Haematology Flashcards
1
Q
Causes for anaemia with low retics
A
Marrow Problem:
Iron, B12, folate, PRCA, AA, anaemia of chronic disease
2
Q
Causes for anaemia with high retics
A
Hemolysis
Thal
Blood loss
3
Q
Microcytic anaemia causes
A
Thal Anaemia of chronic dis Iron def Lead poisoning Siderblastic anaemia
4
Q
Normocytic anaemia causes
A
Renal failure Blood loss Haemolytic anaemia Anaemia of chronic dis Bone marrow failure - AA, infiltration, chemo, PRCA
5
Q
Macrocytic anaemia causes
A
Megaloblastic - B12, folate, cytotoxic drugs ETOH Myelodysplasia Hypothyroidism CLD
6
Q
Target cells
A
Iron def
Liver disease
Haemoglobinopathies
Post splenectomy
7
Q
Stomatocyte
A
Liver disease, ETOH
8
Q
Pencil cell
A
Iron deficiency
9
Q
Spherocyte
A
Warm Hemolysis, septicemia, hereditary spherocytosis
10
Q
RBC Fragments
A
DIC, HUS, microangiopathy, TTP
11
Q
Elliptocyte
A
Hereditary elliptocytosis
12
Q
Tear drop/ poikilocytes
A
myelofibrosis, extramedullary haemopoesis
13
Q
Ferritin role in iron regulation
A
Iron which is not required is stored by ferritin
Water soluable
14
Q
Hepcidin Role in iron regulation
A
Expression mostly in the liver
Regulates iron absorption and the distrubution of iron to tissues
-Binds to ferroportin in the enterocyte or reitculocyte and breaks down ferroportin so irons remains within the cell and does not go into blood stream
15
Q
Regulators of Hepcidin expression
A
Increase Hepcidin:
- Inflammation
- Excess iron
Low levels Hepcidin
- Iron def
- Hypoxia (EPO)
- Erythropoesis
- Haemalytic anaemia, Thal, Haemachromatosis (inappropriately low)
16
Q
Role for Soluble transferrin receptor in iron deficiency
A
In absence of erythroid hyperplasia, Iron def is prinicipal cause of raised soluble transferrin receptor
NOT elevated in anaemia of chronic disease
Helpful in differentiating iron def and inflammation from anaemia of chronic disease
17
Q
What is the role for globin chains in Hb structure
A
Protect haeme from oxidation, so that they are efficient in transporting O2
18
Q
Adult Hb
A
HbA - alpha2Beta2
HbA2- alpha2delta2
19
Q
HbF
A
Alpha2gamma2
20
Q
HbS pathology
A
Sickle Cell anaemia
-Valine for glutamic acid in 6th position of beta chain
21
Q
Sickle cell anaemia vs disease
A
SCA - homozygous for HbS
SCD - Coinheritance of Beta thal gene
22
Q
HbE cause
A
G to A in codon 26 of beta globin gene
- Structurally abnormal
- Behaves like Beta thal mutation
23
Q
Complications and Mx of Transfusion dependent Beta thal major
A
Cx:
-Iron overload, OP, endocrinopathies, renal impairment
Mx
-Transfusion to avoid bony deformity, Iron chelation, consider splenectomy, Mx complications from iron overload
24
Q
Precipitants of Sickle cell crisis
A
Hypoxia Hypo/hyperthermia Altitude Acidemia Pregnancy Sepsis
25
Ix that suggest intravascular haemolysis
Raised plasma haemoglobin
Haemoglobinuria
Urinary haemosiderin
Methaemalbuminaemia
26
Hereditary Spheroctosis
Autosomal Dominant
MCHC increase >360g/L
Defect in cytoskeleton of RBC membrane
Features:
-Jaundice, splenomegaly, gall stones, leg ulcers, haemolytic crisis, aplastic crisis
Dx:
-Blood film, negative DAT, flow cytometry, reduced binding of eosin-5 maleimide
Mx: Splenectomy +/- folate
27
Dx and Mx of warm AIHA
Extravascular hemolysis
Antibody reacts with RBC at 37 degrees (IgG mediated)
Causes classically:
-SLE, CLL/lymphoma, Drugs
Dx: Hemolysis screen positive, Spherocytes, Positive DAT
Mx:
- Supportive and transfusion
- Steroids
- IVIG
- Folate (increased RBC turnover)
- Aza/Mercaptopurine
- Consider DVT prophylaxis
Second line:
-Rituximab, +/- Splenectomy, IVIG
28
Associations of cold agglutinins
Mycoplasma pneumoniae
EBV
Lymphoma
29
Cold agglutinins haemolysis Dx and Mx
DAT +ve to C3d only not IgG
Features of intravasular haemolysis
-Mx:
Keep warm
Rituximab
Steroids only helpful if it is mixed cold and warm haemolysis
30
MAHA definition and causes
Hamolytic anaemia and thrombocytopenia
Causes:
- TTP
- HUS/aHUS
- Pregnancy
- DIC - Prosthetic valves
- Drugs: Gemcitabine
- Cancer
- SLE
31
Diagnosis and Mx of TTP
Low ADAMTS 13 <10%
Tx
- Apheresis, FFP, steroids, Rituximab
- Caplacizumab (anti vWF - not available yet)
32
PNH Features
Pancytopenia
VTE
Chronic paraoxysmal intravascular haemolysis, dark urine
Defective protein PIG-A whish is essential for formation of the GPI anchor; a structure that attaches several srface proteins to the cell membrane: CD55/CD59 (protects RBC from complement mediated lysis)
Cells sensitive to complement mediated lysis
Gold Standard Ix:
-Flow cytomettry lack of CD55/CD59
33
PNH Mx
Eculizumab
Anticoagulation lifelong after 1st thrombosis
Transfusions +/- iron infusions
34
Universal plasma donor
AB blood type
| Have no antibodies in serum
35
Massive transfusion protocol
Start with/ RBC:FFP:Plt close to 1:1:1 ratio
(4 units blood and FFP, and one pool platelets)
-Next pack add in Cryo 8-10 units
After increased ratio of plasma to RBCs improves mortality
36
TACO Definition and Mx
Transfusion Associated Circulatory Overload
- Within 2 hours and rapid
- Usually after large volume
- HTN common
CXR: pulmonary oedema
Mx: O2, Frusemide, ventilatory support
37
TRALI definition and Mx
Transfusion Related Acute Lung Injury
- Within 6 hours, progresses to ARDS
- Initiated by small volume
- Moderate hypotension
Mx: O2 and ventilatory support
38
Acquired Thrombophilias
APLS
| Cancer - LMWH better than warfarin
39
Hereditary Thrombophilias
F5 Leiden/APC resistance
Prothrombin gene mutation
Antithrombin deficiency
Protein C and Protein S deficiency
40
VTE Duration of anticoagulation
Provoked (except cancer)
-3-6 months
Unprovoked
- Minimum 6 months
- Decision to stop based on:
- -# of previous events; >1 cont.
- -Male >>>female recurrence
- -High risk thrombophilia
- -Mobility
- -Elevated D-dimer at completion of initial Rx phase
- -Obesity
- -Sequelae of clot: PulmHTN, PPS
41
CAPS Defintion and Mx
Characterised by widespread thrombotic disease with multiorgan failure
-Mortality ~50% despite anticoagulation and immunosuppression
Mx:
-Steroids, immunosuppression, PLEX, aggressive anticoagulation
42
APLS Diagnostic Criteria
1 clinical and 1 lab criteria needed
Clinical:
- Vascular thrombosis
- 3x miscarriages
- 1x stillbirth
- 1x premature birth due to placental insufficiency or eclampsia
Lab:
-B2GP, LAC, or Anticardiolipin positive in high titres on 2 or more tests 12 weeks a part
43
Lupus anticoagulant testing
- Suspect when prolonged APTT
- Fails to correct with mixing
- Normal TCT
- Prolonged reptilase time
44
Corrected APTT testing
First mix plasma with normal plasma. If it corrects, then factor deficiency will correct, but an inhibitor will not correct.
Correction is defined as coming back within 4-5 seconds of controlled plasma's APTT
45
Which APLS Ab is the most thrombotic
Lupus anticoagulant
| Also the more Abs positive the higher the risk of thrombosis
46
APLS and Pregnancy:
| APLS Abs and previous thrombosis, but no pregnancy complication
Cont with therapeutic anticoagulation
47
APLS and Pregnancy:
| APLS Abs and no prior thrombosis or pregnancy complication
Monitor in antepartum period
| Post partum prophylaxis for 6 weeks
48
APLS and Pregnancy:
| APLS Abs and >1 fetal loss after 10 weeks
low dose aspirin and prophylactic LMWH during pregnancy
+Post partum prophylaxis for 6 weeks
49
APLS and Pregnancy:
| APLS Abs and Hx of preeclampsia
Low dose aspirin in 2nd and 3rd trimester
Post partum prophylaxis
50
VTE prophylaxis in pregnancy if not APLS
prophylactic LMWH if prev unprovoked VTE or whilst on COCP
51
MOA of heparins/LMWH/Fondaparinux
Inhibit coagulation through antithrombin
-Directly inhibit factors II, X (and IX , XI)
Fondaparinux: pentasaccharide used in HITS with normal renal function
52
MOA DOACs
Rivaroxaban and apixaban block factor Xa
Dabigatran blocks thrombin activity
53
Dabigatran level test
Dilute Thrombin Clotting Time (TCT)
| Trade name: Haemoclot
54
How long to W/H DOACs prior to OTs
Low risk: 24 hours pre op
High risk: 2-3 days prior
55
Dabigatran reversal methods
Idarucizumab
HDx
Activated charcoal if just recently ingested
56
Apixaban and Rivaroxiban reversal
Limited evidence
Some case reports suggest prothrombinex
Andexanet Alfa (Decoy Xa level for these agents to bind to) - not PBS approved
57
DAT testing
Detects antibodies attached to RBCs
58
Red blood cell modifications:
ALL PRBCs are leucodepleted
Irradiated
-For prevention of Transfusion related GVHD as there are still very few leucs in PRBC
Washed
-IF previous allergic rxn to plasma
CMV seronegative
-For Tx and Pregnant patients
59
Platelets
Single donor or pooled from multiple
Lasts 5 days at room temp (most likely to cause sepsis due to this)
Indication:
- Bleeding in setting of severe thrombocytopenia
- No effective in patients with rapid platelet destruction (e.g. ITP, TTP)
60
FFP
Plasma with coagulation factors (V, VII, VIII)
Potential to cause infusion rxn or allergic rxn as contains all plasla proteins, antigens, viruses that were in blood at time of collection
61
Cryoprecipitate
From FFP precipitate when thawed
Rich in fibrinogen, FVIII, XIII, vWF, and fibonectin
Indication:
-Only fibrinogen replacement like in DIC
62
Prothrombinex
Coagulation factor concentrate (II, IX, X and low level of VII)
Also contains antithrombin and heparin
Indication:
warfarin reversal
63
Immediate Haemolytic transfusion rxn
Usually due to ABO incompatibility
Results in massive intravasular hemolysis and possibly DIC
Mx
- Stop transfusion
- IV saline/resus
- Correct DIC
- Aim UO >100 ml/hr
- Recheck blood group and Xmatch
- hemolysis screen
- Culture unit for bacteria (clostridium welchii)
64
Delayed haemolytic Transfusion Reaction
Extravascular hemolysis
Antibody coated RBCs are cleared by reticular system
Usually prevented by Xmatch
Occurs 1-2 weeks post transfusion
Supportive Mx, Ix with hemolysis screen
65
Febrile non hemolytic transfusion reaction
Definition:
-Increase temp >1 degree C
Cause:
- Patient's Antibodies against donor leukocytes and cytokine storm (most likely cause)
Prevention:
-Leucodepletion (which is done to all RBCs now)
Mx
-Stop transfusion and supportive Mx and exclude other causes
66
Transfusion associated GVHD
Transfusion of viable T cells that then proliferate and attack the recipient
Onset: 8-10 days
>90% fatal
Presentation:
Fever, rash, N+V+D, hepatitis, pancytopenia
Ix: Tissue typing and Bx
Prevention: Irradiation of RBCs
67
Allergic Rxn with transfusion
Most commonly due to IgA
| -Screen for IgA deficiency/antibodies
68
Post transfusion Purpura
Profound thrombocytopenia <10, wet purpura (mucosa), platelet refractoriness
69
Which virus has the highest risk of transmission with transfusion
Hep B
| 1/800,000
70
Factors produced by normal endothelium to prevent platelet adhesion
NO
| Prostacyclin
71
Aspirin MOA
prevents platlet aggregation by COX inhibition which prevents formation of thromboxane A2 which promotes platelet aggregation
72
Clopidigrel and Ticagrelor and prasugrel MOA and which is reversible
Blocks ADP from binding to P2Y12 receptor on platelets
Role of P2Y12 receptor activation is to promote binding of GPIIb/IIIa receptor to fibrinogen to form clot
Ticagrelor is the only reversible one.
73
Tirofiban MOA
GPIIb/IIIa receptor blocker
74
Dipyridamole MOA
Phosphodiaesterase inhibitor which prevents cAMP to be changed to AMP.
Increased cAMP decreases Calcium release from platelet which prevents aggregation of platelets
75
APTT is a measure of which pathway?
Intrinsic pathway
Above factor 10
Measures the clotting time of the plasma (without tissue factor I.E extrinsic pathway)
76
PT is a measure of what pathway?
Extrinsic pathway
| Factor 7 essentially
77
APTT and PT together assess a problem in what part of the coagulation cascase
The final common pathway (Factor 10 and down)
78
What does INR measure
Measures the clotting time of plasma in the presence of optimal concentration of tissue factor AKA thromboplastin.
Indicates overall efficiency of the extrinsic clotting system
79
Causes for prolonged APTT that correct with mixing
Factor deficiency
Derranged LFTs
Vit K deficiency
80
Causes for prolonged APTT that DO NOT correct with mixing
Lupus anticoagulant
Factor specific inhibitors
Heparin
Abnormal Fibrinogen
81
Causes of prolonged Thrombin Clotting Time when performed after prolonged APTT doesnt correct with mixing
TCT reflects the action of thrombin on fibrinogen
Abnormal fibrinogen
Heparin
Paraprotein esp IgM
82
Reptilase Time
Uses reptiliase instead of thrombin
Unaffected by heparin
Remains prolonged with abnormal fibrinogen
83
Haemophilia A
Factor 8 Deficiency
| X linked recessive
84
Haemophillia B
Christmas disease
Factor 9 deficiency
X linked recessive
85
Differentiating platelet defects from clotting factor deficiency
Platelets defect:
- Skin, mucus membranes, GI
- Bleeding after minor cuts
- Petechiae
- Immediate bleeding after surgery
Clotting Factor Def:
- Deep in soft tissues, muscles, and joints
- Large ecchymoses
- Delayed and severe bleeding after surgery
86
Haemophilia A Mx
1. Biostate
- Factor 8 and vWF - plasma derived
2. Recombinant Factor 8
87
Haemophilia B Mx
Factor 9 replacement either plasma derived (MonoFIX) or recombinant (BeneFIX)
88
DDAVP for haemophilia patients and SE
Can be used in mild cases
Stimulates transient 3-4x increase in Factor 8 and vWF levels as released from storage sites
SE:
Hyponatremia
Fluid retention
Tachyphylaxis
89
Antifibrinolytic therapy for haemophilia
Epsilon aminocaproic acid and tranexamic acid
MOA:
Tranexamic acid binds to lysine residue on fibrin so plasmin cannot cleave it, thus stabilising clot
Useful in mucocutaneous membrane bleeding
90
3 late complications of haemophilia
- Joint destruction due to haemarthroses
- Transmission of blood bourne infection
- Development of inhibitor antibodies
91
When to suspect inhibitors in haemophilia
-Polyclonal antibodies inhibiting the function of exogenous FVIII and FIX
Suspect when:
- Mild and mod haemophilia when bleeding phenotype changes
- Severe haemophilia when they dont respond to treatment
92
Diagnosing an inhibitor in haemophilia
- Fail to increment in factor levels when given bolus
- APTT mix: fail to correct, when previously would have
- Bethesda assay: establishes Dx and quantifies the antibody titre
93
Mx of haemophilia with inhibitor
Activated PCC
- FEIBA (longer half life)
- -Contains activated Vit K dependent factors, 2, 10a, and trace amounts of 7a and 9a
-Recombinant Factor 7a (novo7)
PLEX (rapid)
Immune tolerance induction (steroids, IVIG, Rituximab, cyclo)
94
Novo Seven indications
Anything with an inhibitor
Factor 7 deficiency
95
What is the most common bleeding disorder in the community
vWD
96
Types of vWD
Type 1 - PArtial deficiency
Type 2 - Qualitative defect in vWF
Type 3 Severe deficiency in vWF
97
Features, Diagnosis, and Mx of Type 1 vWD
AD
mucocutaneous bleeding
bruising
Excessive bleeding from trivial wounds
Excessive menstrual bleeding
Dx
-History and vWF <20%
Mx
- DDAVP (except if pregnant or Hx of IHD)
- Tranexamic acid
98
Mx of Type 2 and 3 vWD
Biostate ( contiains factor 8 and vWF)
99
Bernard Soulier Syndrome
Inherited platelet disorder
- Giant platelets and clinically looks like vWD
- GP1b-9-5 abnormality
100
Glanzmann thrombasthenia
Defect in GPIIb/IIIa
101
Pathophysiology of ITP
Platelets coated with IgG aotoantibodies undergo accelerated clearance through Fc receptors expressed by macrophages predominantly in the spleen and liver
Megakaryocyte dysfunction as well in the marrow
Also relative TPO defiency (normal when it should be high)
102
Mx of ITP
Platelets >30 - observe
Platelets < 30
- Steroids
- IVIG
- Anti D
- Rituximab
- TPO mimetics: Eltrombopeg, Romiplostin (SE: rebound thrombocytopenia when stopped suddenly, increased bone marrow fibrosis )
Role for splenectomy if refractory or multiple relapses (2/3) will respond
103
Gestational Thrombocytopenia
Benign, no increased risk of bleeding
Occurs in 2nd or 3rd trimester
Range 70-150
Normal after delivery
104
TTP Diagnosis
Classic Pentad:
| -Thrombocytopenia, MAHA, Fever, neurologic, renal impairment
105
Pathophysiology of TTP
Large multimers of vWF due to ADAMTS13 deficency
-If acquired: Antibody against ADAMTS13
Secondary TTP due to cancer, drugs, BM transplant, infection, chemo - Does NOT have ADAMTS13 deficiency
106
Differentiating HUS from TTP
HUS/aHUS has normal ADAMTS13 level
107
Mx of TTP
PLEX (80% respond)
FFP
Immunosuppression
20% die in first month
108
HITTS
Thrombocytopenia caused by antibody mediated platelet activation secondary to heparin
-More so with heparin than clexane
Occurs 4-10 days post heparin
Transient prothrombotic disorder initiated by heparin
109
Pathophysiology of HITTS
HIT antibodies are directed against neoepitopes on a self protein - PF4 that are expressed when PF4 (on platelets) is bound to heparin
110
Diagnosis of HITTS
Thrombocytopenia AND
- One or more HIT associated event
- -Arterial or venous thrombosis
- -Skin lesion/necrosis at injection site
- -Acute systemic reaction to heparin
-Detection of HIT antibodies in patient serum or plasma (ELISA)
111
Mx of HITTS
Cease heparin and use alternative anticoagulant
- Danaparoid
- Direct thrombin inhibitor (Bivalirudin/Argatroban)
- Fondaparinux (synthetic herparin pentasaccharide)
112
Most common cause of activated protein C resistance
Factor V leiden mutation
113
MCV of Thal compared to iron deficiency
MCV waaaay down in thal and proportionally down in iron deficiency
114
Transferrin in CLD
Transferrin produced by the liver, so transferrin sats may artificially go up because there is not as much transferrin produced, but not in iron overload
115
Where is the most iron stored in the body
RBCs
116
Pathophysiology of anaemia of chronic disease
Diversion of Fe from circulation with less available Fe to erythroid precursors
- Increased synthesis of ferritin bu (IL-1 and TNF alpha) leads to increased storage
- Decreased duodenal absorption
- Blunted EPO response
- Reduced RBC half life due to cytokines
117
Anaemia of chronic disease Ix results
Normocytic anaemia
Low Retics
Ferritin >100 more likely ACD
IF Ferritin 30-100; do soluble transferrin receptor to differentiate between IDA and ACD (Normal in ACD)
118
B12 absorption
B12 released from protein in acidic stomach and binds to R-protein
Intrinsic factor released in stomach but binds to B12 in small intestine
B12/IF find to receptor cubilin and absorbed to portal system via terminal ileum
Transcobalamin 2 - Active - transfer B12 to tissues/BM
B12 stored in liver
119
Pernicious anaemia pathophysiology and testing
AI destruction of gastric mucosa leads to gastric atrophy and achlorhydria + decreased IF
Ix
- IF Ab ( specific)
- Parietal cell Ab (sensitive)
120
B12/Folate tests
Macrocytic anaemia
Hypersegmented neutrophils
Low retics, pancytopenia
BMAT: megaloblastic changes
-intrameduallary hemolysis posssible
Holo-transcobalamin 2
121
Best assessment of long term folate stores
Red cell folate level
122
Folate rescue therapy in MTX toxicity
Folinic acid (leucovorin)
123
Schistocytes
MAHA
124
Causes of MAHA
- TTP
- HUS
- Pre-eclampsia
- Malignant HTN
- Prosthetic valve
- Cancer
- Drugs
125
Evan's Syndrome
AIHA + ITP
126
Paraoxysmal Cold Haemoglobinuria
IgG mediated
| Intravascular haemolysis
127
Cold agglutinins
IgM
Intravascular and extravascular hemolysis
Associations:
Lymphoma
Mycoplasma
EBV
DAT: C3d only not IgG
128
G6PD Deficiency
Get acute hemolytic crisis
Susceptibility to oxidative stress (can't form NADPH which is protective against this stress)
X linked genetics
Film: Bite and blister cells
G6PD assay can only be done when not hemolysing or will be falsely elevated
Mx: Avoid precipitants
-Antimalarials, sulphur drugs, aspirin, Vit K analogues, fava beans
129
Pyruvate kinase deficiency
Chronic hemolysis
Reduced ATP formation, so RBC rigidity
Autosomal recessive genetics
Film: Thorny apple cells
130
Triggers for sickle cell crisis in sickle cell trait
Rare
fever
Hypoxia
Acidosis
General anesthesia
131
Acute chest syndrome in Sickle cell disease
Most common cause of death post puberty in sickle cell
-SOB, hypoxia, pulmonary infiltrates
132
Mx of sickle cell disease
```
Avoid triggers
Folic acid
Vaccines for functional asplenia
Exchange transfusions
Hydroxyurea (increase HbF levels and prevent crisis)
```
Consider stem cell transplant as may be curative, but high mortality
133
Crizanlizumab
Anti P selectin Antibody for prevention of pain crises in sickle cell disease
P selectin - adhesion molecule which is upregulated in inflammation, plays a role in sickle crises and vasoocclusion
134
DIC is most assocaited with which acute leukemia
APML (acute promyelocytic leukemia)
135
Wells Criteria
```
Clinical Sx of DVT
Other Dx less likely
HR >100
Immbolisation > 3 days or surgery in last 4 weeks
PRevious DVT/PE
Hemoptysis
Malignancy
```
136
Most specific test for confirming the diagnosis of complement mediated hemoysis
Free Hb
137
MOA Fibrinolytics
Concert plasminogen to plasmin which breasks down fibrin
138
How to assess apixaban level
modifed Xa level
139
How to assess Rivaroxaban level
Modified anti Xa level
PT will be slightly high
140
How to assess Dabigatran level
TCT high
| Hemoclot
141
Poor Prognostic features in AML
- FLT3 positive
- cKIT gene
- High WCC count at presentation
- Secondary AML or therapy related AML
- Monosomy 7
- Complex cytogenetics
142
Good prognostic factors in AML
- t(15;17)
- t(8;21)
- Inv16
- NPM positie
- CEBPA positive
143
Most important molecular prognostic marker in AML with normal cytogenetics
FLT3
| -Drives TKI activity and proliferation
144
Midostaurin
kinase inhibitor that inhibits FLT3 - improves OS in FLT mutated AML
145
APML
Acutely life threatening, but curable.
- Malignant promyelocytes
- t(15;17) = Differentiation block (PML-RARalpha)
Morphology:
- Hypergranular promyelocytes
- +++ Auer rods, "faggot cells"
- Bilobed or reniform nucleus
Cx:
-DIC
Mx:
-All Trans retinoic acid (ATRA)
146
ATRA Syndrome
Hyperleukocytosis ad pulmonary infiltrates as APML cells differentiate into granulocytes following ATRA
Rx: Steroids and ventilatory support
147
APML translocation
t15;17 (PML-RARalpha)
148
CML translocation
t(9;22) BCR-ABL - Philidelphia
chromosome
-Produces dysregulated protein kinase -drives unchecked proliferation
149
MPD genetics
JAK-2 V617F mutation
150
CMML genetics
5q minus syndrome
151
B-LPDs genetics
IgH promoter (14)
Ig LC promoters (2 and 22)
Oncogenes: cMYC (8), CYCD1 (11), BCL2 (18)
152
Clinical hallmarks of CML
High WCC with full spectrum of myeloid maturation series in peripheral blood
Basophilia and eosinophilia
Splenomegaly
Morphology:
- Bimodal distribution favoring myelocytes and neutrophils
- If blasts >10% then progression to accelerated phase
153
CML Treatment
First line: TKIs
-Imatinib, dasatinib, nilotinib, Ponatinib
Allogenic stem cell transplant in selected cases - failed TKI
Second Line:
-Interferon, cytarabine
T315i mutation - resistance to most TKIs except ponatinib
154
PRV mutation
JAK2 V617F
- Tyrosine kinase in EPO and TPO receptor
- Turned on in the absence of EPO
- Thrombogenic
155
ET mutations
JAK2V617F
CALR
-Phenotype: younger age, high plts, lower risk of thrombosis, better survival
MPL
156
ET Tx
Risk stratify
Aspitin if high risk and/or vasomotor Sx
-High risk features: Age >60, Hx of thrombosis, Plt count >1000
Myelosuppression if high risk
- Hydroxyurea
- Anagrelide
- Interferon
157
PRV Tx
Venesect to Hct <0.45
Aspirin for all
Anticoagulation if Hx of thrombosis
consider hydroxyurea if high risk/thrombocytosis
158
Myelofibrosis Tx
JAK2 inhibitors
- improve Sx and QoL, not survival
- Regardless of JAK2 mutation status
159
MDS treatment shown to improve survival and decrease progression to AML in high risk MDS
Azacitadine
160
5q Minus Syndrome
Form of MDS
Phenotype:
-Middle aged or older female, refractory anaemia (marked macrocytosis), preserved or elevated platelets
Bone Marrow:
- Hypercellular, but <5% blasts
- Increased hypolobular megakaryocytes
PAthophysiology
-?insufficient SPARC and RPS14
Mx
-Lenalidomide
Good prognosis
161
Burkitt Lymphoma Mutations
cMYC (chromosome 8) Driven by IgH enhancer
t (8;14) or t(2;8) or t(8;22)
Mature B cell neoplasm
162
Mantle cell lymphoma mutations
```
Cyclin D1 (chromosome 11)
t(11;14)
```
163
Follicular lymphoma mutations
BCL-2 (chromosome 18) - Anti apoptosis protein
| t(14;18)
164
What virus is implicated in the pathogenesis of splenic marginal zone lymphoma
Hepatitis C
165
Approach to Lymphoma diagnosis
BIOPSY!
-Excisonal is best, but core Bx ok
Then stage disease
- PET/CT
- BMAT
LDH and viral serologies
166
High Grade NHLs
Burkitt's lumphoma
DLBCL (most common NHL)
Mantle Cell lymphoma
167
Low Grade NHLs
Follicular lymphoma
Small lymphocytic lymphoma/CLL
Marginal zone lymphoma
168
EBV associated with which lymphomas
Burkitts
Hodgkins
HIV associated lymphoma
PTLD (post transplant lymphoproliferative disorder)
169
HTLV1 associated with what lymphoma
Adult T cell lymphoma/leukemia
170
HHV8 associated with which lymphoma
Primary effusion lymphoma
171
Hodgkins lymphoma
Bimodal age distribution
- >75% present with mediastinal/upper torso adenopathy
- Most common cause of SVC obstruction in young adults
Morphology:
-Reedsternberg cells
Poor prognosis
- Male
- Hb <10.5
- WCC >15
- Increased macrophages (CD68 positive cells)
- Alb <40
- Age >45
172
Tx Hodgkins
Limited:
ABVD Chemo +/- involved field RTx
Advanced:
ABVD
OR eBEACOPP
Anti PD1 - can be trialled
Auto SCT for relapse
Allo SCT for relapse post autograft
173
Double Hit Lymphoma Mutations
MYC and BCL2/BCL6
Poor outcomes
174
Ann Arbor Staging:
| Stage 1
Lymphoma located in single region
175
Ann Arbor Staging:
| Stage 2
Lymphoma located in 2 seperate regions, confined to one side of the diaphargm
176
Ann Arbor Staging:
| Stage 3
Lymphoma involves nodes or organs on both sides of the diaphragm
177
Ann Arbor Staging:
| Stage 4
Diffuse or disseminated involvement of one or more extra lymphatic organs, including liver, bone marrow, nodular involvement of lungs
178
Ann Arbor Staging:
| A or B
```
A= Absence of B Sx
B= Presence of B Sx
```
179
Hodgkins lymphoma CD stains
CD30, CD15
180
Second cancers in Hodgkins lymphoma
AML
NHL
Breast cancer
Solid organ cancers (thyroid, lung, bone, brain)
181
Brentuximab vedotin
Drug Ab Conjugate
Anti CD30
Releases MMAE toxin and causes apoptosis
For relapsed Hodgkins
182
Commonest indolent NHL
Follicular lymphoma
183
Mx of Follicular lymphoma
Advanced stage at presentation usually, often asymptomatic
Limited:
-Curative intent RTx
Advanced:
-Asymptomatic and low tumor burden: watch and wait
-Symptomatic or high tumor burden: Chemoimmunotherapy
(Obinotuzumab +CHOP/Bendamustine)
Cyclophosphamide, Vincristine, Doxirubicin, Pred = CHOP
Bendamustine shown to have better outcomes and less toxic
If old and frail can trial ritux and lenalinamide instead of chemo
184
Lenolidamide MOA
Thalidomide analogue
Increases proliferation and activity of Tcells and NK cells, inhibits proinflammatory cytokines, causs delay in tumor growth, inhibits angiogenesis
185
DLBCL
H+E: large centroblast like cells diffusely CD20 positive
Mx:
RCHOP
Polatuzumab vedotin (not on PBS)-Binds to CD79b and releases MMAE to trigger apoptosis
Genes for prognosis:
Good = GCB (Germinal cental B cell)
Bad =ABC (activated B cell)
186
Mosunetuzumab
Bispecific T cell engager (BITE)
Targets CD3 and CD20
Redirects T cells to engage and eliminate malignant B cells
Future area for lymptoma treatment
187
Mx Mantle Cell Lymphoma
Aggressive clinical behavior
Mx:
Venetoclax (BCL2 inhibitor) and Ibrutinib
188
CLL Features
Most common adult leukemia
Features:
- Lymph >5x10^9
- Smear cells on film
- CD5/19/23/20 (T cell and B cell positive)
- HLA DR200
Poor Prognostic factors:
- Del17p13.1
- p53 mutation
189
Smear cells
CLL
190
CLL Mx
Younger patients:
-Ritux +FCR
Unfit patients:
- Ritux +Chlorambucil
- Ibrutinib
Del17p:
-Venetoclax + Rituximab
191
Car T cells
Chimeric Antigen Receptor T cell
CD19 targeted T cells
Genetic therapy where T cells from patients are modifed and re-infused
192
Peripheral T cell Lymphoma (PTCL)
Worse prognosis than B cell NHL
Mx
- Romidepsn (HDACi)
- Pralatrexate
193
Diagnostic criteria for MGUS
- Serum paraprotein <30g/L
- Bone marrow clonal plasma cells <10%
- No end organ damage
194
Diagnostic Criteria for smouldering myeloma
| Asymptomatic
- Serum paraprotein >30g/L and/or bone marrow clonal plasma cells >10%
- No end organ disease
195
Diagnostic criteria for multiple myeloma
| Symptomatic
- Paraprotein in serum and or urine
- Bone marrow clonal plasma cells or Bx proven plasmacytoma
- Any myeloma related organ or tissue impairment
196
Presentation of MM
ROTI (Myeloma-Related Organ or Tissue Damage)
CRAB
- Ca level >0.25 mmol/L above ULN or >2.75 mmol/L
- Renal insufficiency: Cr >173 mmol/L
- Anaemia: Hb 2g/dl below the lower limit of normal or Hb <10 g/dl
- Bone lesions: Lytic lesions or osteoporosis with compression fractures
Plus possibly
Hyperviscosity
Amyloidosis
Bacterial infections (>2 in 12 months)
197
Why is a bone scan sometimes negative in MM
IT is n osteoclastic process not osteoblastic as seen in malignancies
198
Staging for MM based on what factors
B2MG and albumin
199
Renal disease in MM
Cast nephropathy most common
-Tubular disease direct damage to PCT with reduced re-absoprtion of LC
```
Others:
-Monoclonal Ig deosition disease
-Hypercalcemia
Amyloid
0Cryoglobulins
-Fanconi's syndrome
```
200
MM Flow cytometry
CD138, CD19, CD56, kappa and lambda chain expression
201
FBE in MM
Rouleaux, cytopenias, Macrocytosis
202
IgM paraprotein most associated with what
MGUS
Lymphoma
Waldenstrom's Macroglobulinaemia
Rarely ever MM
203
Best test to look for isolated plasmocytoma
PET or sestimibi
204
Bad cytogenetics in MM
Chromosome 13 deletion
Hypodiploidy
T(4:14)
T(14:16)
205
Good cytogenetics in MM
T (11:14) - mutation in cyclin D
206
OVerall risk of progression of MGUS to MM
1%/yr
207
Thalidomide MOA
Blocks angiogenesis
T cell stimulator
Works on protein cereblon
208
Thalidomide SE
```
Constipation
Somnolence
Tremor
Painful neuropathy
Thrombosis
Skin Rash
oedema
```
209
Bortezomib MOA
Proteasome inhibitor
| -Anti-apoptosis genes blocked
210
Mx of Transplant candidate with MM
Induction:
-Cyclophosphamide +Bortezomib+Dxm for 4 months
Melphalan stem cell transplant
Maintainence:
-Steroids + Thalidomide/Lenolidomide
211
Mx of Non-Transplant candidate with MM
Lenolidomide+Dex
OR (VCD)
Bortezomib +Melphalan/Cyclophosphamide +PRed
212
Downsides of melphalan in MM
Not used in Tx eligible patients because:
- Stem cell toxicity
- Slower response rates
- Beware in renal function
- cyclo better toelrated
213
Benefits of Autologous SCT in MM
```
Suitable for patients <70
Most benefit in age <60
Mortality rate 1%
Superior to conventional therapy
Improved survival rates, but not a cure
```
214
Definite indications for autologous SCT in lymphoma
Relapsed NHL
Relapsed HD
Incomplete response to primary therapy in NHL
No indication in refractory disease
215
Allogenic vs autologous SCT in Hodgkins
Allogenic has higher mortality
216
Carfilzomib
Proteasse inhibitor for treatment of MM
| -More effective than Bortezomib in relapsed MM (For second line treatment only right now)
217
Daratumumab
Anti CD38 for MM yet to be approved
218
Elotuzumab
Anti-SLAMF7 (CS1) for MM treatment not yet approved
219
Platelet Function disorder vs Coagulopathy
Platelet Function disorder:
- Mucosal bleeding and petechiae common
- Prolonged bleeding from skin cuts
- Sex equal
Coagulopathy
- Deep haematomas common
- >80% male
220
What is VWF
Plasma protein that mediates initial adhesion of platelets at sites of vascular injury and binds FVIII in the circulation
221
Immunophenotype of reed sternburg cells
Cd15 and cd30
222
Antigen implicated in HITs
Pf4
| Platelet factor 4
