Haematology Flashcards
1
Q
Anticoagulant molecules expressed by the vessel wall
A
Thrombomodulin
Endothelial protein C receptor
Tissue factor pathway inhibitor
Heparans
2
Q
Antiplatelet factors expressed by the vessel wall
A
Prostacyclin
Nitrous Oxide
3
Q
Effects of inflammation which make vessel wall prothrombotic
A
Downregulation of anticoagulant molecules
Upregulation of adhesion moiecules
Expression of tissue factor
Reduced prostacyclin production
4
Q
Effects of stasis (of blood flow) that create a prothrombotic environment
A
Accumulation of activated factors
Promotes platelet adhesion
Promotes leukocyte adhesion and transmigration
Hypoxia produces inflammatory effect on endothelium
5
Q
Causes of stasis (of blood flow)
A
Immobility: surgery, paraparesis, travel
Compression: Tumour, pregnancy
Viscosity: Polycythaemia, paraprotein
Congenital: Vascular abnormalities
6
Q
Clotting factor increased in pregnancy:
A
Factor VIII
7
Q
Bence Jones proteins are Ig…
A
IgG
8
Q
Multiple myeloma is a neoplasia of which cells?
A
Plasma cells (effector B cells)
9
Q
B cell differentiation and maturation (in germinal centre). Name cells starting with antigen activated B cell to mature fully differentiated plasma cell
A
Antigen activated B cell
Centroblast
Plasmablast
Plasma cell
10
Q
The premalignant state of multiple myeloma is…
A
Monoclonal gammopathy of undetermined significance (MGUS)
11
Q
Monoclonal gammopathy of undetermined significance (MGUS) is…
A
The premalignant state of multiple myeloma. It carries most of the key genetic abnormalities of MM such as translocations but the cells do not do much harm. Sit in the bone marrow and secrete.
(The older we are the more likely we have it)
12
Q
Chromosomal abnormalities common in multiple myeloma (2)
A
Translocations between chromosome 14 at locus 32 and an oncogene (seen in 50%)
Deletions of parts of chromosome 13 (seen in 50%)
13
Q
Key clinical features of myeloma
A
Calcium elevated: thirst, bones, moans, stones, groans,
Renal failure (plus amyloidosis and nephrotic syndrome)
Anaemia (and pancytopenia): fatigue, infections
Bones: pain, osteoporosis, osteolytic lesions, wedge compression fractures (back pain), pepper pot skull (more correct: raindrop skull), hyperviscosity syndrome.
Infections
14
Q
Key investigations (and results) for multiple myeloma
A
Serum electrophoresis: Dense narrow band Blood film: Rouleaux Urine: Bence-Jones protein ESR: Very high Bone marrow: >10% plasma cells in bone marrow Monoclonal plasma cells
15
Q
Staging system of multiple myeloma
A
Durie-salmon
16
Q
Criteria for MGUS
A
Monoclonal serum protein 70y)
17
Q
Multiple myeloma:
a) median age at diagnosis
b) Most common in which racial group?
A
65-70
Black people
18
Q
Multiple myeloma immunophenotypes:
a) MM cells are typically positive for
b) MM cells are typically negative for
A
a) CD38, CD138, CD56/58, monotypic cytoplasmic Ig
b) CD19, CD20, surface Ig, light chain restriction
19
Q
Features of “smouldering myeloma”
A
> 10% plasma cells in BM but no CRAB/organ/tissue involvement.
CRAB= raised calcium, renal failure, anaemia, bone pathology
20
Q
Features of myeloma bone disease:
A
Lytic lesions Low bone density Pathological fractures Spinal cord compression (paralysis) Hypercalcaemia (renal failure) Bone pain
21
Q
Explain relationship between multiple myeloma and bone disease
A
Plasma cells secrete cytokines that activate osteoclasts and cytokines that inhibit osteoblasts. Osteoclasts stimulate osteoclasts. So treating myeloma bone disease is very important.
Osteoclast activating: RANK-L, MIP1-alpha, TNFalpha. IL-6, IL-3
Osteoblast inhibiting: Dkk-1, sFRP3, HGF, TGF-beta1, sclerostin
22
Q
Briefly describe pathogenesis of myeloma nephropathy
A
Light chains of paraproteins precipitate in the kidneys, they form a glue and block normal flow. Induces an inflammatory response that leads to kidney failure.
23
Q
Treatment of multiple myeloma
A
Steroids Classical cytostatic drugs e.g. melphalan Proteosome inhbitors IMIDs: e.g. thalidomide Supportive treatment for CRAB
Autologous stem cell transplantation (makes use of high dose melphalan)
24
Q
Mechanism of action of melphalan
A
Alkylating agent (nitrogen mustard type). Adds alkyl group to DNA (guanine) forming crosslinks and therefore blocks DNA replication.
25
Mechanism of action of proteosome inhibitors
Proteosome in the cell degrades damaged/unnecessary proteins into amino acids ready to reenter protein production.
Misfolding of (large proteins happens when you have to fold a large amount of protein. The proteins are non-functional and precipitate easily and clog up the ER killing the cell. The proteins are exported and degraded by the ER. If the proteosome is inhibited you get a backlog of this protein, increasing the chance of it clogging the ER and killing the cell. Also causes a shortage of amino acids to create new protein.
26
Examples of proteosome inhbitors
Bortezomib, carfilzomib, and ixazomib
27
% of multiple myeloma patients with lytic lesions or low bone density
80-90%
28
Features of Waldenstrom's macroglobuinaemia
| Histology, clinical,
AKA lymphoplasmacytoid lymphoma
Increased risk in elderly men
Lymphoplasmacytoid cells produce monoclonal iGM that infiltrates lymph nodes and bone marrow
Weight loss, fatigue, hyperviscosity (visual problems, confusion, CCF, muscle weakness)
29
Treatment of Waldenstrom's macroglobuinaemia
Plasmaphoresis for hyperviscosity
| Chlorambucil, cyclophosphamide and other chemo
30
FBC changes in pregnancy
Mild anaemia (dulutional effect)
Macrocytosis (but beware folate deficiency)
Neutrophilia
Thrombocytopenia (increased platelet size as younger platelets are released)
31
Consequences of iron deficiency in pregnancy
Iron deficiency may cause IUGR, prematurity, postpartum haemorrhage
32
The recommended daily allowance of iron in pregnancy is
30mg
33
WHO recommendations for iron and folate supplementation in pregnancy
60mg iron
| 400mcg folic acid
34
Folic acid should be taken in pregnancy until at least... weeks
12
35
Causes of reduced platelet count in preganancy
Physiological: ‘gestational’/incidental thrombocytopenia (most likely if plt between 100-150)
Pre-eclampsia
Immune thrombocytopenia (ITP)
Microangiopathic syndromes
All other causes: bone marrow failure, leukaemia, hypersplenism, DIC etc.
36
Mangement of ITP in pregnancy
IVIG
Steroids
Anti-D (where Rh-D +ve)
Avoid ventouse delivery due to effect of ITP on baby (bleeding risk)
37
Features of microangiopathic haemolytic anaemia on blood film
Thrombocytopenia
Schistocytes(red cell fragment)
Anaemia
38
Brief pathophysiology of microangiopathic haemolytic anaemia
Formation of a fibrin/platelet mesh in small vessels. Damage to RBCs as they are forced through (form schistocytes)
39
Causes of microangiopathic haemolytic anaemia
```
Autoimune: Thrombotic thrombocytopaenic purpura
Haemolytic uraemic syndrome
DIC
Pre-eclampsia
Eclampsia
```
40
What is HELLP syndrome
A variant of pre-eclampsia. Abbreviation of 3 main characteristics
Hemolysis
Elevated Liver enzymes
Low Platelet count
Usually begins in 3rd trimester
High fetal/infant mortality
41
Causes of thrombocytopenia in pregnancy.
Which are definitively treated by delivery of the baby
TTP
HUS
HELLP
Pre-eclampsia
HELLP
| Pre-eclampsia
42
Coagulation changes in pregnancy (changes in coagulation factors)
```
Factor VIII and vWF increase 3-5 fold
Fibrinogen increases 2 fold
Factor VII increases 0.5 fold
(Factor X)
RESULT IN HYPERCOAGULABLE STATE
```
Protein S falls to half basal
PAI-1 increase 5 fold
PAI-2 produced by placenta
RESULT IN HYPOFIBRINOLYTIC STATE
43
DVT in pregancy is more common on which side
Left
| Because of reduced venous return
44
Risk factors for DVT in pregnancy
```
Hyperemesis/dehydration
Bed rest
Obesity
- BMI>29 3x risk of PE
Pre-eclampsia
Operative delivery
Previous thrombosis/thrombophilia
Age
Parity
Multiple pregnancy
Other medical problems:
-HbSS, nephrotic syndrome
IVF: ovarian hyperstimulation
```
45
Warfarin is most teratogenic in which trimester
1st
46
Complications in pregnancy associated with thrombophilia
```
Fetal growth restriction (IUGR)
Recurrent miscarriage
Late fetal loss
Placenetal abruption
Severe pre-eclampsia
```
Possibly due to impaired placental circulation
47
Heparin and aspirin can prevent complications in pregnancy associated with which thrombophilia?
Antiphospholipid syndrome
| in women with recurrent pregnancy loss
48
Post partum haemorrhage is defined as...
>500ml blood loss
49
Haematological factors affecting risk of post-partum haemorrhage
Dilutional coagulopathy
DIC in abruption
Amniotic fluid embolism
50
DIC in pregnancy can be triggered by...
```
Amniotic fluid embolism
Placental abruption
Retained dead fetus
Preeclampsia (severe)
Sepsis
```
51
Signs associated with amniotic fluid embolism
Sudden onset shivers, vomiting, shock. DIC
52
Haemoglobinopathy associated with hydrops fetalis
Alpha 0 thalassaemia
53
Complications in pregnancy associated with sickle cell disease
```
Fetal growth restriction
Miscarriage
Preterm labour
Pre-eclampsia
Venous thrombosis
```
Increased frequency of vaso-occlusive crises
54
Managament of sickle cell disease in pregnancy
Red cell transfusion (top up or exchange)
Prophylactic transfusion:
reduces number of vaso-occlusive episodes
Not clear whether affects fetal or maternal outcome
Alloimmunisation -extended phenotype: Rh D c E, Kell
55
RBC count in:
a) iron deficiency anaemia
b) Thalassaemia trait
a) Low or normal
| b) Increased
56
Causes of anaemia with low MCV
Iron deficiency
Thalassaemia trait
Anaemia of chronic disease
57
Presence of poikilocytes and anaemia suggests...
Iron deficiency
58
Anisopoikilocytosis and anaemia suggests...
iron deficiency
59
Basophilic stippling and anaemia suggests
Beta thalassaemia trait
Lead poisoning
Alcoholism
Sideroblastic anaemia
60
Neutrophils should contain a maximum of... segments
Five
61
Target cells are also known as
codocytes
62
Presence of target cells suggests
Iron deficiency
Thalassaemia
Hyposplenism
Liver disease
63
Howell-Jolly bodies are seen in
Hyposplenism
64
Causes of a poorly functioning spleen include...
Inflammatory bowel disease
Coeliac disease
Sickle cell disease
SLE
65
B12 is absorbed from the...
terminal ileum
66
Should be measured before starting a transfusion of blood products
Baseline temp, pulse, respiratory rate,BP
67
Most acute transfusion reactions will occur in within the first.... (duration) of a transfusion
15 minutes
68
Probable cause?
| During or soon after transfusion (blood or platelets), rise in temperature of 1 degree, chills, rigors.
Febrile non-haemolytic transfusion reaction
69
Cause of febrile non-haemolytic transfusion reaction
White cells in blood products. The patient forms antibodies against them.
70
Treatment of febrile non-haemolytic transfusion reactions
Have to stop or slow transfusion
Treat with paracetamol
Can restart transfusion
71
Symptoms and signs of acute intravascular haemolysis
Restless, chest/ loin pain, fever, vomiting, flushing, collapse, haemoglobinuria (later)
72
The intravascular haemolysis due to ABO incompatible blood is mediated by....
complement
73
Antibodies involved in intravascular haemolysis
IgM
74
Cause of delayed haemolytic transfusion reaction.
Initially alloimmunisation occurs: the patient develops an immune antibody to the foreign antigen in the product.
Then if they are exposed to it again through another transfusion the antibodies will trigger extravascular haemolysis. The haemolysis is driven by phagocytes.
75
Clinical features of a delayed haemolytic transfusion reaction
```
Increased bilirubin
Increased reticulocytes
Decreased Hb
Haemoglobinuria
Can cause renal failure
May require additional transfusion
```
76
Treatment of delayed haemolytic transfusion reaction
Repeat cross match
Treat renal failure
May require another transfusion
77
3 causes of anaphylactic transfusion reaction
Previous exposure to an antigen, develop IgE antibody and react on next exposure (classically IgA deficiency)
IgE antibody passively transferred by transfusion
Antigen passively transferred by transfusion and patient has IgE antibody
78
Requirements for a diagnosis of transfusion associated circulatory overload
Any FOUR of the following that occur within SIX HOURS of transfusion:
```
Acute respiratory distress
Tachycardia
Increased blood pressure
Acute or worsening pulmonary oedema
Evidence of a positive fluid balance
```
79
What is TR-ALI
Transfusion associated acute lung injury:
Acute dyspnoea with hypoxia and bilateral pulmonary infiltrates during or within 6 hours of transfusion, not due to circulatory overload or other likely causes
80
Pathogenesis of Transfusion associated acute lung injury
Donor anti-leucocyte antibodies (HLA or anti-granulocyte Abs)
Interact with patient’s leucocyte antigens
Aggregates of white blood cells get stuck in the pulmonary small capillaries
Release neutrophil proteolytic enzymes and toxic oxygen metabolites causes lung damage
Mechanism not fully understood, antibodies do not always cause problems
81
How do we prevent transfusion associated acute lung injury?
Don’t give plasma from female donors:
Most FFP is male donor
If platelets are pooled from 4 donors, the plasma they are resuspended in is from a male donor
Virally inactivated FFP (pooled, solvent detergent treated) does not cause TRALI
Stop unnecessary use of FFP:
Use vitamin K or PCC/Octaplex for reversing warfarin
82
Which group of patients are most susceptible to transfusion related GvHD and how is it prevented?
Immunosupressed patients
or
If donor HLA matched or HLA-similar to the recipient
Prevention: Irradiate donor blood
83
What is Post Transfusion Purpura?
Purpura appears 7-10 days after transfusion of blood or platelets and usually resolves in 1 to 4 weeks but can cause life threatening bleeding
Affects HPA -1a negative patients
(HPA is human platelet antigen)
84
Treatment of post transfusion purpura
IVIG
| and maybe HPA-1a negative platelets
85
Pathogenesis of haemolytic disease of the foetus and newborn
RhD negative mother pregnant with RhD positive foetus, foetal blood crosses placenta.
Mother develops antibodies against RhD 6 months later
Pregnant again with RhD positive foetus, the antibodies against RhD cross placenta into the foetus.
The antibodies coat the RhD positive foetal red cells and destroy them in the foetal spleen and liver.
Note: only IgG can cross placenta
86
Clinical features of haemolytic disease of the foetus and newborn
Fetal anaemia (haemolytic)
Haemolytic disease of newborn (anaemia plus high bilirubin - which builds up after birth as no longer removed by placenta)
87
Treatment of pregnancy when mother is alloimmunised to RBC antigens
All pregnant women Group and Antibody screen at around 11 weeks (booking) and again at 28 weeks to check for RBC antibodies
If RBC antibody present, quantify, check partner and monitor level of antibody (high or rising - more likely to affect fetus)
Monitor fetus for HDN – MCA Doppler ultrasound
Deliver baby early, as HDN gets a lot worse in last few weeks of pregnancy
If necessary, intra-uterine transfusion can be given to fetus
At delivery - monitor baby’s Hb and bilirubin for several days as HDN can get worse for few days
Can give exchange transfusion to baby if needed to bilirubin and Hb; plus phototherapy to bilirubin
Note: subsequent pregnancies usually worse
88
Mechanism of action of prophylactic anti-D Immunoglobulin
RhD positive (fetal) red cells get coated with anti-D Ig and then they get removed by the mother’s reticuloendothelial system (spleen) before they can sensitise the mother to produce anti-D antibodies
89
Times when fetomaternal bleed likely to occur
spontaneous miscarriages if surgical evacuation needed and therapeutic abortions
amniocentesis and chorionic villous sampling
abdominal trauma (falls and car accidents)
external cephalic version (turning the fetus)
stillbirth or intrauterine death
90
Doses of anti-D used after events likely to cause fetomaternal bleed
At least 250 iu - for events before 20 weeks of pregnancy
At least 500 iu - for events after 20 weeks of pregnancy
and at delivery
91
Doses (and timing) of anti-D given as prophylaxis during pregancy
At least 500 iu anti-D Ig at 28 and 34 weeks or 1500 iu anti-D Ig at 28-30 weeks
92
Antibodies that can cause severe haemolytic disease of the newborn
Anti-D
Anti-c
Anti-Kell
93
Effects of anti-Kell antibodies on a foetus
Haemolysis
| Reticulocytopenia
94
Risk factors for lymphoma
Constant antigenic stimulation
Infection (viral infection of cells)
Immunosupression (HIV and immunosupressants)
95
Examples of conditions in which chronic antigenic stimulation leads to lymphoma
H. Pylori: Gastric MALT
Coeliac disease: Small bowel T cell lymphoma
Sjogren's syndrome: Parotid lymphoma
Hashimoto's thyroiditis: Thyroid marginal zone lymphoma
96
Viral infections that increase lymphoma risk
EBV infects B cells, carrier state regulated by T cells. T cells supressed by immunosupressants.
HIV: EBV infects B cells, HIV leads to loss of T cell regulation of infected B cells
HTLV1: Direct viral integration. Infects T cells by vertical transmission. May develop adult T cell leukaemia
97
Lymphoma associated translocations involve which locus
Ig promoter
98
Within a lymohoid follicle the mantle zone contains...
Naive unstimulated B cells
99
Most common type of non-hodgkin lymphoma
B cell
100
Types of Hodgkin lymphoma
Classical
| Lymphocyte predominant
101
Types of Non-Hodgkin lymphoma
B cell
Precursor B cell neoplasms
Peripheral B cell neoplasms (high and low grade)
T cell
Precursor T cell neoplasms
Peripheral T cell neoplasms
102
Types of lymphoma that begin in the germinal centre
Follicular lymphoma
Burkitt's lymphoma
Diffuse large B cell lymphoma
Hodgekin lymphoma
(also multiple myeloma)
103
Types of lymphoma that begin in the mantle centre
Mantle cell lymphoma
104
Types of lymphoma that begin in the marginal zone
Diffuse large B cell lymphoma
Marginal zone lymphoma
Small lymphocytic lymphoma
Chronic lymphocytic lymphoma
105
Differentiating between B and T cells. B cells express CD... T cells express CD...
B cells: CD20
| T cells: CD3 and CD5
106
High grade non-hodgkin lymphomas
Diffuse large B cell lymphoma
107
Low grade non-hodgkin lymphomas
Follicular lymphoma
Marginal zone lymphoma
Mantle zone lymphoma
Small lymphocytic lymphoma/chronic lymphocytic leukaemia
108
Key clinical features of follicular lymphoma
Middle age/ old age
| Lymphadenopathy
109
Key histological features of follicular lymphoma
Follicular pattern
Germinal centre origin
CD10, bcl2
110
Translocation seen in follicular lymphoma
14;18 translocation involving bcl2 gene
111
Key clinical features of small lymphocytic lymphoma
Middle age/ elderly
| Nodes or blood
112
Key histological features of small lymphocytic lymphoma
Small lymphocytes
Naive or post germinal centre memory B cell
Express CD5 and CD23
113
MALT lymphoma affects which cells
Post germinal centre memory B cells
114
Key clinical features of mantle cell lymphoma
Male predominance
Lymph nodes and GI tract
Disseminated disease at presentation
115
Key histological features of mantle cell lymphoma
Located in mantle zone
Pre-germinal centre naive B cells
Aberrant CD5 and cyclin D1 expression
Cyclin D1 overexpression
116
Clinical features of Burkitt's lymphoma
Seen in children and young adults
Endemic type (equatorial Africa, EBV associated)
Sporadic type (outside Africa, EBV associated),
Immune deficiency type (Non-EBV associated, HIV/post transplant)
Associated with EBV
117
Key histological features of Burkitt's lymphoma
Germinal centre cell origin
| Starry sky appearance
118
Translocation seen in Burkitt's lymphoma
c-myc translocations
8: 14
2: 8
8: 22
119
Key clinical features of diffuse large B cell lymphoma
Middle age/ elderly
| lymphadenopathy
120
Key histological features of diffuse large B cell lymphoma
Germinal centre or post-germinal centre B cell
Sheets of large lymphoid cells
Germinal centre phenocyte= good prognosis
P53 positive, high proliferation fraction= poor prognosis
121
Enteropathy associated T cell lymphoma is associated with...
Coeliac disease
122
Features of peripheral T cell lymphomas
```
Middle age/ elderly
Lymphadenopathy and extranodal sites
Large T cells
Often associated with reactive cell population e.g. eosinophils
Aggressive
```
123
Most common form of cutaneous T cell lymphoma
Mycosis fungoides
| also known as Alibert-Bazin syndrome
124
Key features of anaplastic large cell lymphoma
Clinical:
children and young adults
Lymphadenopathy
Histology
Large epithelioid lymphocytes
T cell or null phenotype
Molecular
t (2;5) translocation
Alk-1 protein expression (better prognosis if positive)
Aggressive
125
Key differences between Hodgkin and NH lymphoma
Spread:
Hodgkin spreads contigiously to adjacent lymph nodes
NHL spreads discontinuously
Locations:
HL: more often localised to a single nodal site
NHL: More often involves multiple lymph node sites
126
Key clinical features of classical Hodgkin lymphoma
```
Young and middle aged
Male predominance
Often involves single lymph node group
EBV associated
Moderately aggressive
```
127
Key histological features of classical Hodgkin lymphoma
Germinal centre/post germinal centre B cell origin
Sclerosis
Mixed cell population with scattered Reed-Sternberg and Hodgkin cells with eosinophils
128
Key clinical features of nodular lymphocyte predominant Hodgkin lymphoma
Isolated lymphadenopathy
| NO association with EBV
129
Key histological features of nodular lymphocyte predominant Hodgkin lymphoma
Germinal centre B cell
| B cell rich nodules with lymphocytic & histiocytic cells
130
Clinical features/presentation of Hodgkin lymphoma
```
Male predominance
Bimodal age incidence: 20-29 and >60
Painless lymphadenopathy (asymmetrical)
Constitutional symptoms: fever, weight loss, night sweats, pruritus, fatigue
Pel-Ebstein fever (cyclical 1-2 week)
Pain in affected nodes after alcohol
```
131
Staging of Hodgkin lymphoma
Stage 1: one lymph node region (can include spleen)
Stage 2: two or more LN regions on same side of diaphragm
Stage 3: two or more LN regions on opposite sides of the diaphragm
Stage 4: extranodal sites (liver, BM)
A: No constitutional symptoms (fever, unexplained weight loss, night sweats)
B: Constitutional symptoms
132
What is a Reed-sternberg cell
Bi-nucleate/multinucleate (owl eyed) cell on a background of lymphocytes and reactive cells.
Associated with Hodgkin Lymphoma
133
Imaging used in Hodgkin lymphoma
CT/PET
134
Chemotherapeutic combination used in Hodgkin lymphoma
Adriamycin (doxorubicin)
Bleomycin
Vincristine
Dacarbazine/DTIC
Every 4 weeks
135
Long term adverse affects of chemotherapy used to treat Hodgkin lymphoma
Pulomary fibrosis
Cardiomyopathy
(Preserves fertility)
136
Secondary malignancies seen after radiotherapy for Hodgkin lymphoma
Breast
Leukaemia
Lung
Skin
137
Hodgkin lymphoma:
Over...% of patients with stage 1 or 2 disease are cured
Around.... % of patients with stage 4 are cured
80%
| 50%
138
Clinical features/presentation of NH lymphoma
Painless lymphadenopathy often involving multiple sites
Constitutional symptoms (fever, weight loss, night sweats, etc)
NO pain after alcohol
139
Very aggressive Non-hodgkin lymphomas
Burkitt's
140
Treatment of diffuse large B cell lymphoma
```
Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisolone
```
141
Follicular Non-Hodgkin lymphoma prognosis
Incurable
| Survival median 12-15 years (with chemo)
142
What is bcl2?
Anti-apoptosis protein
143
Laboratory findings in CLL
Lymphocytosis between 5 and 300 x 109/l
Smear cells
Normocytic normochromic anaemia
Thrombocytopenia
Bone marrow: Lymphocytic replacement of normal
marrow elements
Proliferation of mature B cells (CD19) co-expressing CD5
144
CD35 expressed by which type of B cell
Plasma cell
145
Name 2 systems used for staging CLL
Rai
| Binet
146
Outline Rai staging system
Used to stage CLL
Stage 0 Lymphocytosis only
Stage 1 lymphocytosis plus lymphadenopathy
Stage 2 lymphocytosis plus hepatosplenomegaly +/- lymphadenopathy
Stage 3 lymphocytosis plus anaemia with or without lymphadenopathy, hepatomegaly, or splenomegaly
Stage 4 lymphocytosis + thrombocytopenia
147
Prophylaxis against infections in CLL patients
Aciclovir
PCP prophylaxis for those receiving fludarabine or alemtuzumab (Campath)
IVIG is recommended for those with hypogammaglobulinemia and recurrent bacterial infections
Immunisation against pneumococcus, and seasonal flu
148
50% of CLL deaths are due to
Infection
149
Treatment of autoimmune phenomena in CLL
1st line: steroids
| 2nd line: Rituximab
150
Indications for treating CLL (instead of watching and waiting)
Progressive lymphocytosis:
>50% increase over 2 months
lymphocyte doubling time
151
Treatment of CLL with 17p deletion
BCR kinase inhibitor
152
Treatment of CLL (if not 17p deletion)
Rituximab+ Fludarabine+ Cyclophosphamide (FCR)
Add bendamustine and BCR inhibitor of relapse
153
Transformation of low grade to high grade lymphoma is known as
Richter transformation
154
Treatment of Richter's syndrome
```
Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisolone
```
155
Outline Binet staging system
Clinical staging system for CLL
A: Less than 3 lymphoid areas
B: More than 3 lymphoid areas
C: Anaemia / low platelets
156
Causes of a relative polycthaemia
Alcohol
Diuretics
Obesity
157
Causes of APPROPRIATE raised EPO
High altitude
Hypoxic lung disease
Cyanotic heart disease
High affinity haemoglobin
158
Causes of INAPPROPRIATE raised EPO
```
Renal disease (cysts, tumours inflammation)
uterine myoma
other tumours (liver, lung1)
```
159
Mutations associated with polycythaemia vera
```
JAK2 gene (acquired point mutations)
Calreticulin gene (acquired insertions and deletions, which activate STAT5 by unknown mechanism)
```
160
Average age of polycythaemia vera diagnosis
60
| Also slightly more common in males
161
Presentation of polycythaemia vera
Incidental diagnosis on routine blood testing
Symptoms of increased hyper viscosity:
Headaches, light-headedness, stroke, Thrombosis, retinal vein engorgement
Visual disturbances
Fatigue, dyspnoea
Increased histamine release:
Aquagenic pruritus
Severe burning pain in the hands and feet with a reddish or bluish skin discolouration
Peptic ulceration
Plethora
Gout: due to red cell turnover and overproduction of uric acid
Splenomegaly
162
Treatment of polycythaemia
Reduce viscosity: venesection, hydroxycarbamide
| Reduce risk of thrombosis: aspirin (keep platelets below 400)
163
Epidemiology (age and sex) of polycythaemia vera
Mean age two peaks 55 years and minor peak 30 years
| Females :males equal first peak but females predominate second peak
164
Presentation of essential thrombocythaemia
Incidental finding in half the patients
Thrombosis: arterial or venous, so:
CVA, gangrene, TIA
DVT or PE
Bleeding: mucous membrane and cutaneous
Minor: headaches, dizziness visual disturbances
Splenomegaly usually modest
165
Treatment of essential thrombocythaemia
Aspirin: to prevent thrombosis
Anagrelide: specific inhibition of platelet formation from megakaryocytes, side effects include palpitations and flushing (Possible myelofibrosis risk?)
Hydroxycarbamide: antimetabolite. Suppression of other cells as well. Possible mildly leukaemogenic
166
Essential thrombocythaemia is associated with mutation of...
JAK2 gene
167
Long term complications of essential thrombocythaemia
Risk of myelofibrosis development
| Leukaemic transformation in about 5% after >10 years
168
Chronic idiopathic myelofibrosis involves proliferation of which cells?
Mainly of megakaryocytes and granulocytic cells
169
Myelofibrosis can be secondary. A progression from
Essential thrombocythaemia or polycythaemia vera
170
Myelofibrosis (idiopathic) usually develops at what age
7th decade
171
Classical triad of Budd-Chiari syndrome
Abdominal pain
Ascites
Liver enlargement
172
Presentation of idopathic myelofibrosis
Incidental in 30%
```
Cytopenias: anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: may be massive
Budd-Chiari syndrome
Hepatomegaly
```
```
Hypermetabolic state:
Weight loss
Fatigue and dyspnoea
Night sweats
Hyperuricaemia
```
173
Budd-Chiari syndrome is caused by....
Occlusion of the hepatic vein
174
Investigations and diagnosis of myelofibrosis
Blood film: tear-drop poikilocytes (dacrocytes) and leukoerythroblasts.
Giant platelets
Circulating megakaryocytes
Bone Marrow: dry tap
Trephine biopsy:
Increased reticulin/collagen fibrosis. Megakaryocyte hyperplasia and clustering. New bone formation.
Liver and spleen:
Extramedullary haemopoiesis in spleen and liver
175
Treatment of myelofibrosis (and problems)
Blood products:
Platelet transfusions often ineffective
Splenomegaly makes RBC transfusions increasingly difficult
Splenectomy: often hazardous and can lead to worsening of the condition
Hydroxycarbamide: may lead to worsening of anaemia
Ruxolotinib: a JAK2 inhibitor
, thalidomide, steroids,
allogenic stem cell transplant: may be curative. Young patients only. Experimental.
176
Key features of pre-fibrotic and fibrotic stage of myelofibrosis
Pre-fibrotic: blood changes mild and may be confused with essential thrombocythaemia. Hypercellular marrow.
Fibrotic: Splenomegaly and blood changes. Dry BM tap. Prominent collagen fibrosis. Later Osteosclerosis
177
Ruxolotinib is...
JAK 2 inhibitor.
| Used in myelofibrosis
178
Clinical features of CML
M:F 1.4:1
* 40-60 years
* Weight loss, lethargy, night sweats
* Splenomegaly
* Features of anaemia
* Bruising/bleeding
* Gout
179
Stages of maturation from blast cell to neutrophil
Myeloblast, promyelocyte, metamyelocyte, Band cell, neutrophil
180
Laboratory features of CML
```
•Leucocytosis between 50 – 500x109/l
Mature myeloid cells
Bi phasic peak Neutrophils and myelocytes
Basophils
No excess (
```
181
Genetic mutation found in large proportion of CML patients
translocation 9;22
Translocation of part of long arm of chromosome 22 to chromosome 9 and reciprocal translocation of part of chromosome 9 to chromosome 22.
The latter involves transfer of the ABL oncogene to a breakpoint cluster (BCR) region of chromosome 22. This creates the Philadelphia chromosome, and leads to creation of a fusion gene that leads to synthesis of abnormal ABL protein with tyrosine kinase activity higher than normal.
182
Phases of CML
Chronic phase
Accelerated phase
Blast phase
183
% of blood and BM made up of blast cells in CML:
Chronic phase
Accelerated phase
Blast phase
10%
| >20%
184
Duration of CML chronic phase (natural history)
Months to 4-5 years
185
1st generation tyrosine kinase inhibitor
Imatinib
186
2nd generation tyrosine kinase inhibitor
Dasatanib, and Nilotinib
187
Treatment of CML chronic phase
Disease control: Imatinib 1st line
2nd line: dasatinib/nilotinib.
Potential cure with stem cell transplantation (usually young people)
Reduce symptoms with chemotherapy with: hydroxyurea, busulfan, omacetaxine, or interferon alpha with or without cytarabine. These used to be used for disease management, shorter chronic phase than with imatinib.
188
In context of CML what is a complete cytogenic response?
0% philadelphia chromosome positive cells on cytogenic analysis (20 metaphases)
189
Side effects imatinib
fluid retention
| pleural effusions
190
What is Pelger-Huet anomaly?
dumbel shaped bilobed neutrophils. Associated with lamin B receptor
191
Myelokathexis is...
Congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The neutrophils are retained in the bone marrow.
The disorder is believed to be inherited in an autosomal dominant manner.
192
What is congenital dyserythropoietic anaemia?
Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood.
There are 4 types
193
What is sideroblastic aneamia
In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need to transport oxygen efficiently.
Ring sideroblasts are named so because iron-laden mitochondria form a ring around the nucleus. To count a cell as a ring sideroblast, the ring must encircle a third or more of the nucleus and contain five or more iron granules
194
What are Auer rods?
Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts
195
List subtypes of myelodysplastic syndrome (WHO classificiation)
Refractory anaemia without ringed sideroblasts
Refractory anaemia with ringed sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
Refractory anaemia with excess of blasts 1
Refractory anaemia with excess of blasts 2
5q deletion syndrome/myelodysplastic syndrome with 5q deletion
Myelodysplastic syndrome unclassified: MDS with fibrosis, childhood MDS, others
196
Refractory anaemia without ringed sideroblasts
Blood features
Bone marrow features
Anaemia and no blasts
Erythroid dysplasia with
197
Refractory anaemia with ringed sideroblasts
Blood features
Bone marrow features
Anaemia and no blasts
Erythroid dysplasia with over 15% ringed sideroblasts
Less than 5% blasts
198
Refractory cytopenia with multinlineage dysplasia
Blood features
Bone marrow features
Cytopenia in 2 or more cell lines
Dysplasia in over 10% cells in over 2 cell lines
Less than 5% blasts
199
Mean age of onset of myelodysplastic syndromes
68 years
200
Refractory cytopenia with multinlineage dysplasia and ringed sideroblasts
Blood features
Bone marrow features
Cytopenia in 2 or more cell lines
Dysplasia in over 10% cells in over 2 cell lines
Over 15% ringed sideroblasts
Less than 5% blasts
201
Refractory aneamia with excess blasts 1
Blood features
Bone marrow features
Cytopenias, less than 5% blasts, no Aeur rods
Dysplasias and 5-9% blasts
202
Refractory anaemia with excess blasts 2
Blood features
Bone marrow features
Cytopenias or 5-19% blasts, or Aeur rods.
Dysplasias, 10-19% blasts or Aeur rods
203
Myelodysplastic syndrome with 5q deletions
Blood features
Bone marrow features
Anaemia, normal or increased platelets.
Megakaryocytes with hypolobulated nuclei and less than 5% blasts
204
Myelodysplastic syndrome unclassified
Complex- cytopenias, no Aeur rods, no blasts
Complex- myeloid or megakaryocytic dysplasia, less than 5% blasts
205
Causes of death among patients with myelodysplastic syndromes
1/3 die from infection
1/3 die from bleeding
1/3 die from acute leukaemia
206
Myelodysplastic syndromes develop into... in half of patients
AML
207
Treatment of myelodysplastic syndromes
Prolonging survival:
Stem cell transplant
Intensive chemotherapy
Supportive care:
Blood product support
Antimicrobial therapy
Growth factors (Epo, G-CSF)
Biological modifiers
Immunosuppressive therapy
Azacytidine
Lenalidomide
Oral chemotherapy:
Hydroxycarbamide
Low dose chemotherapy:
Subcutaneous low dose cytarabine
Intensive chemotherapy/ stem cell transplant
AML type regimens
Allo/VUD standard/ reduced intensity
208
All patients with myelodysplastic syndromes have less than....% blasts
20%
| Over 20% is acute leukaemia
209
Clinical features of myelodysplastic syndromes
```
BM failure and cytopenias with expected effects (infection, bleeding, fatigue)
Hypercellular BM
Defective cells e.g.:
Ring sideroblasts (RBC)
Hypogranulation (in WBC)
Micromegakaryocytes
```
210
Which type of myelodysplastic syndrome affects platelets
MDS with 5q deletion
211
Which type of myelodysplastic syndrome affects WBCs
Refractory cytopenia with multilineage dysplasia
212
Basic classification of aplastic anaemia
Severe aplastic anaemia (SAA)
| Non-severe aplastic anaemia (NSAA)
213
Camitta criteria for SEVERE aplastic anaemia
2 out of 3 peripheral blood features
An absolute neutrophil count (ANC) of less than 0.5×109/L
A platelet count (PLT) of less than 20×109/L,
A corrected reticulocyte count (CRC) of less than 1%.
214
Specific (non-supportive) treatment of idiopathic aplastic anaemia
Based on:
Severity of illness
Age of patient
Potential sibling donor
```
A. Immunosuppressive therapy – older patient
Anti-Lymphocyte Globulin (ALG)
Ciclosporin
B. Androgens – oxymethalone
C. Stem cell transplantation
Younger patient with donor (80% cure)
VUD/MUD for > 40 yrs (50% survival)
```
215
Late complications following immunosuppressive treatment for aplastic anaemia
1. Relapse of AA (35% over 15 yrs)
2. Clonal haematological disorders
Myelodysplasia
Leukaemia
~ 20% risk over 10 yrs
PNH (paroxysmal nocturnal haemoglobinuria)
May be a transient phenomenon
3. Solid tumours ~ 3% risk
216
Which patients with aplastic anaemia have immunosuppressive therapy
Older patients
217
Most common form of inherited aplastic anaemia
Fanconi anaemia
218
Mode of inheritance of Fanconi anaemia
X-linked or autosomal recessive
219
Genes responsible for Fanconi anaemia contribute to...
Genomic stability
220
Androgen used in aplastic anaemia
Oxymethalone
221
Age of onset of pancytopenia in Fanconi anaemia
5-10 years
222
10% of Fanconi anaemia cases terminate in...
Acute leukaemia
223
Features of Fanconi anaemia include pancytopenia and...
```
Short Stature
Hypopigmented spots and café-au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hyogonadism
Developmental delay
```
(Congenital malformations may occur in 60-70% of children with FA)
224
% of patients with Fanconi anaemia who develop aplastic anaemia
90%
225
% of patients with Fanconi anaemia who develop myelodysplasia
32% (30% approx)
226
Complications of Fanconi anaemia
```
Aplastic anaemia
Myelodysplasia
Leukaemia
Liver disease
Epithelial cancer
```
227
Skin pigmentation
Nail dystrophy
Leukoplakia
A classical triad seen in....
Dyskeratosis congenita
Also get BM failure!!
228
Features of dyskeratosis congenita
Classical triad:
Nail dystrophy
Leukoplakia
Skin pigmentation
BM failure (85%)
229
What it dyskeratosis congenita
Inherited disorder characterised by:
Marrow failure
Cancer predisposition
Somatic abnormalities
Classical triad of:
Hairy leukoplakia
Skin pigmentation
Nail dystrophy
85% get BM failure
230
Somatic abnormalities/complications of dyskeratosis congenita
```
Epiphora
Learning difficulties/development/mental retardation Pulmonary disease
Short stature
Extensive dental caries/loss
Oesophageal stricture
```
Malignancy
Intrauterine growth retardation
Liver disease/peptic ulceration/enteropathy
Ataxia Hypogonadism/undescended testes
Microcephaly
Urethral stricture/phimosis
Osteoporosis/aseptic necrosis/scoliosis
231
Mode of inheritance of dyskeratosis congenita
X-linked
Autosomal dominant
Autosomal recessive
232
The genes involved in dyskeratosis congenita
DKC1 gene which results in defective telomerase function
TERC gene, which encodes the RNA component of telomerase
Additional recessive unidentified gene
233
Dyskeratosis congenita has 3 patterns of inheritance. All affect...
Telomeric structure and function
234
Management of severe aplastic anaemia: 1st line if:
a) acquired/idiopathic
b) Inherited/constitutional
a) Sibling stem cell transplant if under 40
Immunosuppressive therapy if over 40
b) Oxymethalone
235
Drugs used for immunosuppressive therapy in aplastic anaemia
Anti-Lymphocyte Globulin (ALG)
| Ciclosporin
236
Philadelphia chromosome positive myeloproliferative disorder
CML
237
Bone marrow maximum tolerated irradiation dose
12Gy
238
Autologous bone marrow transplant can be used to treat
Acute leukaemia
Lymphoma
Solid tumours
239
BMT: After infusion of stem cells engraftment takes and immune recovery takes...
14-28 days
| 6-12 months
240
Organs affected by acute GvHD
skin, gastrointestinal tract and liver
241
Organs affected by chronic GvHD
skin, mucosal membranes, lungs, liver, eyes, joints
242
Risk factors for GvHD
```
Degree of HLA disparity
Recipient (and donor) age (older=higher risk)
Conditioning regimen
R/D gender combination
Stem cell source
Disease phase (late is worse)
Viral infections
```
243
Treatments for GvHD
```
Corticosteroids
Cyclosporin A
FK506
Mycophenylate mofetil
Monoclonal antibodies
Photopheresis
Total lymphoid irradiation
```
244
Donor lymphocyte infusions induce remission via process called...
Graft vs tumour effect
245
Donor lymphocyte infusions are used when?
Patient has relapsed after a bone marrow transplant.
246
A non-myeloablative haematopietic stem cell transplant involves...
Preparative regiment followed by
Stem cell transplant followed by
Donor lymphocyte infusion
247
HLA genes are found on which chromosome
6 (short arm)
248
Disadvantages of using unrelated donor for stem cell transplant (compared to sibling)
```
Rejection+++
GvHD+++
More toxicity+++
Delayed immunoreconstitution +++
All worse than with sibling transplant
```
249
What are killer-cell immunoglobulin-like receptors (KIRs)?
Transmembrane receptors expressed on the surface of NK cells and a minority of T cells. They interact with MHC class 1 molecules and can differentiate between allelic variants. This allows them to recognise virally infected or transformed cells. They regulate the activity of their cells.
Most are inhibitory. Recognition of a healthy self cell leads to inhibition of of the NK cell cytolytic function.
250
Advantage of BMT from donor with alloreactive NK cells
Alloreactive NK cells won't be recognised by host KIRs (and therefore won't be inhibited). Advantages:
Alloreactive NK cells kill patient’s DC thus preventing priming of allogeneic T cells and, thus, GvHD
Alloreactive NK cells kill patient’s T lymphocytes. This facilitates engraftment
Alloreactive NK cells kill leukaemic cells. This may reduce leukaemic relapse.
251
Role of host dendritic cells in GvHD
Prime donor T cells (after initial tissue damage)
252
Leukaemia
| Features of bone marrow failure
Anaemia: fatigue, pallor, breathlessness
Neutropenia: infections
Thrombocytopenia: bleeding
253
AML epidemiology (key points)
Increases with age
Prognosis worse with increasing age
40% of adults cured
254
Chromosomal inversion inv(16)/t(16;16) is found in which condition
AML
| Good prognosis
255
Risk factors for AML
Familial or constitutional predisposition
Irradiation
Anticancer drugs
Cigarette smoking
256
The 2 types of genetic abnormality seen in acute leukaemia
Type 1 abnormalities
promote proliferation & survival
```
Type 2 abnormalities
block differentiation (which would normally be followed by apoptosis)
```
257
Examples of genetic abnormalities that lead to core binding factor leukaemias
Special feature of these leukaemias
Translocation 8;21
Inv(16)
There is some maturation. Not all cells produced are blasts
258
Core binding factor is...
dimeric transcription factor
| master controller of haematopoiesis
259
Genetic abnormality found in 12% of adult AML
Inv(16) , t(16;16)
260
```
Key features of acute promyelocytic leukaemia
Including genetic abnormality
Key presenting feature
Key features of affected cells
Treatment
```
* The retinoic acid receptor alpha gene (RARA) on chromosome 15 is translocated (reciprocally) with the promyelocytic leukaemia (PML) gene on chromosome 17. The translocation is denoted as t(15; 17)(q22;q21).
* The fusion gene produced binds with strong affinity to DNA blocking transcription and differentiation of granulocytes (stops maturation at later stage than other acute leukaemias).
* There is an excess of promyelocytes, which contain large granules that can be released into peripheral blood.
* Often patients present with DIC
* Myeloblasts seen in peripheral blood:
* Large cells with large nucleus and relatively little cytoplasm
* Nucleoli present
* Sets of granules forming elongated needles (Auer rods) that are only seen in myeloblasts
* The initial translocation initiates the process but additional mutations are needed for leukaemia to develop.
* Can treat with retinoic acid
261
Treatment pf acute promyelocytic leukaemia
Retinoic acid
262
Genetic abnormality seen in 90% of patients with promyeloctyic leukaemia
t(15; 17)(q22;q21).
263
Clinical features of AML
Bone marrow failure:
Anaemia
Neutropenia
Thrombocytopenia
```
Local infiltration:
Splenomegaly
Hepatomegaly
Gum infiltration (if monocytic)
Lymphadenopathy (only occasionally)
Skin, CNS or other sites
```
Hyperviscosity if WCC is high:
retinal haemorrhages and exudates
264
AML:
| CNS disease is more common with...
Monocytic differentiation
265
AML:
Cytogenic studies, molecular studies and FISH. Which applies to all patients?
Cytogenic studies
266
Treatment of AML
Supportive care
Red cells
Platelets
Fresh frozen plasma/ cryoprecipitate if DIC
Antibiotics
Long line
Allopurinol, fluid and electrolyte balance
Chemotherapy
267
Basis of selective toxicity in AML chemotherapy
Normal stem cells:
often quiescent
checkpoints allow repair of DNA damage
Leukaemia cells:
continuously dividing
lack of cell cycle checkpoint control
268
Why have results of treatment of AML improved?
Better supportive care
Identification of bad prognosis groups for more intensive treatment (more intensive chemotherapy or transplantation)
Specific treatment for acute promyelocytic leukaemia
269
ALL epidemiology
Peak incidence in childhood
Most common childhood malignancy
85% of children cured
Prognosis worse with increasing age
270
Clinical features of ALL
Bone marrow failure:
Anaemia
Neutropenia
Thrombocytopenia
```
Local infiltration:
Lymphadenopathy (± thymic enlargement)
Splenomegaly
Hepatomegaly
Testes, CNS, kidneys or other sites
Bone (causing pain)
```
Lymohadenopathy, CNS infiltration and testicular infiltration more common than in AML
271
ALL features in peripheral blood
```
Peripheral blood
Anaemia
Neutropenia
Thrombocytopenia
Usually lymphoblasts
```
272
ALL features in bone marrow
Lymphoblast infiltration
| Lymphoblasts may be B-lineage or T-lineage
273
Impact of translocation t(9;22) on ALL treatment
t(9;22) — improved prognosis with tyrosine kinase inhibitors e.g. imatinib
274
Example of tyrosine kinase inhibitor
Imatinib
275
Imatinib is a...
Tyrosine kinase inhibitor
276
Treatment of ALL (general principles)
Specific therapy:
systemic chemotherapy
CNS-directed therapy
Supportive care:
blood products
antibiotics
general medical care
277
Supportive treatment used in ALL
Central venous catheter
Red blood cell and platelet transfusions
Broad spectrum antibiotics for fever
Prophylaxis for Pneumocystis jirovecii infection
Hyperuricaemia: hydration, urine alkalinization and allopurinol or rasburicase
Hyperphosphataemia; aluminum hydroxide, calcium
Hyperkalemia: fluids, diuretics
Extreme leukocytosis (WBC > 200 × 109/l): leukapheresis
Sometimes haemodialysis
278
3 (unique) Causes of polycythaemia in neonates
Twin-to-twin transfusion
Intrauterine hypoxia
Placental insufficiency
279
Unique causes of anaemia in the neonate
Twin-to-twin transfusion
Fetal-to-maternal transfusion
Parvovirus infection (virus not cleared by immature immune system)
Haemorrhage from the cord or placenta
280
Congenital leukaemia is particularly common in
Down syndrome
Note: This specific type of neonatal leukaemia (also sometimes called transient abnormal myelopoiesis or TAM) differs greatly from leukaemia in older infants or children
281
Key features of neonatal leukaemia
The leukaemia is myeloid with major involvement of the megakaryocyte lineage
It usually remits spontaneously and relapse one to two years later occurs in only about a quarter of infants
282
FBC:
| Newborn babies, in contrast to adults, have...
Higher Hb
283
Globin chains that form:
HbA
HbA2
HbF
α2β2
α2δ2
α2γ2
284
HbSS
| Red cells become sickle shaped in what sitatuon
Hypoxic conditions
285
Which type of marrow is more susceptible to infarction in sickle cell disease?
Red marrow
286
Sickle cell anaemia:
| Why does splenic sequestration not occur commonly i older children and adults
Recurrent infarction has left the spleen small and fibrotic
287
Cause of hyposplenism in sickle cell anaemia
Recurrent infarction has left the spleen small and fibrotic reducing its ability to filter out bacteria and parasites.
288
Why does folic acid matter more in a child with sickle cell disease than in a normal child or an adult?
Hyperplastic erythropoiesis requires folic acid
Growth spurts require folic acid
Red cell life span is shorter so anaemia can rapidly worsen
289
When does beta thalassaemia manifest (age)?
First 3‒6 months of life
290
Clinical effects of poorly treated thalassaemia major
Anaemia leadfing to heart failure, growth retardation
Erythropoietic drive leading to bone marrow expansion, hepatomegaly, and splenomegaly
Iron overload leading to heart failure, gonadal failure
291
Most inherited haemolytic anaemias are due to defects in...
Red cell membrane
Haemoglobin molecule
Red cell enzymes—glycolytic pathway
Red cell enzymes—pentose shunt
292
Haemolytic anaemias in children:
Red cell membrane defects
Hereditary spherocytosis
Hereditary elliptocytosis
Haemoglobin defects
Sickle cell anaemia
Glycolytic pathway defects
Pyruvate kinase deficiency
Pentose shunt defects
G6PD deficiency
293
Features of G6PD deficiency in the blood film
Heinz bodies, which are denatured haemoglobin
Bite cells (cells with Heinz bodies that pass through the spleen have part of the membrane removed).
294
Causes of crises in G6PD deficiency
Illness (especially infections)
Certain drugs
Certain foods, most notably broad beans
Certain chemicals
295
Mode of inheritance of g6pd deficiency
X-linked recessive
296
G6PD deficiency affects which pathway
Pentose phosphate pathway
297
Importance of the pentose phosphate pathway
Production of NADPH
One of the uses of NADPH in the cell is to prevent oxidative stress. It reduces glutathione via glutathione reductase, which converts reactive H2O2 into H2O by glutathione peroxidase.
If absent, the H2O2 would be converted to hydroxyl free radicals by Fenton chemistry, which can attack the cell.
Erythrocytes, for example, generate a large amount of NADPH through the pentose phosphate pathway to use in the reduction of glutathione.
298
Autoimmune haemolytic anaemia is characterised by (lab results)
Spherocytosis
| Positive direct antiglobulin test (Coombs’ test)
299
Which is more common?
Haemophilia A
Haemophulia B
Haemophilia A (5 times more common)
300
Presentation of autoimmune thrombocytopenic purpura
Petechiae
Bruises
Blood blisters in mouth
