all dividing cells
134
Where is a B12/Folate deficiency first noted in?
Red blood cells
135
What does a B12/Folate deficiency result in?
Megaloblastic anaemia inititally, but will effect other organs
136
What are the 2 dietary sources for B12?
1. Meat (esp. liver & kidney) | 2. Dairy
137
What is the daily requirement of B12?
1ug/day
138
Describe the 5 step process of B12 absorption?
1. B12 ingested (in form of animal protein) 2. B12 released by enzymes/acid in stomach & duodenum 3. Intrinsic factor binds to B12 4. IF-B12 complex binds to cubulin 5. B12 absorbed & binds to transcobalamin in blood
139
What is cubulin?
Specific receptor for intrinsic factor-B12 complex, found in the ilium
140
What makes intrinsic factor?
Gastric parietal cells in fundus/body of stomach
141
How much B12 is lost & why?
1-2ug/day in urine/faeces
142
What are the dietary sources of folate?
Green veg (destroyed by cooking)
143
How is Folate absorbed?
- Most small bowel | - No carrier molecule required
144
For how long is folate stored?
- Few days | - Quickly used up if increased demand (ie. increased cell turnover)
145
Describe the pathophysiology of folate deficiency?
- Disparity in rate of synthesis of the precursors of DNA (deoxyribonucleoside triphosphates) - Abnormality of cell division
146
What are the 2 types of tissues affected by B12 or Folate deficiency?
1. Bone marrow | 2. Epithelial surfaces (mouth, stomach, small intestine, urinary, female genital tracts)
147
What is the blood abnormality caused by B12/folate deficiency?
Megaloblastic anaemia (leucopenia, thrombocytopenia)
148
What are the neurological manifestations of B12 deficiency?
Bilateral peripheral neuropathy or demyelination of | posterior & pyramidal tracts of spinal cord
149
Clinically what can a Folate deficiency in the 1st 12 weeks of the growing foetus cause?
Can cause neural tube defects
150
What are the 2 symptoms of B12/Folate deficiency (anaemia/cytopenia)?
1. Tired: macrocytic/ megagloblastic anaemia (common) 2. Easy bruising: thrombocytopenic (rare)
151
What are the 2 signs of B12/Folate deficiency?
1. Mild Jaundice: haemolysis 2. Neurological problems: nerve disturbance as a result of B12 def, subacute combined degeneration of cord
152
List the 4 possible causes of B12 deficiency?
1. Dietary 2. Pernicious anaemia (no intrinsic factor) 3. Gastrectomy/ Achlorhydria 4. Terminal ileum problem (crohn's, resection)
153
What are the 3 possible causes of folate deficiency?
1. Dietary 2. Extensive small bowel disease (coeliac, severe crohn's) 3. Increased cell turnover (haemolysis, severe skin disorders, pregnancy)
154
What are the 3 other causes of macrocytosis?
1. Reticulocytosis 2. Cell wall abnormalities (lipids) 3. With anaemia (bone marrow failure syndromes)
155
What 3 disorders would cause cell wall abnormalities?
1. Alcohol 2. Liver disease 3. Hypothyroidism
156
What drives erythropoiesis?
Erythropoietin (kidney)
157
What are the 4 "ingredients" for erythropoiesis?
1. Iron 2. B12 3. Folate 4. Minerals
158
Describe the inherited condition- haemoglobinopathies?
- Relative lack of normal globin chains due to absent genes (thalassaemias) - Variant (abnormal) globin chain eg sickle cell disease
159
What 3 things does the severity of haemoglobinopathies?
1. Amount of abnormal haemoglobin 2. Type of abnormal haemglobin 3. Ameliorating factors
160
Where are global chains produced?
Ribosomes
161
Where/What controls haemoglobin production?
Mainly at the transcription level & depends on the availablility of haem.
162
What are the different types of thalassaemias?
- 4 different alpha globin genes (on 2 Ch16) | - 2 different beta globin genes (on 2 Ch11)
163
List the 5 different alpha gene permutations & how many alphas are missing in each?
1. Alpha+ thalassaemia trait (one alpha missing) 2. Homozygous alpha+ thalassaemia trait (2 alphas missing) 3. Haemoglobin H thalassaemia trait (3 alphas missing) 4. Alpha thalassaemia major (4 alphas missing) 5. Alpha minor thalassaemia trait (2 alphas missing)
164
What is the clinical significance of missing one gene in alpha thalassaemia?
Mild microcytosis
165
What is the clinical significance in missing 2 genes in alpha thalassaemia?
- Microcytosis - Increased red cell count - Sometimes very mild (asymptomatic) anaemia
166
What is the clinical significant in missing 3 genes in alpha thalassaemia?
- Significant anaemia | - Bizarre shaped small red cells (HbH disease)
167
What is the clinical significance of missing 4 genes in alpha thalassaemia?
Incompatible with life
168
Describe HbH (haemoglobin H) disease?
- Missing 3 alpha genes - Lack of alpha chains -> excess beta chains - Beta chains end up joining together (HbH)
169
What is needed in HbH (haemoglobin H) disease during periods of stress?
Blood transfusions
170
What is the level of haemoglobin in HbH (haemoglobin H) disease?
65-75g/l
171
Describe Beta thalassaemia major?
- Missing both beta globin genes - Autosomal recessive - Unable to make adult haemoglobin (HbA) - Significant dyserythropoiesis
172
What is the treatment for Beta thalassaemia major?
Transfusion dependent from early life (first couple of years)
173
What is the most significant haemoglobin variant?
Sickle cell disease
174
Describe the pathogenesis of sickle cell disease?
- There is a single amino acid substitution on B globin gene at Position 6 on chromosome 11 - Alpha2betaS2 (sickle)
175
What produces the abnormal haemoglobin sickle (Hb S)?
Glutamine --> Valine
176
What produces the abnormal haemoglobin C (HbC)?
Glutamine --> Lysine
177
What 3 things does the rate of Hb S polymerisation depend on?
1. Deoxygenation rate 2. Hb concentration 3. Hb F
178
What are the 2 clinical results of sickle cell disease?
1. Reduced red cell survival (haemolysis) | 2. Vaso-occlusion (tissue hypoxia/infarction)
179
List the 8 multi-system effects sickle cell disease has on the body?
1. Brain: Stroke/Moya Moya 2. Lungs: Acute Chest syndrome / Pulmonary Hypertension 3. Bones: Dactilytis / Osteonecrosis 4. Spleen: Hyposplenic 5. Kidneys: Loss of concentration/ Infarction 6. Urogenital: Priapism 7. Eyes: Vascular Retinopathy 8. Placenta: IUGR/Fetal loss
180
What is Moya Moya?
Rare, progressive cerebrovascular disorder caused by blocked tangled arteries at the base of the brain (basal ganglia)
181
What are the 3 means of treatment for sickle cell disease?
1. Precent crisis 2. Prompt management of crises 3. Bone marrow transplantation
182
How can you prevent a crisis in sickle cell disease?
- Hydration, Analgaesia, Early intervention - Prophylactic vaccination & antibiotics - Folic acid
183
How can you prompt management of crises in sickle cell disease?
- Oxygen, fluids, analgaesia, antibiotics, specialist care | - Transfusion/Red cell exchange
184
What is the definition of haemolytic anaemia?
Anaemia related to reduced RBC lifespan (no blood loss or haematinic deficiency)
185
Give 3 examples of congenital haemolytic anaemia?
1. Abnormalities of RBC membrane (Hereditary spherocytosis) 2. Hamoglobinopathies 3. Abnormalities of RBC enzymes
186
Describe Hereditary spherocytosis?
- Autosomal dominant - RBC’s spherocytic & polychromatic - Jaundice - Splenomegaly
187
What is the treatment (if required) for Hereditary spherocytosis?
Splenectomy & hyposplenic prophylaxis
188
List the 5 causes of a hyposplenic state?
1. Encapsulated organism pneumococcus 2. Menigococcus 3. Haemophilus 4. Immunisations 5. Long term penicillin V
189
What is the red cell lifespan for haemolytic anaemia?
<20 days
190
Describe the haematology results of haemolytic anaemia?
- Decreased Hb - Increased Reticulocytes - Increased Bilirubin ­ - Increased Spleen ­
191
In chronic haemolytic states what can the raised bilirubin cause?
Pigment gall stones
192
Describe the 3 factors of Pyruvate Kinase Deficiency Anaemia?
1. Chronic / extravascular haemolytic anaemia 2. ATP depletion 3. Autosomal recessive
193
Describe the 3 factors of Glucose 6 phosphate dehydrogenase deficiency?
1. Acute episodic intravascular haemolysis 2. X linked recessive (only affects males) 3. Acute haemolysis from oxidative stress
194
What are the 3 types of acquired haemolytic anaemia's?
1. Autoimmune 2. Isoimmune 3. Non immune
195
What are the 2 types of autoimmune acquired haemolytic anaemia's?
1. Warm type (IgG) | 2. Cold type (IgM)
196
Give an example of an isoimmune acquired haemolytic anaemia?
Haemolytic disease of newborn (HDN)
197
Give an example of a non-immune acquired haemolytic anaemia?
Fragmentation haemolysis
198
Describe the 4 factors of cold autoimmune acquired haemolytic anaemia (AIHA)?
1. Autoantibody IgM (+complement) 2. Mycoplasma infection 3. Idiopathic 4. IgM has 5 receptors so makes agglutinins with the red cells
199
Describe the 5 factors of warm autoimmune acquired haemolytic anaemia (AIHA)?
1. Autoantibody IgG (+/- complement) 2. Idopathic 30% 3. Other autoimmune disease 4. Lymphoproliferative disorder (NHL/CLL) 5. Drug induced
200
Describe the red blood cells in warm autoimmune acquired haemolytic anaemia (AIHA)?
- Spherocytic | - Polychromatic
201
What does drug induced acquired haemolytic anaemia (AIHA) cause?
Usually mild haemolysis
202
What does the immune complex in acquired haemolytic anaemia (AIHA) cause?
Severe haemolysis
203
Give an example of a drug which induces immune complexes in acquired haemolytic anaemia (AIHA)?
Cephalosporins
204
What is the purpose of the Direct Coombs test?
To detect antibody (+/- C’) on RBC surface
205
What 2 occasions is the Direct Coombs Test positive?
1. Autoimmune haemolytic anaemia | 2. Haemolytic disease of the newborn
206
What is the purpose of the Indirect Coombs Test?
To detect RBC antibodies in plasma (via crossmatching)
207
What is the treatment for cold autoimmune acquired haemolytic anaemia (AIHA)?
- Self limiting mycoplasma | - In idiopathic: keep warm
208
What is the treatment for warm autoimmune acquired haemolytic anaemia (AIHA)?
- Stop any drugs - Steroids - Immunosuppression ie. Azathioprine - Splenectomy
209
What are the 2 different types of leukaemia's?
1. Lymphoid | 2. Myeloid
210
What is leukaemia?
- "White blood" - Blood cancer - Accumulation of abnormal leucocytes in marrow +/- blood +/- other tissues
211
How is leukaemia acquired through genetic abnormalities & what does this allow for?
- Cell type in which mutation arises likely to be crucial - Allows diagnostic testing, monitoring, research, pharmaceutical targeting
212
Where do the symptoms of chronic leukaemia come from?
Accumulation of cells
213
Where do the symptoms of acute leukaemia come from?
Marrow failure
214
What are Myelodysplastic syndromes (MDS)?
- Clonal Blood disorder | - Group of cancers in which immature blood cells in the bone marrow do not mature
215
List 5 things that characterise Myelodysplastic syndromes (MDS)?
1. Failure of effective haemopoiesis (low blood counts) 2. Most common in elderly 3. 'Dysplastic’ blood & marrow appearances 4. Approx 25% rate of transformation to AML 5. Consequences of marrow failure
216
How can "low risk" vs "high risk" disease in Myelodysplastic syndromes (MDS) be established?
Proportion of blast cells in marrow & cytogenetic profile (MDS vs AML, Blast % cut-off is 20%)
217
What is the treatment for Myelodysplastic syndromes (MDS)?
- Incurable (other than with stem cell transplant, <65 years) - Supportive care: consider drug therapy (eg azacitidine)
218
What are Myeloproliferative disorders (MPDs)?
- Clonal blood disorders - JAK2 mutation prevalent - Characterised by "Effective" haematopoiesis
219
Describe 3 characteristics of "effective haematopoiesis"?
1. Too many platelets (Essential Thrombocythaemia) 2. Too many red cells (Polycythaemia Vera/ Primary Polycythaemia) 3. Too much fibrous tissue (Myelofibrosis)
220
Describe the outcome & treatment for Essential Thrombocythaemia?
- Good outcome - Risk of vascular events (aspirin) - Cytoreduction (Hydroxycarbamide, venesection or interferon)
221
Describe Acute Leukaemia & the outcomes?
- Clonal disorders - Blastic proliferation in bone marrow - Rapid in onset - Serious compromise of normal marrow elements - Death within days or weeks if untreated
222
Give 2 examples of acute lymphoid leukaemia's?
1. T lymphoblastic leukaemia | 2. B lymphoblastic leukaemia
223
Give 4 examples of acute myeloid leukaemia's?
1. Erythroleukaemia 2. Myeloid leukaemias 3. Monocytic leukaemia 4. Megakaryocytic leukaemia
224
What is it called when the leukaemia type arises in multipotent progenitor cells which have the ability differentiating into both myeloid & lymphoid?
Biphenotypic leukaemia
225
Is acute myeloid leukaemia more prevalent in the young or old population?
Old
226
List 6 options for the, largely unknown, aetiology of acute leukaemia?
1. Chemicals 2. Chemotherapy 3. Radiotherapy 4. Genetic: Down􏰀s Syn, Fanconi Syn 5. Antecedent blood disorders (MDS, MPD) 6. Viruses
227
List 8 features to look for in the history & examination to diagnose acute leukaemia?
1. Rapid onset of symptoms 2. Lethargy 3. Infection 4. Bleeding & bruising 5. Bone pain 6. Gum swelling 7. Lymphadenopathy 8. Skin rash
228
List the 4 features of a peripheral blood test in acute leukaemia?
1. Anaemia 2. Neutropenia 3. Thrombocytopenia 4. Blasts
229
What is the % presence of blast cells in the bone marrow for test in acute leukaemia diagnosis?
>20%
230
What is so important about the M3 subtype of acute myeloid leukemia (M3 AML)?
Patients with APL can quickly develop life-threatening blood-clotting or bleeding problems if not treated
231
Describe the cytogenetics of M3 AML?
Translocation of chromosomes 15 & 17
232
Describe the cytogenetics of M2 AML?
Translocation of chromosomes 8 & 21
233
List the 6 different types of acute myeloid leukaemia's (AML)?
1. Secondary AML 2. Relapsed AML 3. MDS to AML 4. Biphenotypic disease 5. Elderly patients 6. Refractory to induction
234
What are the 3 choices for managing AML?
1. Intensive chemotherapy +/- stem cell transplant (pts <60-65, 5 yr survival approx 50%) 2. Low Dose chemotherapy (pts>60-65, 5yr survival approx <10%) 3. Supportive care (older pts, major co- morbidities, median survival 3-6 months)
235
Describe chemotherapy in managing AML?
- Most young patients entered into trials - High morbidity (bleeding & infection) - Hairloss, sterility, mucositis - Prolonged inpatient stays - Psychological element
236
Describe the relapse rate of AML?
- 40-50% of patients | - Within 2 years
237
What is the % 5 year survival rate for childhood AML?
60-70%
238
Describe the clinical presentation for acute lymphoblastic leukaemia (ALL)?
- The limping child - Purpuric rash - Unexplained, sometimes severe, bone pains - ‘lumps’ vs ‘liquid presentation’ (i.e. lymphoblastic lymphoma vs true ALL)
239
What are 2 standard cytogenetics for acute lymphoblastic leukaemia (ALL)?
- T(9:22) | - T(4:11)
240
List 7 drugs which the chemotherapy for acute lymphoblastic leukaemia (ALL) is based upon?
1. Prednisolone 2. Cyclophosphamide 3. Anthracycline 4. Asparaginase 5. Vincristine 6. Etoposide 7. Cytarabine
241
Describe the chemotherapy management for acute lymphoblastic leukaemia (ALL)?
- CNS directed treatment | - Initial aggressive therapy, then oral maintenance (1- 2 years)
242
What is the % 5 year survival rate for children with acute lymphoblastic leukaemia (ALL)?
90%
243
What is the % 5 year survival rate for adults with acute lymphoblastic leukaemia (ALL)?
40%
244
What are the 6 supportive treatments given to manage Acute leukaemia?
1. Blood transfusion 2. Fresh frozen plasma 3. Platelet transfusion 4. Antibiotics 5. Growth Factors (G-CSF) 6. Granulocytes
245
In what 5 cases would you perform transplant procedures for acute leukaemia?
1. Relapsed patients 2. Refractory patients 3. Poor risk disease in first CR 4. Age less than 60yrs 5. Good performance
246
What is the commonest leukaemia?
Chronic Lymphocytic Leukaemia
247
What is the male:female ratio for Chronic Lymphocytic Leukaemia?
2 males:1 female
248
Describe Chronic Lymphocytic Leukaemia?
- Incidence rises with age (median 67yrs) | - Aetiology unknown
249
List the 7 potential presenting features for Chronic Lymphocytic Leukaemia?
1. None 2. Lethargy 3. Night sweats 4. Weight loss 5. Symptoms of anaemia 6. Lymphadenopathy 7. Infection
250
What is BINET?
Clinical staging for Chronic Lymphocytic Leukaemia (stage A, B & C)
251
Describe stage A Chronic Lymphocytic Leukaemia according to BINET?
- <3 involved nodes | - 10yr survival
252
Describe stage B Chronic Lymphocytic Leukaemia according to BINET?
- >3 involved nodes, liver, spleen | - 7yr survival
253
Describe stage C Chronic Lymphocytic Leukaemia according to BINET?
- Anaemia or thrombocytopenia | - 2yr survival
254
What is the importance of 17p deletions?
- Aggressive disease - Refractory to chemotherapy - Results in loss p53 - Patients may respond to steroids + antibodies
255
Describe B-cell Chronic Lymphocytic leukaemia (CLL)?
- Complex disease - Variable behaviour - Disease biology predicts survival - Therapy tailored to circumstances
256
How would you treat the autoimmune complications resulting from Chronic Lymphocytic leukaemia (CLL)?
1. Steroids | 2. Treat CLL
257
What are 5 factors of Chronic Lymphocytic leukaemia (CLL) which means infection risks are higher?
1. Hypogammaglobulinaemia 2. Cell mediated immunity impaired 3. T Lymphopenia 4. Neutropenia 5. Defects complement activation
258
Do you treat asymptomatic Chronic Lymphocytic leukaemia (CLL) patients?
NO
259
What type of infection is common in Chronic Lymphocytic leukaemia (CLL)?
Pulmonary infection - Bacteria - Viral - Pneumocystis - Fungi
260
List the 6 possible clinical presentations of Chronic Myeloid Leukaemia (CML) & their % ocurrence rate?
1. Asymptomatic (20-50%) 2. Fatigue (34%) 3. Weight loss (20%) 4. Night sweats (15%) 5. Abdominal discomfort (15%) 6. Splenomegaly (50-75%)
261
Describe the natural history of Chronic Myeloid Leukaemia (CML)?
Chronic phase (3 to 5 years) --> Accelerated phase (12 to 18 months) --> Myeloid blast phase (3 to 6 months)
262
Describe the importance of the Philadelphia chromosome in CML?
- This chromosome is defective & short because of reciprocal translocation of chromosome 9 & 22 - Contains a fusion gene called BCR-ABL1 - The presence of this translocation is a highly sensitive test for CML
263
What are the 3 ways to diagnose Chronic Myeloid Leukaemia (CML)?
1. Blood film & clinical features 2. Molecular test on blood (BCR-ABL PCR/FISH) 3. Cytogenetic analysis (􏰀karyotype􏰁)
264
Is it CML if BCR-ABL is negative?
NO
265
What drug can treat Chronic Myeloid Leukaemia (CML)?
Imatinib
266
List 4 possible complications of Chronic Myeloid Leukaemia (CML)?
1. Imatinib resistance 2. Imatinib intolerance 3. Need for 2nd/3rd line TKI inhibitors 4. Accelerated phase/blast crisis
267
Can you perform stem cell transplantation for Chronic Myeloid Leukaemia (CML)?
YES but rarely do it now
268
What are the 2 types of lymphoma's?
1. Hodgkins (15%) | 2. Non-Hodgkins (85%)
269
What are the 2 types of Hodgkins lymphomas?
1. Classical (>90%) | 2. Nodular Lymphocyte predominant
270
What are the 3 types of non-Hodgkins lymphomas?
1. B cell (>90%): indolent/aggressive 2. T cell: indolent/aggressive 3. Natural Killer cell
271
What are the 4 types of classical hodgkins lymphomas?
1. Nodular sclerosing 2. Mixed cellularity 3. Lymphocyte rich 4. Lymphocyte depleted
272
What is the most common type of specific lymphoma?
Diffuse large B cell lymphomas
273
Describe the incidence of lymphoma?
- 5th commonest cancer - Commonest blood cancer - Occurs at any age - Commonest cancer in <30 year olds - Accounts for 1 in 10 cancers in children
274
Describe the incidence of Non-Hodgkins lymphoma?
- 6th commonest cancer in the UK - More common in males - Can occur at any age - Incidence increases with age - ~50% are ≥ 70 years at diagnosis
275
Describe the incidence of Hodgkins lymphoma?
- <1% of all cancers - More common in males - Peak incidence in 20-24 year olds - 50% of cases diagnosed in >45 year olds - 2nd peak in elderly people (70-79 years)
276
List the 4 presenting complains of lymphoma?
1. Lymphadenopathy (painless, rubbery) 2. Splenomegaly 3. B symptoms 4. Anaemia
277
What are the "B symptoms" associated with cancer?
1. Night sweats 2. Weight loss 3. Unexplained fever
278
How do we investigate patients with lymphoma?
1. History 2. Imaging tests (CT, PET scans) 3. Clinical examination (lymph nodes, spleen) 4. Bone marrow biopsy (aspirate & trephine) 5. Blood tests 6. Additional tests (echocardiogram, pulmonary function tests)
279
What are the 6 blood tests you would do to investigate a lymphoma?
1. FBC 2. U&Es 3. LFTs 4. Ca 5. ESR 6. LDH
280
What are the 4 types of lymphomas that PET/CT scans are helpful in?
1. Hodgkins 2. Most Diffuse large B cell lymphomas (DLBCL) 3. Follicular lymphoma 4. Nodular lymphocyte-predominant Hodgkin lymphoma
281
What are the 2 lymphomas that bone marrow aspirate & biopsy are no longer required?
1. Hodgkins | 2. Many Diffuse large B cell lymphomas (DLBCL)
282
Where do we take a bone marrow biopsy from?
Posterior superior iliac spine
283
What is the system called for staging a lymphoma?
Ann-Arbor Classification system (Stages I-IV)
284
Describe a stage 1 lymphoma according to the Ann-Arbor Classification system?
Single lymph node group
285
Describe a stage 2 lymphoma according to the Ann-Arbor Classification system?
More than 1 lymph node group SAME side of diaphragm
286
Describe a stage 3 lymphoma according to the Ann-Arbor Classification system?
Lymph node groups BOTH sides of the diaphragm (includes spleen)
287
Describe a stage 4 lymphoma according to the Ann-Arbor Classification system?
Extranodal involvement e.g. liver, bone marrow
288
What else is added to the staging (stage 1-4) number of a lymphoma and why?
A or B added after to signify absence or presence of B symptoms
289
What is a rare feature of Hodgkins lymphoma?
Alcohol induced pain
290
What is early stage lymphoma according to the Ann-Arbor Classification system?
Stage 1 or 2A
291
What is advanced stage lymphoma according to the Ann-Arbor Classification system?
2B or 3 or 4
292
When are most Hodkins lymphomas diagnosed?
Early stage
293
When are most Non-Hodgkins lymphomas diagnosed?
Advanced stage
294
What are the 8 factors affecting treatment decisions for lymphomas?
1. Type of lymphoma 2. Stage of lymphoma 3. Age 4. Performance status 5. Co-morbidities 6. Elderly care liaison service 7. Support eg family circumstances 8. Patient’s preference
295
Give an example of an indolent B cell Non-Hodgkins lymphoma?
Follicular lymphoma
296
Give 2 examples of aggressive B cell Non-Hodgkins lymphoma?
1. Diffuse large B cell lymphoma | 2. Burkitt's lymphoma
297
What is CD20?
- Antigen expressed on B-lymphocytes | - Target for treatment with the monoclonal antibody Rituximab
298
Describe Follicular lymphoma?
- Low grade - Characterised by translocations involving BCL2 gene - Slow growth but reduced cell death (apoptosis)
299
Describe the incidence of Follicular lymphoma?
- 20-25% of all lymphomas - B cell lymphoma - Incidence increases with age - Median age at diagnosis 65 years - Often present with stage 4 disease
300
Follicular lymphoma is usually _______?
Incurable
301
What are less commonly seen in Follicular lymphoma?
B symptoms
302
What is the treatment for early stage (1A/2A) Follicular lymphoma?
Localised radiation
303
What is the treatment for asymptomatic advanced stage Follicular lymphoma?
If there is no bulk & no end organ compromise then just watch and wait
304
What is the treatment for symptomatic &/or organ compromised advanced stage Follicular lymphoma?
- Rituximab + chemo (CVP or CHOP or Bendamustine) - Followed by maintenance Rituximab every 2 months for 2 years
305
What is Rituximab?
Anti CD20 monoclonal Antibody
306
What may Follicular lymphoma transform into?
Diffuse large B cell lymphoma (2-3% per year)
307
Follicular lymphoma has a tendency to ______?
Relapse
308
What is the pre & post Rituximab treatment survival rate for Follicular lymphoma?
- PRE: 7-8years | - POST: >12 years
309
Describe Diffuse large B cell lymphoma?
- High grade - Resemblence to activated B-cells (immunoblasts, centroblasts) - Heterogeneous entity: variable phenotype - Associated with various translocations & genetic abnormalities - High proliferation fraction, variable rate of cell death
310
Describe the incidence of Diffuse large B cell lymphoma?
- Commonest subtype of Non-Hodgkins Lymphoma (~40%) - Mostly adults but wide age range & can occur in children - Incidence increases with age - 2/3 > 60 years
311
List the 4 different types of presentations for Diffuse large B cell lymphoma?
1. Lymphadenopathy 2. Extra-nodal presentation common (30-40%) 3. Pyrexia of unknown origin 4. Night sweats & weight loss
312
List 5 sites of Extra-nodal presentation in Diffuse large B cell lymphoma?
1. Waldeyer’s ring 2. Gastrointestinal tract 3. Skin 4. Bone 5. CNS
313
What is the outlook when diagnosed with Diffuse large B cell lymphoma?
Agressive but curable in >50%
314
What is the treatment for early stage (1A) Diffuse large B cell lymphoma?
R-CHOP x 3 & radiotherapy
315
What is the treatment for late stages of Diffuse large B cell lymphoma?
R-CHOP x 6
316
What does R-CHOP (chemotherapy) stand for?
``` R= rituximab C= cyclophosphamide H= adriamycin (doxorubicin) O= vincristine P= prednisolone ```
317
When do you give R-CHOP chemotherapy?
Day 1 of a 21 day cycle
318
Describe Burkitt lymphoma?
- High grade - Characterized by translocations involving MYC gene & IG gene partner (simple karyotype) - Very high rate of proliferation (nearly all cells in cell cycle) - High rate of cell death (apoptosis)
319
Describe the usual 3 presentations of Burkitt lymphoma?
1. Short history 2. Marked B symptoms 3. Rapidly growing tumours with massive tumour bulk
320
List the 7 sites for extra nodal disease present in Burkitt lymphoma?
1. Jaws & facial bone (african children) 2. Ileocaecal region of GIT 3. Ovaries 4. Kidneys 5. Breast 6. Lymph nodes & bone marrow (immunosuppression) 7. CNS involvement at presentation or relapse
321
What is an issue in Burkitt lymphoma?
Tumour lysis syndrome
322
What is the outlook for a Burkitt lymphoma diagnosis?
Short survival unless treated but responds well to chemotherapy
323
Describe treatment for Burkitt lymphoma?
Intensive chemotherapy (CODOX-M/IVAC)
324
What is the aim of treatment for Burkitt lymphoma?
To cure (70-90% long term survival)
325
Describe Classic Hodgkin Lymphoma?
- High grade with prominent component of reactive cells | - Neoplastic cell resembles atypical activated B-cell as is seen in some viral infections (e.g. EBV)
326
What % of Classic Hodgkin Lymphoma cases are associated with EBV infection?
Approx 40%
327
What is Classic Hodgkin Lymphoma characterised by?
Strong expression of CD30 & loss of some B-cell antigens
328
Describe the incidence of Classic Hodgkin Lymphoma?
Bimodal age incidence
329
Describe the presentation of Classic Hodgkin Lymphoma?
- Painless lymphadenopathy (neck lump, cough, dyspnoea) - B symptoms - Itch preceding diagnosis for months - Alcohol related pain
330
What does the prognosis of Classic Hodgkin Lymphoma depend on?
Stage of disease
331
Describe the spreading of Classic Hodgkin Lymphoma?
- Spreads from 1 nodal group to immediately adjacent nodes | - Later, haematogenous spread to liver, lungs, bone marrow
332
What is the cure rate of early/advanced stage Classic Hodgkin Lymphoma?
- Early: >90% | - Advanced: 75-85%
333
What is the treatment for early stage Classic Hodgkin Lymphoma?
Usually combined modality ie chemotherapy (ABVD) followed by radiotherapy
334
What is the treatment for advanced stage Classic Hodgkin Lymphoma?
Chemotherapy (ABVD)
335
What are the 5 late effects of Classic Hodgkin Lymphoma?
1. Malignancy 2. Cardiac 3. Pulmonary 4. Fertility 5. Endocrine
336
What does ABVD chemotherapy stand for?
``` A= adriamycin (doxorubicin) B= bleomycin V= vinblastine D= dacarbazine ```
337
When would you give ABVD chemotherapy?
Days 1 & 15 of 28 day cycle
338
Describe Plasma cell myeloma?
- Neoplastic cells resemble normal plasma cells - Express plasma cell markers e.g. CD138 - Aberrant phenotype
339
List the 4 factors of an aberrant/abnormal phenotype in Plasma cell myeloma?
1. CD19 negative 2. CD56 positive 3. Cyclin D1 positive 4. Light chain restriction
340
What is Plasma cell myeloma?
Neoplasm of mature plasma cells with varied clinical course
341
Describe the incidence of myeloma?
- 1% of all cancers - 15% of blood cancers - Median age of onset ~71 years - Prevalence is increasing as population ages & survival improves
342
List the 5 non-specific symptoms of Plasma cell myeloma?
1. Backache/rib pain (60%) 2. Fatigue 3. Symptoms from hypercalcaemia (30%) 4. Recurrent infections 5. Renal impairment (25-30%)
343
What do the abnormal plasma cells in myeloma patents produce?
Abnormal ‘monoclonal protein’ called a paraprotein or “M” protein
344
List the 5 different types of Paraprotein?
1. IgG 2. IgA 3. IgM (very rare) 4. IgD 5. IgE (very rare)
345
What type of Paraprotein is more commonly associated with lymphoma ie. Waldenstroms macroglobulinaemia?
IgM
346
What is a light chain myeloma?
When only part of the Ig molecule is produced
347
What is a non-secretory myeloma?
Rare, no Ig is produced
348
What is the classical triad which typifies myeloma?
1. Increased plasma cells in bone marrow 2. Clonal immunoglobulin or paraprotein 3. Lytic bone lesions
349
What 4 tests help to diagnose a myeloma?
1. Blood tests 2. Urine tests (look for light chains "Bence-Jones proteins) 3. Bone marrow aspirate 4. Imaging
350
List the 6 blood tests that you would perform to diagnose Myeloma?
1. FBC 2. ESR 3. U&Es 4. Ca 5. Serum protein electrophoresis 6. Serum free light chain (SFLC) quantity
351
Describe the appearance of peripheral blood in myeloma?
Rouleaux RBC (stacking)
352
Describe the look of Myeloma neoplastic plasma cells in Immunocytochemistry?
Monoclonal & therefore produce only one type of immunoglobulin light chain (kappa/lambda)
353
What does electrophoresis show in Myelomas?
Monoclonal bands
354
What form of imaging is best for identifying lytic lesions in Myelomas?
MRI
355
What is the clinical spectrum of Plasma Cell Myelomas?
Asymptomatic --> highly aggressive disease
356
What are the combination of factors which lead to a diagnosis of Plasma Cell Myelomas?
Neoplastic plasma cells in bone marrow: >=10% of total cells + at least one of the following: 1. End-organ damage (CRAB criteria) 2. Biomarkers of malignancy
357
What is the CRAB criteria for diagnosing Plasma Cell Myelomas?
- Hypercalcaemia - Renal insufficiency - Anaemia - Bone lesions: >=1 lytic lesion on skeletal X-ray, CT or PET/CT
358
What are the 3 biomarkers of malignancy in Plasma Cell Myelomas?
1. Clonal plasma cell percentage >=60% 2. Serum free light chain ratio >=100 3. >1 focal lesion on MRI
359
What is the treatment for asymptomatic Myelomas (smouldering)?
Watch & wait
360
What is the treatment for symptomatic Myelomas?
- Chemotherapy + steroid + thalidomide - Radiotherapy - Supportive therapy
361
What treatment can be given to young, fit patients with Myelomas?
Autologous transplant
362
List the 4 supportive therapies given to symptomatic Myeloma patients?
1. Biphosphates (reduce pain, pathological features, hypercalcaemia & need for radiotherapy) 2. Blood transfusion/EPO 3. Surgery 4. Interventional radiology
363
Describe the prognosis for Plasma Cell Myelomas?
- Incurable - Median 5.5years - Overall 5yr survival ~50%
364
Describe the natural history of Multiple Myeloma?
Smoldering Myeloma --> Myeloma --> Remission --> Relapse --> Remission --> Relapse --> Refractory
365
What does MGUS stand for?
Monoclonal gammopathy of undetermined significance
366
What % of Myeloma cases have Bence Jones proteins?
>50%
367
What % of Myeloma cases have immune paresis?
>95%
368
Describe Monoclonal gammopathy of undetermined significance (MGUS)?
- <10% marrow plasma cells - Serum M paraprotein <30 - Absent lytic bone lesions - Absent symptoms
369
What are the 2 purposes of lymphocytes?
1. Production of antibodies (B-cells, Plasma cells) | 2. Direct action against pathogen (cytotoxic effect) (T-cells, Natural Killer cells)
370
How are B-cells developed?
- Produced in bone marrow from stem cell progenitor | - Mature B-cells circulate in peripheral blood & populate lymphoid & other organs
371
What does B-cell interaction with an antigen result in the production of?
1. Memory B cells | 2. Plasma cells (subset return to bone marrow)
372
How are T-cells developed?
- T-cells originate in bone marrow from stem cell progenitor - Precursor T-cells migrate to thymus & develop into mature T-cells - Mature T-cells circulate in peripheral blood & populate lymphoid & other organs
373
What is a lymphoma?
Malignancy derived from lymphocytes (B-lymphocytes, T-lymphocytes, Natural killer cells)
374
How is a lymphoma unlike leukaemia?
Generally presents with a tumour mass & most commonly develops in lymph nodes
375
What are the 4 possible risk factors for lymphoma?
1. Immunosuppressive disorders/treatment (HIV, autoimmune) 2. Infections (EBV, H. pylori) 3. Age (increases with age increase) 4. Having a close relative with lymphoma 5. MULTI-HIT THEORY
376
How does lymphoma arise generally?
Genetic abnormalities in lymphocytes result in altered expression of genes involved in growth control (net growth of tumour)
377
What is the difference between leukaemia & lymphoma locations?
- LEUKAEMIA: widespread involvement of bone marrow & peripheral blood - LYMPHOMA: discrete tissue masses
378
Describe precursor B-cell & T-cell neoplasms?
- Neoplasms of immature B&T-cells - Usually present as leukemia (acute leukaemia) - Rarely present as tissue masses
379
Describe mature B-cell and T-cell neoplasms?
- Neoplasms of mature B&T-cells - Usually present as solid tissue masses - Includes some entities that present with leukaemic picture (chronic leukaemia)
380
Describe Acute B-lymphoblastic leukaemia?
- Neoplastic precursor B-cells (blasts) in peripheral blood & bone marrow - Most cases in children - Aggressive but curable disease
381
Describe B-cell chronic lymphocytic leukaemia?
- High white cell count due to neoplastic lymphocytes in bone marrow & peripheral blood - Most patients elderly - Usually a slowly progressive but incurable disease
382
Describe Plasma cell myeloma?
- Bone marrow based malignancy formed of mature plasma cells - Associated with (clonal) immunoglobulin production (usually IgG) - Variable clinical course
383
Describe Acute T-lymphoblastic leukaemia/lymphoma?
- Usually adolescent males - Often present with thymic/mediatinal mass (T- lymphoblastic lymphoma) +/- peripheral blood involvement (T-lymphoblastic leukamaemia) - Aggressive but curable
384
Describe T-cell leukaemia's?
- Proliferation of mature T-cells in peripheral blood | - Various type with different clinical behaviours
385
What is needed to diagnose a lymphoma?
Excision or core Biopsy (lymph node, other tissue, bone marrow)
386
What are the 3 problems with diagnosing lymphoma?
1. Malignant lymphocytes in NHL look very like their normal counterparts 2. Morphology on its own may not be able to tell us that the tissue is malignant 3. Multiple techniques required
387
List the 7 laboratory tests that you can perform to diagnose malignant haematology?
1. Morphology (what it looks like down the microscope) 2. Immunohistochemistry 3. Flow cytometry 4. Karyotyping 5. Fluorescence in situ hybridization: FISH 6. PCR: clonality assays 7. Gene sequencing/array based technologies
388
What are the 4 general features that lymphoma subtypes are classified on?
1. Morphology 2. Immunophenotype (expression patterns of specific proteins as viewed down a microscope/flow cytometry 3. Genetic features 4. Clinical features
389
What does lymphoma resemble in many cases?
Normal stage of B-cell development & maturation
390
What are the 2 general categories of Non-Hodgkin Lymphoma?
1. Nodal (60%) | 2. Extranodal (40%)
391
Describe the cell cycle characteristics of low grade lymphoma?
- Tend to be widely disseminated at presentation, often involving bone marrow - Indolent clinical course - Incurable
392
Low grad lymphoma have neoplastic cells mostly of ____ size?
Small
393
High grade lymphoma have neoplastic cells usually of ____ size with activated _______?
- Large | - Blast-like appearance
394
Describe the cell cycle characteristics of high grad lymphoma?
- Tend to be localised at presentation - Rapid growth & early death if untreated - Often curable (up to 80-90% with some subtypes)
395
What is Ki67?
A protein expressed by cells in cell cycle (S-phase) i.e. dividing or proliferating cells express this protein
396
How can you detect the presence of Ki67 in tissue sections?
Using immunohistochemistry
397
What are the 2 cells which can be affected in follicular lymphoma?
1. Centrocytes | 2. Centroblasts
398
Describe the genetic abnormality in follicular lymphoma?
- t(14;18) - Results in upregulation of BCL2 protein - Switches of normal apoptosis that takes place in germinal centres - Present in 85-90% of follicular lymphoma
399
What is BCL2?
Anti-apoptotic protein
400
Describe the varied immunophenotype of diffuse large B-cell lymphoma?
- Most cases BCL6-positive but variable CD10 & BCL2 expression - A proportion of cases resemble activated/germinal centre B-cells
401
List 3 activated B-cells which the immunophenotype of diffuse large B-cell lymphoma can resemble?
1. CD10- 2. BCL6+/- 3. IRF4+
402
List 3 germinal centre B-cells which the immunophenotype of diffuse large B-cell lymphoma can resemble?
1. CD10+ 2. BCL6+ 3. IRF4-
403
What cells are neoplastic in Burkitt lymphoma?
Centroblasts
404
What are the 3 epidemiological variants of Burkitts lymphoma?
1. Endemic Burkitt lymphoma 2. Sporadic Burkitt lymphoma 3. Immunodeficiency associated Burkitt lymphoma
405
Describe Endemic Burkitt lymphoma?
- Equatorial Africa & Papua New Guinea - Regions overlap with those of endemic malaria - Strong association with Epstein-Barr virus - Most common childhood malignancy in these areas
406
Describe Sporadic Burkitt lymphoma?
- Type seen in Western Europe & North America - 1-2% of all lymphoma - Children & young adults (median age = 30 years)
407
List 2 situations of Immunodeficiency associated Burkitt lymphoma?
1. HIV | 2. Post-transplant
408
List the 3 possible MYC chromosomal translocations associated with Burkitts lymphoma?
1. t(8;14) [IGH] 2. t(2;8) [Kappa] 3. t(8;22) [Lambda]
409
What does the MYC gene do?
Drives proliferation but is also linked to apoptosis
410
Describe the morphology of classic Hodgkin Lymphoma?
Neoplastic cell is very large B-cell with blast-like morphology (Reed-Sternberg cells)
411
Describe the Reed-Sternberg cells commonly seen in classic Hodgkin Lymphoma?
- Abundant cytoplasm - Binucletae (also monocuclear & multinucleate variants) - Prominent nucleolus (one per nucleus)
412
When can cell similar to Reed-Sternberg cells be seen?
Some inflammatory conditions, e.g. infectious mononucleoisis
413
What 2 things does the morphological subtypes of Classic Hodgkin Lymphoma depend on?
1. Number & type of reactive cells | 2. Presence or absence of fibrosis
414
List the 4 potential locations of mixed cellularity classic Hodgkins lymphoma?
1. Lymphocytes 2. Histiocytes 3. Neutrophils 4. Eosinophils
415
Describe nodular sclerosing classic Hodgkins lymphoma?
- Bands of sclerosis divide node into cellular nodules | - Variable cytology
416
Describe the appearance of Lymphocyte predominant classic Hodgkins lymphoma?
Reed-Sternberg cells in background of small lymhocytes
417
Describe lymphocyte depleted classic Hodgkins lymphoma?
- Increased Reed-Sternberg cells - Few lymphocytes - May be numerous histiocytes
418
Describe the Reed-Sternberg cells defective B-cell signature?
- CD20 negative | - PAX5 positive
419
What does the classic Hodgkin lymphoma morphology strongly express?
CD30 +/- CD15
420
What are plasma cells?
Immunoglobulin producing cells of the immune system (IgG, IgA etc)
421
List the 2 abnormal immunoglobulins detected in peripheral blood for Plasma cell Myeloma?
1. “M-protein” | 2. “Paraprotein” (immunoglobulin)
422
List the 2 abnormal fragments detected in peripheral blood or urine for Plasma cell Myeloma?
1. “Free light chain” (blood) | 2. “Bence Jones protein” (urine)
423
Describe the 4 possible cytogenetic abnormalities associated with Plasma cell Myeloma?
1. Translocations involving IGH on chromosome 14q32 2. Monosomy or partial deletion of chromosome 13 (50% of cases) 3. MYC rearrangements (50% of cases) 4. Deletion &/or mutation of TP53
424
Describe the morphology of neoplastic cells in Plasma Cell Myeloma?
- Eccentric nucleus with “clock-face” chromatin | - Abundant cytoplasm with perinuclear clearing (‘hof)
425
Describe the normal phenotype for a plasma cell myeloma?
- Express CD19 & CD138 - Negative CD20 - Express either Kappa or Lambda light chains (roughly equal no.)
426
What does light chain restriction mean regarding neoplastic plasma cells?
Marked excess of kappa or lambda light chain
427
What is the clinical course of Plasma cell myeloma related to?
1. Stage | 2. Genetics (TP53 deletion = poor outcome)
428
What is the stage of Plasma cell myeloma based on?
Serum beta-2-microglobulin & albumin level
429
Describe the definition of smouldering (asymptomatic) myeloma?
Presence of 10-60% clonal plasma cells in bone marrow but no other myeloma defining event
430
Describe the progression of smouldering (asymptomatic) myeloma?
May have stable disease for many years but many ultimately progress to symptomatic plasma cell myeloma (in around 5 years)
431
Describe Monoclonal Gammopathy of Uncertain significance (non-IgM)?
- Serum M protein <30g/l - Clonal plasma cells in bone marrow <10% - Absence of end organ damage
432
What is the risk of Monoclonal Gammopathy of Uncertain significance (non-IgM) progressing to myeloma?
Low risk (1% per year)
433
What is a Plasmacytoma?
Single localised tumours consisting of monoclonal plasma cells
434
Describe the features of Plasmacytoma?
M protein may be detectable but no other typical features of plasma cell myeloma
435
What are the 2 types of Plasmacytoma's?
1. Solitary plasmacytoma of bone | 2. Extraosseous (extramedullary) plasmacytoma (GIT, lymph nodes, breasts, thyroid etc)
436
How can both types of Plasmacytoma's be managed?
Local radiotherapy
437
What 3 things does the process of coagulation require?
1. Platelets 2. Endothelium 3. Coagulation factors
438
What are the 5 stages of cutting yourself?
1. Blood vessel damage 2. Disrupt endothelium 3. Exposure of tissue factor & collagen 4. Primary haemostasis (recruitment of platelets) 5. Secondary haemostasis (activation of coagulation factors)
439
What are the 3 steps in Primary Haemostasis?
1. Platelet Adhesion (GPIb-V-IX binds to Von Willebrand Factor) 2. Platelet Activation (release of granular contents & exposure of phospholipids) 3. Platelet Aggregation
440
List the 4 cascade of events associated with secondary haemostasis?
1. Initiation (extrinsic pathway) 2. Propagation (intrinsic pathway) 3. Thrombin generation 4. Fibrin production (clot)
441
What does every step in the coagulation cascade require?
- Phospholipid (from platelet surface) | - Calcium
442
What is the prothrombinase complex?
Activated factor 10 (Xa) + factor 2 (II) + Activated factor 5 (Va)
443
What does activated factor 2 (IIa) stimulate in the coagulation cascade?
Fibrinogen --> Fibrin
444
What does activated factor 13 (XIIIa) stimulate in the coagulation cascade?
Fibrin --> Cross linked fibrin
445
What does Factor 7 (VII) and tissue factor turn into in the coagulation cascade?
VIIa + X
446
What are the 5 mechanisms which regulate the coagulation cascade in secondary haemostasis?
1. Protein C (APC) 2. Antithrombin 3. Tissue factor pathway inhibitor (TFPI) 4. Thrombomodulin 5. Protein S
447
What is the main enzyme in the fibrinolysis process?
Plasmin
448
What do tissue plasminogen activator (t-PA) & urokinase convert?
Plasminogen (inactive) --> Plasmin (active)
449
What in inhibits tissue plasminogen activator (t-PA) & urokinase?
Plasminogen activator inhibitors (PAI-1 & 2)
450
What inhibits Plasmin?
alpha2 antiplasmin
451
What does Plasmin convert?
Cross linked fibrin --> Fibrin degradation products (FDPs) including D-dimers
452
What does TAFI stand for?
Thrombin-activatable fibrinolysis inhibitor
453
What are the 2 ways to assess primary haemostasis?
1. In vivo: Bleeding time | 2. Ex vivo: FBC (platelet count), Light transmission aggregometry (platelet function)
454
What are 4 ways to assess secondary haemostasis?
1. Prothrombin time (PT) 2. Activated partial thromboplastin time (APTT) 3. Thrombin clotting time (TCT) 4. Individual coagulation factor assays
455
What are the 4 principles of coagulation tests?
1. Add reagents to PPP 2. Perform assay at "body temp" 37oC 3. Time to form clot 4. All results expressed in seconds & ratio to normal plasma
456
Describe Prothrombin time (PT)?
Simulates activation via the extrinsic pathway
457
Describe the coagulation cascade & PT?
Factor VII + Tissue factor --> VIIa + X ---> Xa + II, Va --> IIa --> Fibrinogen --> Fibrin clot
458
What is the normal range for prothrombin time (PT)?
10-13sec
459
What is the ratio for prothrombin time (PT)?
Patients PT/Average of 20 normal PTs (normal 1.0-1.2)
460
What 3 factors does prothrombin time (PT) depend on?
1. Factors in extrinsic & common pathways 2. Factors VII 3. Factors X, V, II & Fibrinogen
461
What does INR stand for?
International Normalised Ratio
462
What is INR?
Standardised form of prothrombin time
463
What does INR monitor?
Oral coumarins ie. warfarin
464
List 4 Vitamin K dependent coagulation factors?
1. II 2. VII 3. IX 4. X
465
What is a patients INR result factored by?
International sensitivity index (ISI)
466
What does every thromboplastin have?
Its own ISI: calculated from international standard thromboplastin (close to 1.0)
467
What is Activated partial thromboplastin time (APTT)?
Simulates activation via the intrinsic pathway
468
Describe the coagulation cascade pathway & APTT?
XII --> XIIa + XI --> IX + XIa --> IXa --> Xa + II, Va --> IIa --> Fibrinogen --> Fibrin clot
469
What is the normal range for activated partial thromboplastin time (APTT)?
26-38 secs
470
What are 2 examples of contact factors added when performing an activated partial thromboplastin time (APTT)?
1. Kaolin | 2. Silica
471
What 3 factors foes the APTT depend on?
1. Factors in intrinsic & common pathways 2. Factors VIII, IX, XI & XII 3. Factors X, V, II & Fibrinogen
472
What is Thrombin Clotting Time (TCT)?
Measurement of conversion of fibrinogen to fibrin clot
473
Describe the 3 steps to performing a Thrombin Clotting Time (TCT)?
1. Add at 37oC: patients plasma, bovine thrombin, less calcium or phospholipid dependent 2. Time to clot 3. Ratio: Patient TT/Average normal TT
474
What is the normal range for Thrombin Clotting Time (TCT)?
10-16 secs
475
What 2 factors does Thrombin Clotting Time (TCT) depend on?
1. How much fibrinogen is present in plasma | 2. How well that fibrinogen functions
476
What 3 things can prolong Thrombin Clotting Time (TCT)?
1. Inhibitors of thrombin (e.g. heparin, dabigatran) 2. Fibrin degradation products (FDPs) 3. Inhibitors of fibrin polymerisation (paraproteins)
477
What factor is being tested in Prothrombin Time (PT) (extrinsic pathway)?
Factor 7
478
What 4 factors are being tested in APTT (intrinsic pathway)?
Factors 8, 9, 11 & 12
479
What 4 factors are involved in the common coagulation pathway?
Factors 1, 2, 5 & 10
480
What does an increased Prothrombin time (PT) suggest?
Low factor VII (7)
481
What does an increased APTT suggest?
- Low Factor VIII, IX, XI or XII (8, 9, 11 or 12) | - Lupus anti-coagulant
482
What does an increased PT & APTT suggest?
- Common pathway factor low (factor 1, 2, 5 or 10) | - Multiple factors low
483
What are the 3 classes of antithrombotic agents?
1. Anticoagulants 2. Fibrinolytic agents 3. Anti-platelet agent
484
What is the main function of Anticoagulant drugs?
Inhibit formation of fibrin clot
485
Give 3 examples of anticoagulant drugs?
1. Heparins & Fondaparinux 2. Oral warfarin 3. Direct oral anticoagulants (DOACs)
486
Describe Heparins & Fondaparinux (anticoagulants)?
- Injection (parenteral) - Act via antithrombin - Antagonise Factor Xa (+/- thrombin)
487
Describe warfarin (anticoagulant)?
- Oral - Vitamin K antagonist - Lowers Factors II, VII, IX & X
488
Give 3 examples of Xa inhibitor drugs (DOACS)?
1. Rivaroxaban 2. Apixaban 3. Edoxaban
489
Give an example of a IIa inhibitor drug (DOACs)?
Dabigatran
490
Give 2 examples of indirect Xa inhibitor drugs (DOACs)?
1. Fondaparinux | 2. Danaparoid
491
Describe the mechanism of action of heparin?
- Mixture of glycosaminoglycans of differing polysaccharide chain length - Augment activity of endogenous antithrombin - Do not cross placenta - Short half life
492
What are the 4 pharmacological factors To take into account when comparing Unfracturated heparin (UFH) to Low Molecular Weight Heparin (LMWH)?
1. Bioavailability 2. IV half life 3. Protein binding 4. Monitoring
493
What are the 3 possible side effects to take into account when comparing Unfracturated heparin (UFH) to Low Molecular Weight Heparin (LMWH)?
1. Heparin induced thrombocytopenia 2. Osteoporosis 3. Hyperkalaemic
494
List 5 reasons that make Low Molecular Weight Heparin (LMWH) better compared to Unfracturated heparin (UFH)?
1. Has superior pharmacokinetic profile allowing predictable dose response 2. Safer side effect profile 3. The clinical efficacy at least equal to UFH 4. Higher drug costs but lower consumable costs & do not require monitoring 5. Can be used in out-patients
495
What anticoagulant effect does Heparins have?
Immediate but short acting
496
List 4 indications for the use of Heparin?
1. Acute DVT or PE (subcut LMWH) 2. Cardiac bypass surgery (iv UFH) 3. Acute coronary syndromes (along with anti- platelet agents) 4. Prophylaxis against VTE (medical & post-op patients [low dose LMWH], obstetric patients)
497
What is inhibited by Warfarin?
Vitamin K dependent oxidisation reductase (VKOR)
498
Describe the mechanism of Warfarin?
- Oral vitamin K antagonist - Failure of gamma-carboxylation of Glu residues --> dysfunction Factors II, VII, IX & X - Delayed onset & offset - Narrow therapeutic window
499
What is the effective half life of Warfarin?
~36 hrs
500
What does Warfarin require?
Regular INR monitoring
501
What is the normal INR value for people not on warfarin?
1.0
502
What is the target INR for people on warfarin?
2.0-3.0
503
What 3 clinical scenarios have proven Warfarin's efficacy?
1. Atrial Fib: 68% relative risk reduction in annual stroke 2. Acute DVT/PE: reduces risk of recurrent/fatal PE 3. Prosthetic heart valve: reduces annual risk of valve thrombosis & stroke
504
What 2 things is Warfarin NOT effective for?
1. Immediate Anticoagulation | 2. Short term thromboprophylaxis
505
Do DOACs need coagulation monitoring?
NO
506
What are the contra-indications for all DOACs?
- Pregnancy & breast feeding, - Liver disease with cirrhosis +/- coagulopathy - Some drugs
507
List the 4 cons of Warfarin?
1. Requires very individualised dosing 2. INR monitoring 3. Many drug, food & alcohol interactions 4. Renal impairment may increase bleed risk
508
List the 3 pros of Warfarin?
1. Slow onset & offset results smooth anticoagulation 2. Rare side effects other than bleeding 3. Rapid reversal with Prothrombin complex concentrate (PCC) & Vitamin K
509
List the 4 cons of DOACs?
1. May require dose adjustment based on Creatinine Clearance (CrCl) 2. Requires annual review 3. Renal impairment 4. Currently no rapid reversing agent
510
List the 3 pros of DOACs?
1. Rapid onset & offset: anti-coagulation within 3hrs of 1st dose 2. Few drug and no food or alcohol interactions 3. More minor side effects than Warfarin
511
What is the main action of Fibrinolytic drugs?
Enhancement of fibrinolysis (breakdown of fibrin thrombosis)
512
What are the 2 major classes of fibrinolytics?
1. Kinases | 2. Tissue plasminogen activators (tPA)
513
Give 2 examples of Kinase fibrinolytics?
1. Streptokinase | 2. Urokinase
514
Give 3 examples of Tissue plasminogen activators (tPA) fibrinolytics?
1. Alteplase 2. Tenectaplase 3. Reteplase
515
Describe the mechanism of action of Kinase fibrinolytics?
- Bind of plasminogen (releases plasmin, enhanced breakdown of fibrin) - Activity on both clot bound & free plasminogen (significant bleeding risk)
516
Describe Streptokinase?
- Derived from streptococci bacteria | - Antigenic (recent strep infection/previous use of streptokinase, can be rendered ineffective)
517
Describe Urokinase?
- Grown from renal cells in culture | - Not antigenic
518
What did Kinase previously get used as?
Treatment for MI
519
What is the half life of Kinases?
15-20mins
520
What is the route of Kinases?
Bolus dose, then infusion
521
What are the 3 problems associated with Kinases?
1. Streptokinase antigenic 2. Significant bleeding risk 3. Cell derivatives
522
Describe the mechanism of action of tPA derived fibrinolytics?
- Activates plasminogen - Plasmin cleaved from plasminogen (plasmin breaks down fibrin) - Relatively selective for clot bound plasminogen - Minimal unwanted fibrinogenolysis
523
What is the half life of Alteplase/Tenectaplase (tPA derivatives)?
4-5mins
524
What is the route for Alteplase/Tenectaplase (tPA derivatives)?
Bolus then infusion
525
Reteplase has a _____ half life?
Longer
526
What is the route for Reteplase?
Bolus only
527
What are the 3 uses of tPA derivatives?
1. Acute MI for patients not suitable for PCI- Alteplase, Tenecteplase, Reteplase 2. Ischaemic stroke- Alteplase 3. Massive PE with haemodynamic instability- Alteplase
528
What are the 2 potential side effects of tPA derivatives?
1. Significant risk of haemorrhage (any organs, particularly intracerebral) 2. Stroke
529
What drugs can you use for catheter directed thrombolysis?
All fibrinolytic drug types
530
What are the 4 pros for catheter directed thrombolysis?
1. Smaller doses 2. Administered directly into vessel containing thrombosis 3. Less systemic effect 4. Paradoxically not necessarily less bleeding
531
What are the 3 uses of catheter directed thrombolysis?
1. Acute limb ischaemia 2. Massive DVT 3. Blocked central venous catheter (CVC)
532
What are the 2 actions of antiplatelet drugs?
1. Inhibit platelet activation | 2. Inhibit platelet aggregation
533
Describe the action of antiplatelet drugs?
Irreversible blockage of ACP receptor (P2Y12)
534
Give 2 examples of antiplatelet drugs which work by irreversibly blocking the ACP receptor (P2Y12)?
1. Clopidogrel | 2. Ticlodipine
535
What are the 2 actions of Clopidogrel & Ticlodipine (antiplatelet drugs)?
1. Decreases expression of GPIIb/IIIa | 2. Reduced binding of fibrinogen
536
Give 2 example of antiplatelet drugs which work by antagonising GPIIb/IIIa?
1. Abciximab | 2. Tirofiban
537
What are the 3 actions of Abciximab & Tirofiban (antiplatelet drugs)?
1. Monoclonal antibodies antagonise IIb/IIIa receptor 2. Reduce platelet aggregation 3. Reducing binding of fibrinogen
538
Give an example of an antiplatelet drug which works by irreversibly inhibiting cyclooxygenase?
Aspirin
539
What are the 2 actions of Aspirin (antiplatelet drug)?
1. Blocks conversion arachidonic acid --> Thromboxane A2 | 2. Decreases platelet activation
540
Give an example of an antiplatelet drug which works by inhibiting phosphodiesterase II?
Dipyridamole
541
What are the 3 actions of Dipyridamole (antiplatelet drug)?
1. Increased platelet concentration of cAMP 2. Increased cAMP leads to decreased platelet responsiveness to ADP 3. Reduced platelet aggregation
542
How does Picotamide (antiplatelet drug) work?
Inhibits thromboxane synthesise & blocks thromboxane receptors
543
What is the treatment for acute MI?
- Aspirin indefinitely - Ticagrelor/clopidogrel for upto 12 months - +/- Tirofiban acutely
544
What is the secondary prevention drug for cardiovascular disease?
Aspirin
545
What is the treatment for acute stroke/TIA/secondary prevention?
- Clopidogrel | - Dipyridamole + aspirin if clopidogrel not tolerated
546
What is the treatment for peripheral vascular?
- Clopidogrel | - Aspirin if clopidogrel not tolerated
547
Describe Disseminated Intravascular Coagulation (DIC)?
- Acquired - Activation of coagulation cascade (microthrombi) - Exhaustion of coagulation cascade (bleeding)
548
List the 5 potential causes of Disseminated Intravascular Coagulation (DIC)?
1. Sepsis 2. Malignancy 3. Massive haemorrhage 4. Severe trauma 5. Pregnancy complications ie. pre-eclampsia, placental abruption, amniotic fluid embolism
549
What 5 laboratory investigations would you do to diagnose Disseminated Intravascular Coagulation (DIC)?
1. PT 2. APTT 3. Fibrinogen 4. D-dimers 5. FBC & film (platelets, RBC fragments)
550
What are the 2 main treatments for Disseminated Intravascular Coagulation (DIC)?
1. Treat underlying cause | 2. Fresh frozen plasma +/- platelets if bleeding or high risk for bleeding
551
What 3 things can we do when a Warfarin patients INR is too high?
1. Stop warfarin or reduce dose 2. Give vitamin K1 (oral or IV) 3. Give coagulation factors (II, VII, IX, X) or prothrombin complex concentrates (Beriplex, Octaplex)
552
Describe coagulopathy in liver disease?
- Poor coagulation factor synthesis - Vit K deficiency - Poor clearance of activated coagulation factors - Disseminated Intravascular Coagulation (DIC) - Hypersplenism - Reduced thrombopoietin synthesis
553
What are 2 other names for Haemophilia A?
1. Classical haemophilia | 2. Factor VIII deficiency
554
What is the inheritance for Haemophilia A?
X-linked
555
What would the APTT result be for Haemophilia A?
Prolonged APTT
556
What are the 4 means of treatment for coagulation factor deficiency?
1. Education (patients & doctor) 2. Desmopressin (DDAVP) 3. Replacement therapy (FFP, plasma derived factor concentrate, recombinant produced factor concentrate) 4. Gene therapy
557
Describe Rare bleeding disorders?
- Autosomal recessive | - Decrease factor levels --> Increase bleeding severity
558
What are the 2 roles of von Willebrand factor?
1. Facilitates platelet adhesion & aggregation in primary homeostasis 2. Binds FVIII & prolongs its half life in plasma (influences secondary haemostasis)
559
Describe Von Willebrand disease?
- Most common mild bleeding disorder - Autosomal dominant with variable penetrance - Mucosal type bleeding pattern - Reduced VWF +/- reduced platelet aggregation +/- reduced FVIII
560
Describe severe inherited platelet disorders?
- Rare - Autosomal recessive - Mucosal type bleeding pattern
561
What are the 2 severe inherited platelet disorders?
1. Glansmanns thrombasthenia | 2. Bernard Soulier syndrome
562
Describe Glansmanns thrombasthenia?
- Absent/defective GP IIb/IIIa | - Normal platelet count
563
Describe Bernard Soulier syndrome?
- Absent/defective GP Ib/V/IX | - Macrothrombocytopenia
564
What do Von Willebrand factor (VWF) and collagen facilitate?
Platelet adhesion to sub endothelium
565
What do Von Willebrand factor (VWF) and fibrinogen facilitate?
Crosslinking of activated platelets
566
What are the 4 means of treatment for Inherited platelet disorders?
1. Pressure 2. Tranexamic acid / Desmopressin (DDAVP) 3. Platelet transfusion (HLA matched) 4. rFVIIa
567
What are the 3 natural anticoagulants which can be deficient in inherited thrombophilia?
1. Antithrombin 2. Protein C 3. Protein S
568
What are the 2 specific genetic mutations in inherited thrombophilia?
1. Factor V Leiden (resistance to APC) | 2. Prothrombin gene mutation (increased prothrombin)
569
What would be the result of a 50:50 (patients plasma with normal plasma) dilution of APTT in factor deficiency?
Full correction
570
What would be the result of a 50:50 dilution (patients plasma with normal plasma) of inhibition problem?
Partial correction
571
Describe Lupus anticoagulation?
- Phospholipid dependent antibody - Interferes with phospholipid dependent tests i.e. APTT - APTT prolonged - If persistent, may be associated with prothrombotic state
572
What makes Antiphospholipid Syndrome?
Persisting Lupus anticoagulant + thrombosis or recurrent fetal loss
573
How would you test for lupus anticoagulant?
- APTT often prolonged - APTT 50:50 dilution only partially corrects - DRVVT ratio prolonged - DRVVT ratio corrects with excess phospholipid
574
List the 3 possible antiphospholipid antibodies present in Antiphospholipid Syndrome?
1. Lupus anticoagulant 2. Anti cardiolipin antibodies 3. Beta-2 glycoprotein-1 antibodies
575
Give 2 clinical scenarios for Antiphospholipid Syndrome?
1. Venous/arterial thrombosis | 2. Recurrent miscarriage
576
What are the 3 management techniques for splenic injury?
1. Conservative 2. Interventional radiology 3. Splenectomy
577
What is the definition of major haemorrhage?
- Loss of more than 1 blood volume within 24 hrs (around 70mL/kg, >5 litres in a 70kg adult) - 50% of total blood volume lost in less than 3 hrs - Bleeding in excess of 150mL/min
578
What are the 4 priorities to manage major haemorrhage?
1. Early recognition (est. blood volume varies dependent on patients weight) 2. Get help 3. Control bleeding (surgery, interventional radiology) 4. Transfuse early
579
When is a blood transufsion necessary?
After 30-40% loss
580
What is not a reliable indicator in an acute situation of major haemorrhage?
Haemoglobin
581
What are the 7 factors in management of a major haemorrhage?
1. A, B, C 2. Oxygen 3. Monitoring 4. IV access 5. Bloods (FBC, coagulation, fibrinogen, U&E, LFT, Ca) 6. Tranexamic acid (if trauma <3 hrs ago) 7. Keep patient warm
582
What blood would you give in major haemorrhage?
- O negative | - Use group-specific blood as soon as available (10-20mins)
583
What 3 things should you remember when managing a major haemorrhage?
1. Dynamic situation 2. Concealed blood loss 3. Measured blood loss is often inaccurate
584
What are the 4 complications associated with major haemorrhage?
1. Hypothermia 2. Acidosis 3. Coagulopathy 4. Hypocalcaemia
585
How would you avoid hypothermia in a major haemorrhage?
- Blood warmer - Patient warmer - Foil hat - Monitor temp
586
How would you avoid coagulopathy in a major haemorrhage?
- FFP - Platelets - Cryoprecipitate - Liaise with blood bank

MBChB Year 3 (15 decks)

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