Haematology - Coagulation and Bone Marrow in Health and Disease Flashcards
(400 cards)
1
Q
Haematopoiesis
A
The process from which blood cells are produced and developed from a pluripotent stem cell
2
Q
Where does haemopoiesis occur in the foetus
A
Foetal yolk sac, liver, spleen and lymph nodes
3
Q
Where does haemapoiesis occur in babies in children
A
All bone marrow (red marrow —> yellow marrow)
4
Q
Where does haemopoiesis occur in adults
A
Bone marrow of axial Skelton and proximal long bones
5
Q
Extramedullary haematopoiesis
A
Haemaopoiesis occurring ourisde of the bone marrow e.g. liver and spleen
6
Q
When does extra medullary haematopoiesis take place
A
Bone marrow disease e.g. myelofibrosis when marrow becomes occupied w/ fibrotic tissue
Yellow (fatty) marrow can also be recruited top produce blood cells
7
Q
What may extramedulalry haematopoiesis lead to
A
Enlargement of liver +/- spleen
8
Q
Erythropopiesis
A
Production and development of red cells
9
Q
Production and development of granulocytes
A
Granulopoiesis
10
Q
Thrombopoiesis
A
Production and development of platelets
11
Q
Function of maegakaryocytes
A
Produce platelets and stay in bone marrow - does not pass into blood stream
12
Q
Properties of haemopoeietic stem cells
A
Differentiation
Self-renewal
13
Q
How long does it take for a stem cell to become a formed blood cell
A
2-3 weeks
14
Q
How does the micorenevornment affects the function of haematopoietic stem cells
A
Growth factors
Interaction w/ neighbouring cells
15
Q
Examples of growths factors stimulating different haematopoietic stem cells
A
Epo Tpo IL-5, IL-6 G-CSF M-CSF GM-CSF
16
Q
Composition of blood
A
Specialised connective tissue w/ 4 main components: RBC, WBC, plasma and platelets
17
Q
Where are blood cells found in the blood
A
Suspended in plasma
18
Q
Blood volume in M and F
A
5-6L in M
4-5L in F
19
Q
Cells formed from myeloid progenitor cells
A
RBC
Platelets
Granulocytes - eosinophil, basophil, neutrophils
20
Q
Cells formed from lymphoid progenitor cells
A
B cells
T cells
NK cells
21
Q
When will affected cell lineage number go up in the blood
A
If the stem cells is ‘overactive’ either because of clonal genetic defect (mlaignancy) or because environment drives activity
22
Q
Why must haematoppoiesis be regulated
A
Blood cell production must match blood cell destruction
Production may need to be increased in certain situation e.g. bleeding, infection
23
Q
How do haematopoietic growth factors affect cell production
A
Stimulate increased production
24
Q
Red cells and erythropoietin (epo) feedback loop
A
Low blood oxygen causes liver and kidney to please epo into bloodstream
This increases number of red cells and increases oxygen-carrying capacity
25
Why might a high blood count occur
Primary - abnormal bone marrow
Secondary - normal bone marrow
Red cell destruction due to asnet or poorly perfuming spleen (hyposplenism)
26
Which is the most common reason for high blood counts
Secondary causes
27
Primary causes of leucocytosis
Leukaemia
Lymphoma
Myeloproliferative disorders
Bone marrow must be treated/ managed
28
Secondary causes of leucocytosis and thrombocytois
```
Infection
Infl
Infarction
Tumour
Stress/ trauma - leucocytosis only
```
29
Example of a condition causing primary thrombocytosis
Essential thrombocythemia
| Treat/ manage bone marrow e.g. hydroxycarbamide
30
What is haematocrit (Hct)
Ratio of RBC to total blood volume
31
True erythrocytosis vs apparent polycythemia
True erythrocytes 'polycythemia' is an increased number of red cells (increased Hct)
Apparent polycythemia is caused by reduced plasma volume
32
Primary causes of erythrocytosis - clonal stem disorders
Polycythemia vera
| Treat/ manage the bone marrow e..g venesection +/- hydroxycarbamide, plus aspirin
33
Causes of apparent polycythemia
Overweight
Smoking
Alcohol excess
Medications e.g. diuretics
34
Secondary causes of erythrocytosis - raised epo
```
Low oxygen in the blood e.g COPD
Tumours
Doping
High affinity Hb - high altitudes
Polycystic renal disease
L to R shunt in heart
```
35
What can polycythemia vera and essential thrombocythemia lead to in untreated
Thrombosis
36
Reasons for low blood counts
Underproduction
| Reduced survival in the circulation
37
Reasons for leucopenia - underproduction
Drugs affecting stem cells e.g. chemo
| Part of pancytpenia due to marrow failure
38
Reasons for leucopenia - reduced survival
Autoimmune
Drugs
Consumption - flu
Combi e.g viral hepatitis - both the virus and drugs used to treat cause reduced survival
39
Reasons for thrombocytopenia - underproduction
Drugs affecting stem cell
liver failure (tpo underproduction)
Part of pancytopenia due to marrow failure
40
Reasons for thrombocytopenia - peripheral destruction
Autoimmune (ITP)
Hypersplenism (hiding in the spleen)
Drugs
Infections/ infl/ sepsis increases consumption of platelets
41
Hypersplenism
Inappropriate removal of erythrocytes, granulocytes or playlets from blood
42
What do pts w/ hypersplenism characteristically have
Splenomegalyu
Destruction or pooling of 1/1+ by the cell ---> release of immature cells in PB
Normal bone marrow
43
Drugs causing peripheral destruction of platelets
Penicillin
Furosemide
NSAIDs
44
Reasons for low blood counts caused by reduced production
```
Myeloma - bone marrow overrun w/ functionally useless cells; normal cells incl stem cells crowded out
Myelodysplasia
Metastatic malignancy
Myelofibrosis
Leukaemia
Lymphoma
Aplastic anaemia
Haematininc deficiency
```
45
Aplastic anaemia
Empty bone marrow cased by stem cell failure
Can be primary or most commonly secondary e.g. drug-induced, viruses
BM no longer produces blood cells
46
What does haematinic deficiency cause in blood counts
Pancytopenia
47
White cell malignancies divided by lineage
Myeloid cells - AML, myeloproliferative disorders and myelodysplasia
Lymphoid cels - ALL, CLL, lymphoma, myeloma
48
White cell malignancies of immature cells (blasts)
AML
| ALL
49
White cell malignancies of mute cells
```
Myeloproliferative disorders
Myelodysplasia
CLL
Lymphoma
Myeloma
```
50
What are the myeloproliferative disorders
Polycythemia Vera (PV)
C/c myeloid leukaemia (CML)
Essential thrombocythemia (ET)
Myelofibrosis
51
Myledysplasia (MDS)
Haematopoietic stem cell malignancies, related to myeloproliferative disorders
Abnormal maturation as well as abnormal proliferation in BM
Dysplastic cells don't get into blood
52
What does MDS present with on a FBC
Pancytopenia
53
What % of MDS pts evolve into AML
20%
54
Myelofibrosis
Malignant proliferation of reticulin fibres in bone marrow
55
Features of myekofibrosis
Anaemia
Leucoerythroblastic blood film
Splenomegaly
56
What can myelofibrosis dveelpi from
MPN or be primary
57
MPN
Myelo proliferative neoplasms
58
What can myelofibrosis transform into
AML
59
Causes of low blood counts w/ normal bone marrow (reduced cell survival)
Immune cellular destruction
Drugs
Haemorrhage
Hypersplenism
60
When would you see Auer rods on a blood film
Acute (myeloid) leukaemia - blasts
61
Causes of hyposplenism
Splenectomy e.g. therapeutic or due to trauma
Auto-infarction e.g SCD
Infiltration e.g metazoic malignancy
Under-functioning e.g. coeliac disease
62
Hyposplenism on a blood film
Howell-Jolly brides
Target cells
Acanthocytes
63
Causes of neutrophilia
```
Bacterial infection **
Infl cords
Burns
Cigarette smoking
Steroids (glucocorticosteroids)
G- CSF
Solid tumours
Myeloproliofertiave disorders e.g. CML *
```
64
General causes of lymohocytosis
```
Viral infections e.g. EBV *
Hypospleinsim
TB
Brucellosis
CLL
Lymph. w/ 'spillover'
```
65
General causes of eosinophilia
```
Allergic reaction - most common
Vasculitis
Drugs
Worm infestations
Cancer (esp solid tumours and lymphoma)
```
66
Most common causes of microcytic anaemia
IDA
| ACD
67
Most common cause of microcytic anaemia
Vit B12 or folate déficiency - causes pancytopenia
68
What addn info can we get from a blood film
Morphology of rd cells, white cells and platelets
Morphology of any abnormal cells incl blasts
Blood borne infections e.g. malaria
Roleuax (stacking of RBCs), agglutinates, fibrin clots, platelet clumping
69
Rouleaux on blood film
Stacking of RBCs
70
When does rouelaux occur
In infection
Reaction condns
Myeloma
71
Lymphoma
Cancer of the lymph nodes
72
Classification of lymphoma
Hugh grade or low grade
B-cell or (less commonly) T cell
Hodgkin or Non-Hodgkin
73
What do lymphoma pts px with
(Painless) swellings - lymphadenopathy
+/- B symptoms
May be incidental finding on MRI
74
B symptoms seen in lymphoma
Night sweats
Fever
Unintentional wt loss >10% in 6/12
75
What may lymphoma pts present with
Hepatosplenomegaly
Symptoms related to cytopenias
Symtoms related to lumps in/compressing important structures e.g. kidneys, lungs, bowel
Pruritus
76
Hx of high grade vs low grade lymphoma
Short vs longer or 'no' hx
77
Growth of high grade vs low grade lymphoma
Quickly vs slowly
78
Which lymphoma pts are symptomatic
High grade
79
Difference in approach to treating high grade vs low grade lymphoma
Treatment always required immediately vs watch and wait
80
Which lymphoma in a lifelong illness
Low grade - not curable
81
Which lymphoma. treatment involves intensive chemo
High grade
82
How many curative opportunities are there in high grade vs low grade lymphoma
One change in high grade (or maybe two) Bute low grade can usually be treated again and again
83
Staging of lymphoma
Ann Arbor
```
Stage I (best) - IV (worst)
Looks at LN and organ involvement
```
A: absence of B symptoms
B: B sx
84
How is lymphoma diagnosed
Bx of lump - core bx ro whole node excision
| NOT fine needle aspirate (FNA)
85
Burkitt lyphoma
Very rapidly growing subtype of high-grade B-cell NHL
86
Genetic cause of Burkitt's lymphoma
t(8; 14) - translocation of chromosome 8 to 14
87
What is endemic Burkitt's lymphoma associated w/
EBV infection
88
Is Hodgkin lymphoma low-grade or high-grade
High
89
Epidemiology of Hodgkin lymphoma
Most common in young adults and 60+
| M > F
90
What infection is associated w/ Hodgkin lymphoma
EBV
91
Px of Hodgkin lymphoma
Pruritus
Often present w/ mediastinal mass - SVC obstruction, bronchial compression (cough, SOB, stridor)
Alcohol-induced LN pain
92
Dx of Hodgkin lymphoma
Bx - scattered Reed Sternberg (owl eyes) cells and reactive cells
93
Treatment and prognosis of Hodgkin lymphoma
Different chemo to NHL
| Prognosis particularly good
94
Imaging for lymphoma staging and response
PET scan
95
In which lymphoma is extra-nodal disease common
NHL
GI tract - gastric MALT lymphoma in c/c H. pylori infection, small bowel lymphoma
Skin- mycosis fungoides
96
Most common leukaemia
CLL
97
Usual findings of CLL
incidental lymphocytosis on FBC
98
If there is only lymphadenopathy and NO lymohocytosi, what should be suspected
Small lymphocytic lymphoma (SLL), low grade NHL
99
Diagnosing CLL
FBC, blood film (leucocytosis and smear cells)
Examination findings
Immunophenotyping - monoclonal antibody w/ immunological marker for CD5 and CD19
100
When would you treat CLL immediately
Bulk disease e.g. lymphadenopathy
Disease obstructing major organ
Bone marrow failure
B sx
'Watch and wait' approach is usually used
101
Drug treatment for CLL
Monoclonal antibody + chemo e.g. rituxumab, fludarabine and cyclophosphamide
B-cell signalling inhibitors (tablets) e.g. ibrutinib
102
Epidemiology of CLL
Usually >70 yrs
| Generally slowly progressive
103
Genetic cause of CML
t(9:22) - 'philadelphia chromosome'
| Codes for a anew protein, BCR-ABL, a tyrosine kinase
104
Why is CML always treated when diagnosed
Can progress to AML
105
CML px
Incidental - neutrophilia w/ granulocyte precursors
Sx related to anaemia and splenomegaly e.g. pain and early satiety
B sx
106
Dx of CML
FBC (neutrophilia and presence of myelocytes) and blood film
FISH to look for Philadelphia chromosome
Bone marrow bx to assess phase
107
FISH
Fluroscent in-situ hybridisation
108
Treatment of CML
Tyrosine kinase inhibitor e.g, imatinib
Daily tablets lifelong
Aim for low levels of BCR-ABL, use PCR
109
A/c leukaemia px
Consequences of cytopenias e.g. bleeding, anaemia, infections
Short hx - treatment required quickly
ALL pts sometimes have lympadenopathy or hepatosplenomegly at dx
110
Dx of a/c leukaemia
Blasts on blood film or BM (> 20%)
| Dx confirmed w/ immunophenotyping (distinguishes AML from ALL)
111
Epidemiology of a/c leukaemia
ALL more common in children (little people)
| AML more common in elderly (mature people)
112
APML
A/c promyelocytic leukaemia
| Subtype of AML associated w/ DIC (medical emergency)
113
Treatment options for a/c leukaemia
Intensive chemo, may involve allogenic stem cell transplant (may be curative, v toxic)
Low intensity chemo (may prolong life but not curatiev, still toxic)
Palliative care - sx control at home
114
Aside from chemo , what else to a/c leukaemia pts need
```
Hickman line
Prophylactic antimicrobials
Transfusions (Red cells, platelts)
Treatment of neutropenic sepsis
Pian control
Antiemetics
Psychological support
```
115
Haemostasis
The arrest of bleeding
116
What does a hyperocagulable state lead to
Thrombosis
117
What does reduced coagulation lead to
Bleeding disorder
118
Phases of CML
C/c
Acceleration
Blast - crises
119
Rule of 1/3 in CLL
1/3 don't progress
1/3 progress lowly
1/3 undergoes Richter's transformation to become aggressive high-grade lymphoma.
120
Features of all types of leukaemia
BM failure causing pancytopenia
B sx
Generalised painless lymphadenopathy
Hepatosplenomagly
121
Sx of thrombocytopenia
Bleeding
Ecchymoses (bruises)
No-blanching petechiae (smaller)/ purpura (bigger)
122
Specific sx of AML
Infiltration --> gum hypertrophy, skin infiltration
| DIC in APML
123
Specific sx of ALL
Children w/ FTT
CNS involvement
Painless unilateral testcular swelling
Renal enlargement
124
CNS involvement in ALL
Inc cranial nerve palsies and meninges due to mets to meninges --> neck stiffness and papilloedema
125
Papilloedema
Optic disc swelling
126
Stages of haemostasis
Tissue injury --> thrombus formation -> tissue repair --> dissolution of the thrombus
127
How does haemostasis work?
Vasoconstriction - limits blood flow to the injured region
Formation of platelet plug
Formation of fibrin mesh - to stabilise the thrombus
Clot dissolution - through the action of plasmin
128
Steps of formation of platelet (primary haemostatic) plug
Adhesion - platelets come into contact w/ damaged sub endothelium
Activation - vWF factor causes platelets to adhere to ECM collagen
Aggregation - platelet-platelet interaction via fibrinogen
129
Examople of primary haemostasis
Von Willebrand disease
130
Features of Von Willebrand disease
Usually pattern = mucosal haemorrhage
Bleeding at time of trauma/ surgery
Menorrhagia
Nose bleeds
131
What do the symptoms of Von Willebrand disease vary according to
Amount of vWF (most commonly mild form of disease)
132
Secondary haemostasis
Stabilisation of platelet plug
Fibrin acts like gun giving the platelet mass strength allowing to function as a secure patch and protect the base to allow repair and healing
133
Purpose of coagulation
To produce a stable haemostat plug via localised fibrin clot formation at the site of vessel injury
134
Mechanism of blood coagulation
Enzymatic cascade of series of coagulation proteins sequentially activated and a plied which results in a fibrin clot
135
Coagulation pathways
Intrinsic
Extrinsic
Common
136
Factors in intrinsic coagulation pathway
XII ---> XIIa
XI ---> XIa
IX ---> IXa
137
Factors in extrinsic coagulation pathway
VII
VII + TF ---> VIIa: TF
Tissue factor released when vessels are injured
138
Factors in common coagulation pathway
X ---> Xa: Va
II (prothrombin) ---> IIa (thrombin)
III (fibrinogen) ----> fibrin (IIIa)
139
Congenital disorder of 2' haemostasis
Low blood clotting factors - Haemophilia A or B
140
Haemophilia A vs B
A - lack of factor VIII
| B - lack of factor IX
141
Usual pattern of haemophilia
Joints/ soft tissue bleeding
Bleeds into 'target' joints --> arthritis joint
Retroperitoneum
Bleeding at times of trauma/ surgery
142
What do the sx of haemophilia vary accord to
Amount of factor 8/9 - lower levels, worse the bleeding
143
Acquired disorder of 2' haemostasis
Warfarin, liver disease (clotting factors produced in liver)
| Much more common than congenital
144
What stops the coagulation process from forming thrombi throughout the circulation
Coagulation inhibitors
| Fibrinolysis - breakdown of the fibrin clot by plasmin
145
Coagulation inhibitors in body
Antithrombin
Protein C
Protein S
146
How does fibrinolysis stop the coagulation process from forming thrombi throughout the circulation
Plasminogen ---> palms
| Fibrin breaks down into fibrin degradation products (FDPs) AKA D-dimers which stabilises 1' haemostatic plug
147
Blood used in lab coagulation tests
Anticoagulated blood - coagulation proteins inactivated by anticoagulant (citrate) - blue bottle
Clotted blood - Coagulation proteins not present, no anticoagulant - yellow bottle
148
Coagulation testing
```
Measurement of time intakes to for a fibrin clot in plasma
As the coagulation factors have been invited, an 'activator' is added to start the coagulation
Different pathways (and coagulation factors) can be assessed by added different activators
```
149
Coagulation screen
```
Prothrombin time (PT)
Activated partial thromboplastin time (APTT)
Thrombin time (TT) - less commonly used
```
150
Prothrombin time
Tissue factor is added too ample of plasma along w/ Ca
| Time until fibrin formation is measured by shining a light (initial solution is transparent)
151
What pathway does PT look at
Extrinsic and common
152
What factors does PT look at
VII
| V, X, prothrombin, fibrinogen
153
Normal clotting time for PT
10-13s
154
When is PT abnormal
Liver disease
Warfarin
DIC
155
Activator in APTT
'Contact activator'
| Phospholipid and Ca
156
What pathway does APTT look at
Intrinsic and common
157
What clotting factors does APTT look at
VIII, IX, XI, XII
| V, X, prothrombin, fibrinogen
158
Normal clotting in AOTT
24-38 s
159
When is APTT abnormal
Haemophilia A/B
DIC
Lupus anticoagulant
160
Activator in TT
Thrombin
161
Pathway measured in TT
Fibrinogen to fibrin
162
Factors TT look at
Fibrinogen
163
Normla clotting time for TT
14-16
164
When is tT abnormal
Low fibrinogen states
165
Causes of over coagulation
Too many cells
Deficiency of natural anticoagulants
Other coagulation abnromlaities
166
Too many cells causing over coagulation
Increased platelets
| Increased RBCs
167
Other coagulation abnormalities causing overcoagulation
Factor V Leiden variant - factor V which is resistant to inactivation by Protein C
Prothrombin gene variant - elevated levels of prothrombin
168
What can bleeding disorders arise due to
Problems w/ blood vessel wall
Problems w/ vWF
Problems of platelets
Problems w/ the coagulation factor cascade
169
Inherited vascular defects that can cause bleeding disorders
Hereditary haemorrhage telangiectasia
| CTD
170
Acquired vascular defects that can cause bleeding disorders
Senile purpura
Steroids
Scurvy
Amyloid
171
Causes of low platelets causing bleeding disorders
Inherited - rare
| Acquired - immune (ITP, TTP), bone marrow failure, drugs
172
Causes of functional platelet abnormality leading to bleeding disorders
Inherited - rare
| Acquired - drugs e.g. aspirin, clop, uraemia (renal failure)
173
Inherited problems w/ the coagulation cascade
```
Haemophilia A (factor VIII deficiency)
Haemophilia B (factor IX deficiency)
```
174
acquired problems w/ the coagulation cascade (factor deficiencies)
Drugs e.g. warfarin, heparin, DOACs
Severe liver disease
DIC
Massive blood loss
175
TTP
Thrombotic Thrombocytopenia purpura
176
Genetic cause of TTP
Absent ADAMTS13 (due to an antibody), leads to ultra large vWF multimer which binds platelets in the microcirculation
177
What does TTP cause
Micro thrombi and consumption of platelets
| Ischaemia in critical organs
178
Classical pentad of TTP
```
Fever
MAHA
Renal impairment
Fluctuating neurological signs - blood clots in microcirculation of brain
Thrombocytopenia
```
179
MAHA
Microangiopathic Haemolytic Anaemia
180
Is TTP a haematological emergency
Yes - remove plasma w/ multimers
181
What is anticoagulant therapy
Using drugs to treat and/or prevent thrombosis
| Conventionally doesn't incl antiplatelets e.g. aspirin
182
Common indication for anticoagulants
```
Prevention of CVA in AF
Treatment of VTE
Prevention of recurrent VTE
Prevention of valvular thrombosis/ embolism in metallic heart valves
Treatment of ACS
Thromboprophylaxis
```
183
Types of DOACs
Factor Xa inhibitors - apixaban, rivaroxaban, edoxaban
| Thrombin inhibitors - dabigatran
184
Parenteral thrombin inhibitor
Argotroban
| Bivalirudin
185
MOA of warfarin
Competitivlh natganoised vit K, which is necessary for production of clotting factors II, VII, IX and X
186
Speed of warfarin onset of actin
Slow, several days until therapeutic
187
INR calculation
INR = (PT pt/ PT control)^ thromboplastin ISI
188
Why are pts on warfarin monitored w/ INR
High inter-pt variation
189
Strength of warfarin tablets
```
1mg = brown
3mg = blue
5mg = pink
```
190
Warfarin monitoring
Regular monitoring needed
Pts provided w/ a yellow book
Target INR:: 2.5 (range 2-3) is the standard intensity - some indications have higher target INR range
191
What is the incidence of haemorrhage proportional to
INR - BUT can occur within target range
192
Factors affecting INR
Individual variation/ genetic
Drugs (incl alcohol) can potentiate the effects of warfarin
Diet e..g. vit k
Intercurrent illness
Mistaken dose e.g elderly, visually impaired
193
Implication of drugs potentiating warfarin
INR must be checked within 5 days of starting/ stopping new drugs
194
Types of heparins
```
Unfractoinated heparin (UFH)
LMWH e.g. dalteparin, tinzaparin, enoxaparin
```
195
Administration of heparins
IV or s/c
| Destroyed by gastric acid so oral administration not possible
196
What is UFH a mixture of
Different wt heparin molecules
197
MOA of UFH
Potentiates antithrombin increasing anticoagulant effect
198
Clinical uses of UFH
Initial treatment of VTE
| Anticoagulant 'bridging therapy' to cover surgery in Hugh thrombotic risk pts
199
How does UFH affect clotting screen
Prolongs APTT - if used at treatment doses requires regular monitoring of APTT
200
Time for UFH onset of action
Immediate but large doses required for full therapeutic anticoagulant (continuous IV infusion)
201
When are small doses of UFH given
Thromboprophylaxis (s/c injection)
202
Monitoring for UFH
Large inter-person variability - measure APTT
203
Plasma half-life fo UFH
Short (20-120 MINS)
204
Potential side effect of UFH
Heparin induced thrombocytopenia (immune reaction)
205
Reversal agent for UFH
Protamine
206
MOA of LMWH
Majority of effect is anti Xa (indirectly through antithrombin)
Lesser degree of thrombin inhibition
207
When would you give a higher over a lower dose of LMWH
High dose for full anticoagulation
| Lower dose used for VTE prophylaxis
208
Can APTT be used to assess LMWH effect
No
| Variable effect of APTT - may be normal
209
Onset time of LMWH
Immediate
210
Monitoring for lMWH
Non required
| Unless severe renal failure or extremes of body wt - can use anti Xa
211
What is treatment dose for LMWH based on
Wt
212
Excretion of LMWH
Renal - will accumulate in renal failure
213
Which has a longer plan a half-life out of UFH and LMWH
LMWH - so can be given for most indications
214
What is the risk of HIT with LMWH
Much lower than UFH
215
Reversal agent for LMWH
None available
216
APTT target for pts being anticoagulants w/ UFH
2.0
| Measure APTT ration every 6 hrs until stable
217
MOA of fondaparinoux
Effect mediated by antithrombin
| Only inhibits factor Xa
218
Effect of fondaparinoux in APTT
Does not prolong APTT
219
Onset of fondaparinous
Immediate
220
Monitoring for fondaprinous
None required
221
Excretion of fondaparinous
Renal
222
Administration of fondaparinous
S/c injection
223
Clinical uses of Fondaparinous
Treatment of VTE
Treatment of ACS
Thromboprophylaxis
224
Reversal agent for fondaparinous
None available
225
Administration of DOACs
po
226
Metabolism of DOACs
Part renal, part hepatic
227
Current clinical uses of DOACs
Prevention of CVA in AF
Treatment of VTE
Thromboprohylaxis
228
Initiating anticoagulation - rapid onset required vs slow induction acceptable
Rapid onset required e.g. VTE - heparin or DOAC
| Slow indication acceptable e.g. AF - warfarin or DOAC
229
Initiating anticoagulation when rapid onset is required
Heparin - usually LMWH s/c and warfarin (po) is started at the same time. Stop heparin once INR in therapeutic range
OR DOAC but some DOACs need initial LMWH
230
Initiating anticoagulation when slow induction acceptable
Warfarin - start conventional does e.g. 3mg OD, arrange monitoring of INR
OR DOAC
231
Mx of suspected VTE using LMWH and warfarin
Start s/c LMWH on suspicion of DVT or PE (if no significant bleeding risk)
Confirm dx
Start warfarin using standardised loading schedule
232
Stopping LMWH after a VTE
When INR 2-3 for 2 days
233
Duration of anticoagulation when treating AF
Usually continues lifelong providing benefits > risks
234
Duration of anticoagulation therapy for VTE
1st calf vein thrombosis - 6/52
1st provoked VTE - usually 3/12
1st unprovoked VTE - minimum of 3/12 (usually 6/12), may be indefinite
2nd VTE - consider indefinite anticoagulation based on risk:benefit evaluation
235
What type of bleeding do we see in pts on anticoagulation
```
Minor skin bruising (v common)
Epistaxis
GI haemorrhage
Muscle haemotoma
Haematuria
ICH (rare)
```
236
What % of pts on long term anticoagulant w/ warfarin will have an episode of major bleeding
2%
| Most pts will make a full recovery from the bleeding episode providing its managed correctly
237
Which pts on anticoagulation have a higher risk of major bleeding
```
Elderly
Renal failure
Liver failure
Recurrent falls
Concurrent anti platelet or NSIAD use
Alcoholism
Cancer
```
238
Mx of warfarin over anti coagulation
Stop warfarin
| If bleeding or INR > 8 need to reverse
239
Reversal of warfarin/ bleeding on warfarin
Vit K - oral or IV
| PCC if major bleeding/ bleeding into critical site/ to allow emergency surgery
240
Reversing warfarin w/ vit K
Most of warfarin effect will have reverse 6 hrs later
241
Reversing warfarin w/ PCC
Immediately reverses warfarin effect by replacing clotting factors (give w/ vit k )
242
What is key to investigate when a pt has been over anticoagulated/ bleeding
Look for cause for over anti coagulation e.g. new drugs, alcohol, diet change, confusion about dose, diarrhoea, incorrect dose, renal failure
243
Mx of heparin over anticoagulation
Stop heparin - short half-life, may be sufficient
Local measures e.g apply pressure
Consider TXA
If bleeding, consider protamine sulphate
244
What should be checked before restarting anticoagulation after over-anticoagulation
Check risk; benefit ratio - does pt still need anticoagulant
245
Reversal agents for DOACs
Idarucizamab reverses dabigatran
| No antidote for Xa inhibitor yet, PCC should be considered in life-threatening bleeding
246
Examples of haemostats caused by factor deficiencies
```
Haemophilia A (Factor VIII)
Haemophilia B (Factor Ix)
Von Willebrand disease (vWD deficiency)
```
247
Genetics of haemophilia A
X-linked monogenic disease, where the F8 gene locus lies on the long arm of the X chromosomes
Homologous recombination - inversion of Factor VIII (flip tip inversion)
248
Clinical subtypes of haemophilia
Mild
Moderate
Severe
249
Prevalence of haemophilia A
~1: 5,000 males WW
250
Haemophilia B prevalence
~1 :20,000 WW
251
Genetics of haemophilia B
X-linked recessive
Gene affected is F9
Factor IX acts as proteolytic enzyme in the coagulation cascade
252
Prevalence of vWD
Most common inherited bleeding disorder
| Up to ~1: 100 WW
253
Inheritance pattern of vWD
Autosomal dominant or recessive - depends on functional impact of underlying mutation
254
Which chromosome if the VWF locus found on
12
255
What is vWF a carrier molecule for
Circulating fator VII
| Also promotes adhesion of the platelets to a d aged endothelium
256
What is a paraprotein
Monoclonal antibody arising from a clone of lymphocytes or plasma cells
257
Chains in antibodies
Heavy chain - either IgG, IgA, IgM, IgE or IgD
| Light chain - either kappa or lambda
258
Detection of paraprotein
Appears as an addn abnormal band on serum protein electrophoresis
259
How are serum free light chains detected
Immunoassay - detected the surface usually hidden where the light chain binds to the heat chain
Two assays - one of lambda and one for kappa
260
Why is the ratio of serum free light chains useful
Allows us to detect clonality - whereas a polyclonal increase in cells e.g infection will lead to a raised kappa and lambda light chains
261
What is myeloma
Malignant proliferation of plasma cells (>10g/L) of. a paraprotein (>30g/ L)
262
Clinical spectrum of myeloma
Variable - frorm asymptomatic to rapid decline and death
263
Epidemiology of myeloma
Makes up 1% of cancers
10-15,000 myeloma pts at any one time in the UK
Median age is 60-65yrs, rare <30
264
Cardinal features of myeloma
Increases bone marrow plasma cells (>10%)
Bone destruction
Paraprotein band in blood (81% of pts) - unless light chain myeloma (17%) or non-secretory (very rare, <2%)
265
Clinical features of myeloma
End organ damage. 'CRAB' criteria
| Also infections and spinal cord compression (plasmacytoma or fractures)
266
CRAB criteria for myeloma
C - elevated calcium
R - renal failure -
A - anemia
B - bone pain
267
Hypercalcaemia in MM
```
Sx such as:
Bone pain
Renal stones - rare as hypercalaemia needs to be long standing
Groans (abdominal pain)
Psychic moans (organic psychosis)
Polyuria
Cardiac arrest
```
268
Renal impairment in MM
Due to Its obstructing kidney tubules
| Causes deranged U&Es., proteinuria (frothy urine/ dipstick), light-chain casts on urinalysis
269
Anaemia in myeloma
BM infiltration and failure causing pancytopenia --> anaemia, thrombocytopenia, neutropenia
Although the levels of plasma cells are high, aren't working properly, because the Igs secreted don't work - immunoparesis
270
Mevhaism of bone disease in myeloma
Myeloma cells produced factors e.g. osteoportegrin and RANK-L, resulting in:
Activation pf osteoclasts (increased resorption)
Inhibition of osteoblasts (decreased production)
Net result = bone resorption
271
Bone destruction in myeloma
Lytic lesion can be imaged on Xray/ CT/ MRI/ PET
Vertebral collapse - back pain, loss of height, kyphosis, nerve compression
Pathological fractures
272
Paraprotein in myeloma
Serum paraproteins:
IgG in 53% pts
IgA in 25%
Light chains only in 17% (free kappa or lambda)
273
What haematological malignancy is IgM associated with
Lymphoma NOT myeloma
274
What have the measurement of Bence Jones proteins been replaced with
BJ proteins (light chains in urine) superseded by serum free light chains - to measure paraproteins
275
What are serum free light chins used in the dx of
Light chain myeloma and primary amyloid
276
Clearance fo serum free light chains
Rapid: t1/2 = 2 days vs 30 days for IgG
277
Ix of suspected myeloma
```
FBC and blood film
Renal function i.e. urea, creatinine
Serum Ca
Serum protein electrophoresis
Serum free light chains
Bone marrow bx - increased plasma cells
Skeletal survey
```
278
What imaging is involved in skeletal survey
CT
MRI
PET
279
General measures that need to be managed when treating myeloma
```
Renal failure
Hypercalacaemia
Pain
Fractures
Soinal cord compression
Anaemia
Infection
Hyperviscosity
Psychological distress
```
280
Mx for renal failure in MM
IV fluids (may require dialysis)
281
Mx for hypercalcaemia in MM
IV fluids, bisphosphonates
282
Mx of pain in MM
Analgesis
| RT
283
Mx of fracture in MM
RT
| Surgery
284
Mx of spinal cord compression
Steroids
| RT
285
Mx of anaemia in MM
Transfusion
| Erythropoietin
286
Mx of infection in MM
Abx
287
Mx of hyperviscosity in MM
Plasma exchange
| Urgent chemo
288
Mx of psychological distress in MM
Psychological support
289
Which pts are treated of MM using chemo
Most common in pts over 70
| For those ,70, chemo followed by high dose chemo and autologous stem cells transplant
290
Chemo for MM treatment
1. Collection - stem cells harvested from BM or BM
2. Processing - stem cell is concentrated
3. Cryopreservation - frozen for preservation
4. Chemo - high dose chemo and/or RT
5. Infusion - thawed stem cells infused back into pt
291
Thalidomide in myeloma mx
Prolongs survival survival
| Used as a single agent agent or with other chemo
292
Side effects of thalidomide in MM mx
```
Neuropathy
VTE
Sedation
Constipation
Phocomelia (birth defects)
```
293
Drug treatments for MM, bar thalidomide
Lenalidomide, pomalidomide
Daratumamab
Bortezonib, carfililzomin, ixazomib
Trials of new steroids
294
Lenalidomide, pomalidomide for MM
More potent analogues
Immunomodulatory and anti-angiogenic
Less neuropathy, sedation, constipation than thalidomide
295
Daratumamab for MM
Anti-CD38 antibody (expressed by plasma cells)
296
Bortezomib, carfilzomib, ixazomib
Proteosome inhibitors
| In combi w/ steroids
297
How can we classify causes of paraproteinaemia
B cell or plasma neoplasms
| Not associated w/ B cell/ plasma cell neoplasm
298
Causes of paraproteinaemia caused by B cells or plasma neoplasms
```
MGUS
Plasmacytoma
Lymphoma
Primary amyloidosis
Others e.g. POEMS
```
299
Causes of paraproteinaemia not associated w/ B cell/ plasma cell neoplasms
Infections e.g Hep C, HIV
CTD
Carcinomas
Transplant-related
300
MGUS
Monoclonal gammopathy of undetermined significance
301
Features of MGUS
Paraproteinaemia (lower than in myeloma i.e. 30g/L and usually <10g/L)
Bone marrow plasma cells are <10%
No CRAB criteria or end-organ damage
302
Prevalence of MGUS
HIgh prevalence in >80 (10%)
| 1% per yr evolve to myeloma
303
Mx of MGUS
Watch and wait
304
When to suspect myeloma
Paraproteinaemia (or abnormal light chain ratio) plus CRAB
305
Plasmocytoma
Tumoural mass plasma cells
306
Plasmacytoma and MM
Clonal proliferation of plasma cells identical to those in myeloma, but manifest as localised mass in bone or soft tissue solitary plasmacytoma of bone or solitary extramedullary plasmacytoma
307
Treatment of plasmacytoma
HIgh dose RT if truly localised i.e. no underlying myeloma
308
Low grade lymphoma and paraproteinaemia
Lymphoma cells making a paraprotein, usually IgM
| Clinical behaviour that of a low-grade lymphoma nor a myeloma
309
What adds risks seems from lymphoma cells making a paraprotein
Addn risk of hyperviscosity
310
Amyloidosis
Insoluble protein deposits in organs
311
Primary amyloidosis mechanism
A protein conformational disorder associated w/ clonal plasma cells
Clonal plasma cells make light chain fragmnents which are deposited in organs as insoluble amyloid proteins ---> damage to affected organ(s)
312
Target organs for amyloidosis
```
Heart
Kidneys
Nerves
Liver
Gut
Skin
```
313
Result of amyloidosis in heart
Congestive cardiomyopathy
314
Result of amyloidosis in kidneys
Nephritic syndrome +/- renal insufficiency
315
Result of amyloidosis in nerves
Peripheral neuropathy
316
Result of amyloidosis in liver
Hepatomegaly
317
Result of amyloidosis in gut
Macroglossia, malabsorption
318
Result of amyloidosis in skin
Deposits
319
Diagnosing primary amyloidosis
Tissue bx
| Evaluation of plasma cell abnormality
320
Tissue bx for primary amyloidosis dx
Bx affected organ
| S/c fat aspirate
321
Evaluation of plasma cell abnormality for primary amyloidosis dx
```
FBC, U&Es, Ca
Serum protein electrophoresis
Serum free light chains
Bone marrow bx
Skeletal imaging
```
322
Primary amyloidosis treatment plan
Supportive treatments
| Treatments of the underlying cause
323
Supportive treatment in primary amyloidosis mx
Renal transplant
Maximise cardiac function
Minimise fluid retention
324
Treatment of the underlying cause in primary amyloidosis mx
Chemo similar to that used for myeloma
Treat plasma cell clone rather than amyloid itself
Gradual regression of amyloid burden
325
Outcomes of primary amyloidosis
Progressive accumulation of amyloid
Variable, pt-spp amyloid protein turnover
Untreated prognosis 12-14 months but organ spp
Very poor w/ cardiac involvement (<6 months)
326
Function of lymphatic system
Maintenance of fluid balance within tissues
Absorption and carriage of water-insoluble fats from the intestines
Protection of the body through the generation of an immune response
327
Components of the lymphatic system
Lymphatic vessels
LN
Spleen
Thymus
328
Where are lymph channels found
in interstitial space
329
Path of superficial lymphatics vs deep lymphatics
Superficial follow veins
| Deep lymphatics follow arteries
330
What do lymphatic channels receives
Lumbar and intestinal lymph nodes
331
Where does the thoracic duct enter the thorax
Aortic hiatus in the diaphragm
332
What part of the mediastinum is the thoracic duct found
Posterior
333
What does the thoracic duct
L subclavian and jugular lymphatic ducts
334
What does the thoracic duct open into
The angle between the L internal jugular and l subclavian veins (brachiocephalic vein origin)
335
What is the R lymph duct formed of
R subclavian and jugular trunks
| Drains into corresponding veins on the R
336
Where are LNs found
Distrubuted throughout the body
337
What do LNs allow the interaction of
Antigens, APCs and lymphoid cells in the generation of an immune response
338
Where is the spleen found
L upper quadrant
| Long axis in the line of 10th rib
339
Infective causes of splenomegaly divided by pathogen types
Bacterial - TB, endocarditis
Viral - EBV
Protozoal - malaria, leishmaniasis
340
Haematological cause of splenomegaly
Haemolytic anaemia
341
Immunological causes of splenomegaly
RhA
| Sarcoidosis
342
Metabolic causes of splenomegaly
Rare inherited enzyme deficiencies e.g. Gaucher's
343
Vascular cause of splenomegaly
Portal HTN (cirrhosis)
344
Neoplastic causes of splenomegaly
Lymphoma
Leukaemia
Myeloproliferative disorders
345
Types of lymphadenopathies
Infective
Neoplastic
Immunological
Metabolic
346
Causes of lymphadenopathies
Local bacterial infection
Infective mononucleosis
TB, HIV
347
Immunological cause of lymphadenopathies
Sarcoidosis
348
Metabolic cause of lymphadenopathies
Thyrotoxicosis
349
Classical subtypes of Hodgkin lymphoma
Nodular sclerosing - most common
Mixed cellularity - immunocompromised pts
Lymphocyte rich - far, best prognosis
Lymphocyte depleted - rare, poor prognosis
350
What types of Hodgkin lymphoma may progress to diffuse large B-cell lymphoma
Nodular lymphocyte predominant
351
Indolent subtypes of NHL incl
Follicular lymphoma
MALT lymphoma
Small-cell lymphocytic lymphoma
352
Difference in the spread of HL vs NHL
HL tends to spread from one to another in a contiguous manner, NHL spreads more haphazardly
353
Features of malignant neoplasms
```
Non-encapsulated
Invasive
Poorly differentiated
Mitotic figures common
Can have rapid growth
Relatively anapaestic
```
354
Anaplastic
Cancer cells that divide rapidly and have little to no resemblance to normal cells
Many pleomorphic cells
355
Naming of epithelial cancers
Glandular: adenoma --> adenocarcinomas
Squamous: papilloma --> SCC
356
Naming of mesenchymal cancers
Adipose tissue - lipoma --> liposarcoma
Nervous tissue - neurofibroma --> neurofibrosarcoma
Snmooth muscle - leiomyoma --> leiomyosarcoma
357
Possible predisposing factor for CML
Ionising radiation
358
Where can the blasts in CML infiltrate
Any extramedullary site (spleen, liver, LN, skin & soft tissue)
359
Epidemiology of MALT lymphoma
6-7% of all B-cell lymphoma
Median age 70s
Hx of c/c infl disorder --> accumulation of extra nodal lymphoid tissue (acquired MALT)
360
What organism causes a gastric MALT
H. pylori
| Abx tx results is remission of gastric MALTs after radiation of H. pylori
361
Lymphoproliferative disorders in the immunosuppressed
Primary immune disorders
Post-transplant lymphoprolifertaive disorders (PTLDs)
Iatrogenic Immunodeficicny-associated Lymphoproliferrauce disorders (IIALDs)
HIV-associated lympho proliferative disorders
362
MM and cytokines
Myeloma cells express a spp receptor for IL-6, which is the major growth and survival factor for MM cells
IL-6 is produced by cells in the bone marrow micro-enviromenent
363
Therapeutic options for DLBCL
Chemo - R-CHOP
| RT
364
R-CHOP
5 chemo drugs featuring rituxiumab, cyclophosphamide etc
365
What do myeloproliferative disorders all have in common
JAK-2 mutation
366
Features of all MPN
BM failure --> anaemia, thrombocytopenia, leucopenia
| Hepatosplenomegaly
367
Spp sx of essential thrombocytheamia
Clotting tendency --> headache, chest pain, gangrene, ALI
368
Spp sx of polycytheamia vera
Plethoric rosacea and pruritus after a bath
Hyperviscosity ----> headache and dizziness
Gout
Sole/ palm during
369
Cause of isolated, prolonged APTT (prolonged APTT w/ normal PT)
Haemophilia
370
What causes a prolonged PT w/ an abnormal APTT
Warfarin
371
What causes both prolonged PT and APTT
DIC
372
epo in polycythaemia vera
Low - all 'used up'
373
Clinical significance of neutropenia
Recurrent infection
| Risk of neutropenic sepsis - life-threatening
374
Clinical significance of neutrophilia
Hypercoagulability
375
Clinical significance of lymphocytosis
If well, no treatment required
| May be sign of CLL
376
Clinical significance of eosinophilia
Eosinophilic asthma
377
ITP
Immune thrombocytopenic purpura
378
What is immune thrombocytopenic purpura
Autoantibodies against the platelet membrane which sensitizies the platelet causing their premature removal out of the circulation
379
Sx of ITP
Spontaneous bleeding, easy bruising, epistaxis i.e. nosebleeds or menorrhagia
380
Mx of DIC
Focus on treating underlying cause
Resus via ABCDE
Ventilatory and haemodynamic support in ICU
Give FFP and cryoprecipitate as well as anticoagulant
381
Clotting screen in vWD
Normal PT
| Prolonged APTT
382
Myeloid malignancies
AML and CML
MDS
Myeloproliferative neoplasms (ET/ PV/ MF)
383
Lymphoid malignancies
ALL and CLL
HL and NHL
MM
384
What do DIC and TTP have in common for blood film finding
Red cell fragments
385
Blood ix findings for DIC
Low platelets
Long PT/ APTT
Low fibrinogen
386
Clotting screen in TTP
Normal
387
Px of PV
Aquagenic pruritus
B sx
Headaches
Early satiety
388
What should pt's w/ PV NOT do
Take Fe supplements
389
How do we monitor success of PV therapy
Repeat FBC - looking fir Hit to reduce to 0.45
390
What are the indications for hydroxycarbamide in PV therapy
Inadequate reduction in Hct
Thrombosis (increase in platelets)
Haemorrhage
391
How can tissue samples be performed for LN bx
Core bx
Excision bx
NOT fine needle aspirate
392
Potential side effects of chemo
Immunosuppression
Feel sick
GI upset
Hair loss
393
What procedures should be considered in men before commencing chemo
Sperm cryotherapy preservation
394
Features of meningococcal meningitis
```
Severe headache
Photophobia
O/E unwell
Pyrexia
Neck stiffness
Petechiae
```
395
What investigations are required after a blood transfusion reaction
```
Repeat G&S on all samples + cross-match
DAT on post transfusion sample
Examine blood for bacterial contamination
FBC & film
Coag screen for DIC
Renal + liver function tests
```
396
Px of ET
```
Asymptomatic
Thrombosis
Burning sensation hands and soles
Cold peripheries
Splenomegaly
```
397
Ann Arbor staging of lymphoma
Stage I - involvement of single nodal group
Stage II - involvement of 2/2+ nodal groups on same side of diaphragm
Stage III - involvement of nodal groups on both sides of the diaphragm
Stage IV - disseminated disease w/ involvement of extra-lymphatic organs
398
Complications of CLL
Anaemia
Hypogammaglobulinaemia ---> recurrent infection
Warm AIHA (10-15% pts)
Richter's transformation
399
Richter's transformation
CLL cells enter LN and become high-grade, fast-growing, NHL
400
Poor prognostic factors for HL
Raised ESR
Lymphocyte depleted type
Anaemia
