Haematology - Part 2 Flashcards
1
Q
Macrocytic anaemia causes
A
B12/folate deficiency, marrow damage (e.g. alcohol), haemolysis (as reticulocytes are pumped out)
2
Q
Normocytic anaemia causes
A
Chronic Disease
3
Q
Microcytic anaemia causes
A
Iron deficiency, Hb Disorders, sometimes chronic disease
4
Q
Where is iron absorbed
A
7% absorbed in the duodenum (some in the jejunum)
We have no excretion mechanism for iron
5
Q
What stores and transports iron
A
Transferrin - transports
Ferritin/haemosiderin - stores
6
Q
Blood results of iron defeciency anaemia
A
Low ferritin is the key sign and a high number of hypo chromic cells
7
Q
Causes of iron defeciency
A
Blood loss, increased demand, reduced intake
8
Q
Common cause of iron deficiency in the elderly
A
GI problems, think bleeding i.e. colon cancer in elderly men
9
Q
What causes megaloblastic anaemia
A
Due to problems in DNA synthesis due to B12/folate defeciency.
B12 needed to make folate, folate needed to make purine/pyrimidine DNA bases
10
Q
What congenital rarities cause megaloblastic anaemia
A
transcobalmin defeciency, orotic aciduria
11
Q
Where do we get vitamin B12 from
A
Only from animal sources
Absorbed in the terminal ileum using intrinsic factor from gastric parietal cells
stores sufficient for years
12
Q
Causes of B12 defeciency
A
reduced intake, gastric problems (e.g. gastrectomy), or small bowel problems e.g. diverticulosis, ileostomy, fish tapeworm
13
Q
Where do we get folic acid from
A
Green veg, beans, peas
We need a decent daily diet to get enough
Absorbed in the upper small bowel
Stores sufficient for 4 months
14
Q
Cause of folic acid defeciency
A
Poor intake
Increased demand
Malabsorption
Drugs/alcohol/ITU
15
Q
Features of B12/folate defeciency
A
pancytopenia megaloblastic anaemia mild jaundice glossitis/angular stomatitis anaemia sterility
16
Q
lab results of B12/folate deficiency
A
High LDH/bilirubin, check for antibodies, do GI investigations and B12 absorption tests.
17
Q
What is Pernicious Anaemia
A
The main cause of B12 deficiency
Autoantibodies made to intrinsic factor –> other autoimmune associations
Also associated with atrophic gastritis with achlorydia
Higher risk of stomach cancer
18
Q
What is Subacute Combined Degeneration of the Cord (SACDC)?
A
Due to severe B12 defeciency
Demyelination of the dorsal and lateral columns and the peripheral nerves
Get neurological symptoms, numbness and weakness, unsteady and dementia
19
Q
How to treat SACDC
A
Give B12 and folate acid, do not give folate acid alone. B12 for life and folate to boost stores.
May need K+ and Fe initially
20
Q
3 Areas where haemolysis can occur
A
Inside cell: (Haemoglobinopathies or enzyme defects e.g. G6P)
Membrane: hereditary spherocytosis etc.
Outside cell: autoantibodies, drugs, heart valves (fragmentation of the blood)
21
Q
Blood results shown in haemolysis
A
Raised LDH/bilirubin Low haptoglobin High MCV (due to reticulocytes) Urinary haemosiderin Blood film fragments
22
Q
How to treat autoimmune haemolytic anaemis
A
Steroids/immunosuppression
Transfusion difficult due to difficulty cross matching
23
Q
3 causes of anaemia of chronic disease
A
Poor Fe Metabolism
Reduced Epo response
Reduced bone marrow activity
24
Q
What is the main cause of anaemia of chronic disease
A
CYTOKINES - macrophages produce inflammatory cytokines to try and cause iron release
IL-1, IL-6, TNF & Hepicidin
25
What is the main regulator of iron absorption and release from macrophages
Hepicidin!
26
What are iron stores like in anaemia of chronic disease
Normal stores but poor absorption/release
27
How to treat anaemia of chronic diesease
Expo + Transfusion (but transfusion often rare due to mild symptoms)
28
Whats it ITP
Immune Thrombocytopenia Purpura
Rarely life threatening --> can cause cerebral haemorrhages
29
Main causes of ITP
Often in children post viral --> usually self limiting
| Get low platelets, petechiae and brusing (particularly on the lower legs
30
How to treat ITP
Steroids first
Immunosuppression second
Thrombo-mimetics (elthrombopig and romiplastin) cause bone marrow to make more platelets)
31
What are 2 thrombo-mimetics
Eltrombopid and romiplastin
32
What is TTP
Thrombotic Thrombocytopenia Purpura
RARE BUT URGENT
33
TTP Symptoms
Fever, neurological sypmtoms, haemolysis
34
Most common causes of TTP
```
Most autoimmune (ADAMTS-13/VWD)
Seek evidences of microangiopathy, look for blood film fragments, damaged vessels activate clotting, platelets used up causing DIC
```
35
Treatment of TTP
Plasma transfusion
Steroids
Vincristine/Rituximab
Monitor ADAMTS-13 --> an enzyme we just need to be ok
36
2 Stages of B Cell Differentiation
1) Antigen Independent - in the bone marrow
| 2) Antigen Dependent - in the lymphoid tissues
37
What is expressed for all of B cell differentiation
CD19
38
What is expressed during heavy gene rearrangement
CD79 + PAX
39
What is expressed at the end of light gene rearrangement
sIgM
40
What is expressed on plasma cells
CD38
41
What are the transformed cells of the germinal centre called
Centro blasts, they either undergo apoptosis or become centrocytes
42
How many chains are there in immunoglobulins
4, two are heavy (IgM,G etc), 2 are light (kappa or lamda)
43
When do we do immunofixation
After electrophoresis - do if we see an M speak
It detects and identifies monoclonal antibodies
Classified further than electrophoresis
44
Where would you find Bence Jones protein and what does it indicate
In the urine, indicating myeloma
45
Who is myeloma more common in
Afro-caribbeans
46
What is the criteria for having myeloma
clonal plasma cells>10%, biopsy proven AND CRAB symtpoms
47
What are CRAB symptoms
hyperCalcaemia
Renal insufficiency
Anaemia
Bone pain/lesions
48
What organ is often involved in myeloma
KIDNEYS
| If AKI suspected with myeloma GIVE STEROIDS ASAP
49
How to manage myeloma
intensive chemo (generally only for younger and fitter)
VCD 4 cycles
then GCSF
Then big chemo after to recover
50
What is MGUS
Precedes all myeloma cases, absence of end organ damage.
| Serum M protein
51
What is amyloidosis
light chain fragments misfold and aggregate and form beta fibrils deposited in organs e.g. kidneys
52
What does amyloidosis present with
low albumin and nephrotic proteins in the urine
53
What can amyloidosis also cause
cardiac/liver involvement, ESRF, and peripheral neuropatthy
54
What does MGUS present with
Normal bloods but high paraprotein
55
What is a paraprotein
A protein associated with cancer or other disease
56
What is follicular lymphoma
Neoplastic disorder of lymphoid tissue
IT IS A TYPE OF NON_HODGKIN LYMPHOME
Presents with lump in the neck
57
What is Hodgkin Lymphoma characterised by
Hodgkin Reed Steinberg Cells (HRS) --> these lack Ig hence avoid apoptosis
58
What is hodgkin lymphoma associated with
EBV
59
What does amyloid stain like
apple green
60
What are the 3 main chronic myeloproliferative disorders
Polycythaemia Vera
Thrombocytosis
Myelofibrosis
61
Polycythaemia Symtpoms and Signs
Insidious onset, itching, gout, tinitis, malaise, headache, engorged retinalveins, splenomegaly
62
Diagnosis of Polycythaemia Vera
Raised Hb, Hct over 0.5
Deteremine if relative or absolute
Loss of fat spaces in the bone marrowo
63
causes of secondary polycythaemia Vera
Expo producing tumours, central hypoxic process, CO poisoning, R-->L Heart shunts, altitude, renal disease
64
Second line test for polycythaemia Vera
Test the Epo
If Epo raised think secondary --> do a chest X-ray, abdomen USS and ABG
If Epo Normal think primary
65
Causes of primary PV
1) JAK2 mutation --> point mutation means JAK2 always activated whereas normally Epo activates it
2) Bone marrow problems
3) Exon12 mutatino
66
Treatment of PV
Venesections and aspirin
67
Thrombocytosis causes
```
Primary = essential, no known cause
Secondary = iron deficiency, post op, inflammation, haemolyisis, post-chemo
```
68
Tests of thrombocytosis
FBC, ferritin, CRP, CXR, ESR
69
Mutations in Thrombocytosis
JAK2 mutation in 50%
CALR Mutation in 50% --> encodes for calreticulin gene that is cell signalling protein in the ER, mutation in exon 9 of the gene. BUT causes lower thrombosis risk with the mutation
70
Treatment of thrombocytosis
Anti platelets and aspirin for all
| Cytoreduction if you have a risk factor
71
What are risk factors in thrombocytosis
```
Age
Diabetes
Hypertension
Previous thrombotic events
Platelet count over 1500
```
72
What does cytroreduction consist of
Hydroxycarbamide --> anti-folate to inhibit DNA synthesis
Interferon
Anagleride --> specific inhibitor of megakaryocytes
P32 --> can induce leukaemia so only use for 6 months
73
What is myelofibrosis
Rearrangement of the architecture of the bone marrow and fibrosis is laid down
74
Presentation of myelofibrosis
Pancytopenia, splenomegaly, B Symptoms (night sweats, fever and weight loss)
75
What are B symtpoms
fever, night sweats and weight loss
| Characteristic of blood cancers
76
What do we see in myelofibrosis investigations
Tear drop shaped RBC, blast cells and nucleoerythromatic cells in the blood
JAK2 mutatino in 50%
CALR mutation in 30%
77
Cause of splenomegaly
CHICAGO
C - cancer
H - haematological (myelofibrosis, CLL, hairy cell leukaemia)
I - infection (schistosomiasis, EBV, malaria, leishmaniosis)
C - congestion, liver disease/portal
A - autoimmune (SLE, haemolysis)
G - glycogen storage disorders
O - other (amyloid, sarcoid)
78
Treatment of myelofibrosis
Supportive care
JAK2 inhibitors (massively reduce splenomegaly)
Bone marrow transplant
79
Chronic Myeloid Leukaemia Genetics
Chr 9 (abl) gene translocated to Chr 22 (bcr gene)
creates bcr/abl fusion gene coding for a tyrosine kinase
PHILADELPHIA CHROMOSOME
80
CML Presentation
Leucocytosis, leucoerythroblasts in blood, anaemia, splenomegaly, fatigue, gout, abdominal pain, venous occlusion (DVT, priapism, retinal vein), abdominal discomfort
81
Treatment of CML - old
Chemo and bone marrow transplant
82
Normal breakpoint of CML gene
p210
83
New treatment of CML
Gleevec (imatnib) --> tyrosine kinase inhibitor
Massively reduces splenomegaly
But imatnib resistance is arising --> new drugs target different parts of tyrosine kinase to overcome the problem
84
What is acute leukaemia the result of?
The accumulation of early myeloid or early lymphoid progenitors in the bone marrow or other organs
Due to somatic mutation in single cell of early progenitor --> can be somatic or terminal of illness (myelofibrosis or previous chemo)
85
what are the 2 main types of acute leukaemia
acute lymphoblastic leukaemia
| acute myeloid leukaemia
86
ALL properties
Affects B & T lymphoblasts
Blast cells in peripheral blood, much less cytoplasm than AML cells
87
AML Properties
Affects myeloid progenitors and their first divisions
Blast cells in peripheral blood, contain granulocytes with large nucleus
88
What are the presenting features of acute leukaemia
Anaemia, infection, bruising/haemorrhage
89
Where does AML infiltrate
Rare to infiltrate other organs, mainly in the bone marrow. Can infiltrate to the liver/skin
90
Where does ALL infiltrate
Lymphoid organs --> lymph gland swellings in cervical, mediastinal, loin, axillay.
Hepatomegaly
91
Common infections found in AML
Staph. aureus infection of orbit
Perianal infections due to Staph. Faecalis and E.coli --> this may be the presenting feature
Haemorrhage (haemorrhagic ecchymoses)
92
Common infections in ALL
Oral candida
93
What does gum hypertrophy suggest?
AML monocytic subtype M5
94
Main methods of acute leukaemis diagnosis
Immunological markers --> flow cytometry
FISH
Cytochemistry etc.
95
2 methods of AML classification
FAB and WHO
96
What are immunological markers in acute leukaemia diagnosis?
Monoclonal Ab to antigens on cells --> fluorochroe attached
| Allows Fluorescence activtivated cell sorting (FACS)
97
Cytogenetics of AML
(8:21) translocation, 15:17 translocation and monosomy 7 all have good prognosis
98
Cytogenetics of ALL
9:22 translocation is bad prognosis - Philadelphia chromosome encodes a tyrosine kinase which is the main driver for immature cell proliferationn
99
Chromosome abnormalities in ALL
More changes in chromosome number
Hyperdiploidy - good prognosis
Hypodiploidy - bad prognosis
100
Poor prognosis factors in ALL
Age(over 10), high WCC, mole, T cell ALL
101
15:17 PML-RAR translocation indicates what
Acute promyelotic leukaemia
| Explains its response to all trans retinoic acid
102
AML-ETO 8:21 translocation
Can monitor it see response to treatments in AML
103
Molecular Pathology in AML: Abnormal Cell Proliferation
FLT3 (bad prognosis), Ras and C-Kit mutations
104
Molecular Pathology in AML: Block in differentiation
CBF-AML, PML-RAR and MLL translocations
105
Molecular Pathology in AML: Tumour suppression
NPM1 --> NPM1 is a good prognosis
106
Treatment of AML
2 induction chemo, 2 consolidation chemo and further chombination chemo
Bone marrow transplants potentially in younger patiens
107
Treatment of ALL
Induction and consolidation chemo
BUT ALL often spreads to CNS/testis and conventional chemo doesn't cross the BBB
Give intrathecal methotrexate
108
Chance of sibling being a HLA bone marrow match
25%
| Can harvest bone marrow from peripheral blood, give GCSF a few days prior
109
What is neutropenic sepsis
a complication of chemo given for acute leukaemia
| Danger of overwhelming infection of both from negative and positive infections
110
When do people become neutropenic
days 10-21 in intensive chemo
111
What is neutropenic fever
Pyrexia in the presence of a neutrophil count less than 1x10^9 - neutrophil count often falls below 0.2
112
Treatment for neutropenic sepsis
Broad spectrum antibiotics (tazocin and gentamicin)
113
Other protective measures against neutropenic sepsis
Hand hygiene
Protective isolation
Prophylactic antibitoics (leufloxacin)
Granulocyte colony stimulating factors
114
What antibiotic is given prophylactically to protect against neutropenic sepsis
Leufloxacin
115
What causes the clinical features of acute leukaemia
The impaired production of normal cells
116
What are the 3 components of Virchow's triad
Change in blood constituents, change in blood flow, vascular endothelium
117
What is the main cause of arterial thrombosis
Atherosclerosis
118
What is the main component of an arterial clot
Platelet rich
119
Main cause of venous thrombosis
Mainly due to venous stasis or a hypercoaguable state
120
Main component of venous clot
fibrin rich
121
What is post thrombotic syndrome
1/3 of people develop it after a clot
| Get chronic leg symptoms (swelling, discomfort, ulceration) due to damage to veins post clot
122
How to prevent VTE's
Risk assessment are prophylaxis
NOTE ASPIRIN AND ANTIPLATETS ARE NOT ACCEPTABLE PROPHYLAXIS TO STOP A VTE
123
What is treatment of VTE if patient is prone to bleeding
Mechanical treatment e.g. compression stockings
124
VTE Risk factors
oral contraceptives, cancer, over 60, HRT, immobility, major trauma, family history, varicose veins with phlebitis
125
How to low dose LWMH and fondaparinux work
Enhance anti-thrombin
126
What is Rivaroaxiban (also aprixiban)
A direct FX inhibitor, acts independent of antithrombin
127
What is Dabigatron
Direct thrombin inhibitor
128
Unfractioned heparin acts on what
Anti-thrombin and Xa (slightly more anti-thrombin effect)
129
LMWH acts on what
Doesn't directly interact with antithrombin, or interacts with Xa less than 18 polysaccharid units
Predominantly FXa effect
130
Fondaparinux (paraenteral)
Only FXa effect
131
When is D-dimer produced
Breakdown of fibrin clots by plasmin, produces a specific cross-linking patters
132
What do we look for on Doppler US
non-collapsing veins, intravascular defect, loss of flow
133
What do we do if we suspect a PE
CT - PA
| VQ scan - ventilation-perfusion mismatch is diagnostic of a PE
134
Treatment of DVT/PE
LMWH Heparin first then transition onto Heparin after at least 5 days
135
How do FXa: Rivorixaban works
Acts via antithrombin
136
How does dabigatran work
Acts independent of antithrombin to directly inhibit
137
does LMWH affect the INR
No
138
Do all anticoagulants affect bound thrombin
No only direct thrombin inhibitors can
139
Benefits of direct thrombin inhiitors
Uniform dose for all patients and rapid onset of action
Exceptions: lower dose for elderly, those with renal insufficiency, VTE prevention and AF
140
Heritable types of thrombophilias
Deficiencies of antithrombin and protein C/S
Activated Protein C resistance
Dysfibrinogenaemias
Prothrombin 2021A
141
Acquired thrombophilias
Antiphospholipid syndrome
142
Effects of thromophilias
DVT, PE, Superficial thrombophlebitis, thrombosis in veins
protein c defeciency - warfarin induced skin necrosis
APS - fetal wastage and arterial thrombosis
143
What does antithrombin inhibit
FII, FX, thrombin
144
How is Protein C activated
thrombin binds to thrombomodulin on endothelial walls and activates it, protein S binds as a cofactor
145
What does protein C cleave by proteolysis
FV and VIII
146
How are defeciencies in protein C,S and antithrombin inherited
Autosomal dominantly
147
What is factor V leiden mutation
Point mutation G to A where protein C cleaves factor V making it resistance
Heterozygous - slight increased risk of bleeding, no risk of recurrent bleeding
Homozygous - x30 increased risk of bleeding
148
Prothrombin 2021A mutation, describe
Mutation in the untranslated 3' enhancer region of the prothrombin gene, causes increased prothrombin levels
149
What is antiphospholipid syndrome
Antibodies against phospholipids
150
How do we diagnose APS
Antibodies present on 2 occasions 8 weeks apart AND venous or arterial thrombosis or 2 miscarriages
151
are the majority of APS cases primary or secondary
Primary
152
RBC Functional differences in children
Larger RBC with higher oxygen affinity and higher haematocrit
153
What happens to haematopoiesis in the newborn
Switches off for the first 10 weeks
154
When does blood count reach normal values
By 3 months
155
What RBC genes are on chromosome 16
alpha (can send out zeta then alpha)
156
what RBC genes are on chromosome 11
beta (can send out epsilon then gamma)
157
HB in 4-14 weeks
HB Gower 1 - epsilon and zeta
158
Hb Portlant
epsilon, gamma
159
Hb Gower - 2
alpha epsilon
160
HB at 14 weeks gestation
HB F - alpha, gamma
161
neonatal Hb
Hb-A (45%) - alpha, beta rest is HbF
162
HbA2
alpha, delta
163
WBC Count in children
Higher
164
What Ig can cross the placenta
IgG can, IgM cannot
165
What IgG are in breast milk
All of them - passive immunity
166
When can we make anatibodies
Can make them at 2-3 months but can't mount a sufficient immune response until 6 months
167
When do we start vaccinating children
2-3 months
168
When do platelets reach adult value
18 weeks gestation
169
functional differences in platelets at birth
hyperresponsive to vWF
hyporesponsive to certain agonists
Differences balance out
170
What coagulation factors are normal at birth
fibrinogen, factor V, VIII and XIII
171
Can coagulation factors cross the placenta
Not effectively
172
When do coagulation factors reach normal levels
6 months
173
Describe Vitamin K relationship in utero/newborn
Metal vitamin K is just 10% of the mothers --> can cause hemorrhagic disease of the newborn hence we give vitamin K injections
174
What exacerbates the problem of vitamin K in pregnancy
If you are on oral anticonvulsants --> hence give mothes oral vitamin K too
175
Is warfarin teratogenic
Yes
176
What happens to coagulation inhibitors in neontaes
Concentrations reduced, antithrombin, heparin cofactor II, protein C/S, TFPI
177
Summarise neonatal haemostasis changes
Reduced coagulation factors
Reduced concentration of coagulation inhibitors
Functionally different platelets
Raised D-Dimer and vWF
Unique forms of fibrinogen and plasminogen
178
Congenital causes of anaemia in childhood
Haemaglobinopathies, bone marrow failure, peripheral destruction and blood loss (twin to twin transfusion)
179
Why can you get peripheral destruction of RBC
Rh/ABO incompatability
Membrane defects e.g. hereditary spherocytosis
Enzyme defects e.g. G6PD, PK
Infection
180
What do children with ALL often present with
anaemia
181
Causes of acquired anaemia in children
Nutritional defeciency
bone marrow failure
peripheral destruction homeless or blood loss
182
What is Immesten Greysbeck syndrome
Rare cause of B12 deficiency where you can't move B12 out and make use of it
183
Congenital causes of bleeding/bruising
Platelet problems (mostly)
Clotting factor problems
Connective tissue disorders e.g. Ehlers Danlos
184
Acquired causes of bleeding/bruising
Trauma, tumour, infections (meningococcus, HIV)
Immune - Primary is ITP, TTP
Secondary - SLE, ALPS
Bone marrow failure or drug related
185
What do we not use to treat TTP
Platelets as just causes more clots
186
What is ALPS
Autoimmune lymphoproliferative disorder - autsomal dominant inheritance
