Haematology Flashcards
0
Q
What happens at G1-S checkpoint?
A
Cell checks integrity of DNA to ensure that it is in a fit state to be replicated
1
Q
Definition of haemopoietic growth factors
A
Soluble mediators that regulate proliferation and differentiation of haemopoietic progenitors
- exert their effect by binding to high affinity receptors on cell surface
2
Q
What happens at G2 checkpoint?
A
Checks that DNA replication has been satisfactory.
3
Q
Definition of apoptosis
A
Regulated process of physiological cell death
4
Q
Why apoptosis and not just necrosis?
A
Ensures the destruction of the cell without releasing any lysosomal or granule content that would cause an inflam reaction
5
Q
2 pathways to activate apoptotic enzymes
A
- receptor mediated
- mitochondrial
6
Q
Steps in apoptosis
A
- activation of caspase proteases
- cell shrinkage
- cleavage of DNA
- condensation of nuclear chromatin
- fragmentation of nucleus
- phagocytosis of apoptotic bodies by macs
7
Q
Describe the receptor mediated pathway
A
- signaling through fas or TNF receptor via an intracellular death domain
- triggers intracellular cascade of caspase a
8
Q
Describe mitochondrial pathway
A
- irreparable damage to cell contents triggers cytochrome C release from mitochondria
- activates caspases
- regulated by various Bcl proteins (control perm of mitochondrial membrane)
9
Q
How does p53 activate apoptosis?
A
- raises the level of BAX
- increases cytochrome C release
10
Q
Protection from apoptosis
A
- Bcl 2
- ratio of BAX to Bcl 2 determines cells susceptibility to apoptosis
11
Q
How apoptosis affected in follicular lymphoma tr
A
Translocation of Bcl 2 to immunoglobulin heavy chain locus
- over expression if blc 2
- reduced apoptosis
- accumulation of malignant cells
12
Q
Definition of clonal evolution
A
If the mutation in the progeny gives it a survival advantage above the parent, the original cell may be replaced
13
Q
What is classification of leukemia based on?
A
- morphology/phenotype/ flow cytometry
- cytogenetics
- molecular genetics
14
Q
Metabolic effects of ALL and Burkitts
A
- tumour lysis syndrome
- hyperuricaemia
- fever
15
Q
Definition of acute leukemia
A
Presence of at least 20% blasts in peripheral blood or bone marrow
16
Q
Definition of blasts
A
Immature cells located in the bone marrow that differentiate though series of cell divisions into mature cells present in normal peripheral blood
17
Q
Normal % blasts
A
<5
18
Q
Broad categories of AL
A
- Acute lymphoblastic leukemia
- acute myeloid leukemia
- mixed phenotype (rare)
19
Q
Non-specific features of AL
A
- unwell
- tired
- general aches and pains
- fever
20
Q
Signs of bone marrow infiltration
A
- anaemia
- bleeding tendency
- infections
21
Q
Signs of tissue infiltration
A
- gum hypertrophy
- lymphadenopathy
- splenomegaly
- CNS disease (ALL)
22
Q
What is classification of AL based on?
A
- morphology of blood and bone marrow
- cytochemistry
- immune phenotype (FC)
- genetic abnormalities (karyotyping/FISH/PCR)
23
Q
What is the most common secondary leukemia?
A
AML
24
Tests for initial diagnosis
- FBC
- differential count
- morphology of slide
25
Tests for definitive diagnosis
- bone marrow aspirate
| - bone marrow trephine biopsy
26
Morphology of ALL
Scanty cytoplasm
Primitive nuclei
No granules
No auer rods
27
Additional tests to diagnose AL
- lumbar puncture to exclude CNS disease
- HIV test
- DIC screen (acute promyelocytic leukemia)
- electrolytes and renal function
28
Immunophontype markers for blasts
- CD34
| - HLA-DR
29
Chromosome changes seen in haematologic malignancies
- increase or decrease in no. of chromosomes (ALL)
- loss of chromosomes
- gain of chromosomes
- translocations (AML, ALL, Burkitts)
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Supportive therapy
- anaemia (filtered irradiated packed red cells to maintain Hb >8g/dl
- thrombocytopenia (plt transfusion)
- prevention of gout and TLS (hydration and allopurinol)
- prevention of nausea (anti-emetics to prevent)
31
How to prevent infections
- single room with revers isolation
- regular hand-washing by staff and visitors
- avoid anybody with obvious infection
- no fresh fruit or vegetables
- antibiotic and anti fungal prophylaxis
- attention to mouth care
- care of IV lines
32
Definition of induction therapy
Course of chemo given to induce remission
- leukemia no longer detectable in blood or BM
- reduction in tumour burden by 99%
- does not imply cure
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Definition of consolidation therapy
- further courses of chemo given once remission is achieved
| - aims to eradicate disease
34
Definition of high dose intensification therapy
Bone marrow transplant
35
Definition of maintenance therapy
Less intensive, often oral chemo, as an out patients
- usually given monthly
- given to maintain remission (usually in ALL)
36
Two main types of stem cell transplants
- autologous (patients own, returned after chemo)
| - allogeneic (matched donor, more risky)
37
Possible complications of therapy
- TLS
- normal BM also killed
- affects normally dividing cells in GIT
- immune suppression
38
Bad risk factors for ALL
- age >35
- high white cell count at diagnosis
- CNS disease at presentation
- t(9:22), t(4:11)
- if it takes more than 4 weeks if weekly chemo to a
Achieve remission
39
Definition of Burikk lymphoma
A highly aggressive mature B cell neoplasm with extremely short doubling time and high tumour burden
40
Pathogenesis of Burkitts
- translocations involving myc oncogene
- most t(8:14)
- t(2:8)
- EBV is implicated in pathogenesis
41
3 clinical variants of Burkitts
- endemic
- sporadic
- immunodeficiency-associated
42
Presentation of endemic Burkitts
- jaw/facial mass
- 4-7 years
- EBV in most
- does not manifest as acute leukemia
43
Presentation of sporadic Burkitts
- massive abdo mass with ascites
| - retro peritoneal masses with spinal cord compression
44
Burkitt morphology
Monomorphic, medium sized cells
- deeply basophillic cytoplasm with lipid vacuoles
- round nuclei
- finely clumped/ dispersed chromatin
- multiple nucleoli
45
Prognosis and treatment for Burkitts
- highly aggressive but potentially curable
- poor prognosis if bone marrow and CNS involvement, high serum LDH
- very high dose combo chemo used
46
Types of chronic lymphoproliferative B cell leukemias
- chronic lymphocytic leukemia
- hairy cell leukemia
- pro lymphocytic leukemia
- some types of NH lymphomas may spill into blood
47
Types of chronic lymphoproliferative T cell leukemias
- T pro lymphocytic leukemia
- large granular lymphocytic leukemia
- adult T cell leukemia
48
Diagnosis of CL
- chronic persistent lymphocytosis
- morphology
- immunophenotype
- cytogenetics
- genetics
49
Epidemiology of CLL
- 60-80
- common in western world
- genetic predisposition
- monoclonal mature B lymphocytes accumulates
- only diagnosed if clonal B cells >5x10(9)/l
50
Clinical features of CLL
- mostly picked up on routine blood counts
- non-tender symmetrical lymph node enlargement
- anaemia
- thrombocytopenia
- splenomegaly
- immunosuppressive
51
Lab features of CLL
- normochromic anaemia
| - decrease in serum Ig
52
Morphology of CLL
- lymphocytes increased
- small round lymphocytes
- smear cells
- immunophenotyping NB
53
Prognostic markers of CLL
- genetics (del17p is poor)
- rapid lymphocyte doubling time is poor
- staging
- LDH
- high expression of ZAP70 is poor
- CD38 is poor
54
When not to treat CLL
If stage 0/1 - normal life span of 12 years
55
What to treat in CLL
- problematic organomegaly
- bone marrow suppression
- haemolytic episodes
56
Chemo treatment for CLL
- fludarabine
- cyclophosphamide
- rituximab
Monthly for 4-6 cycles
57
Presentation of hairy cell leukemia
- rare
- males 40-60
- severe infection, anaemia, splenomegaly
- no lymphadenopathy
- responds well to chemo
58
Features of B cell pro lymphocytic leukemia
- very rare
- more aggressive
- poor prognosis
59
Features of T pro lymphocytic leukemia
- very high WCC
| - skin, serous effusions
60
Features of large granular lymphocyte leukemia
- mostly have cytopenias
| - RA associated
61
Features of adult T cell leukemia
- common in Caribbean and Japan
- htlv1 assoc
- skin lesions, heparosplenomegaly, lymphadenopathy, hypercalcaemia
62
Development of multiple myeloma
- peak in 60s
- early - over expression of cyclin D
- accumulation of genetic damaging events
- important in elderly patient with persistent bone pain
63
Clinical features of Mm
- bone pain
- anaemia
- recurrent infections
- renal failure
- bleeding (paraproteins interfere)
- amyloidosis
- hyper viscosity
64
Investigations for MM
- presence of paraprotein (GADE)
- serum free light chains
- urine BJP
- normochromic normocytic anaemia
- high ESR
- skeletal survey - osteolytic lesions
- increased serum calcium
- increased creatinine (renal failure)
- cytogenetics and FISH
65
Supportive management in MM
```
Renal
- rehydrate
- management of hypercalcaemia and hyperuricaemia
Bone disease
- bisphosphonates
Anaemia and infections
- antibiotics
Bleeding
- plasmapheresis
```
66
Other plasma cell disorders
- monoclonal gammopathy of undetermined significance
| - plasma cell leukemia
67
Definition of amyloidosis
- group of disorders
| - deposition of protein in fibrillation form extracellularly
68
Systemic AL amyloid
- clonal proliferation of plasma cells
- serum paraprotein often very low
- free light chain ratio skewed
69
Classification of chronic myeloproliferative neoplasms
- chronic myelogenous leukemia
- polycythemia Vera
- essential thrombocythemia
- primary myelofibrosis
70
Common clinical feature of chronic myeloproliferative neoplasms
- splenomegaly and hepatomegaly
- thrombosis
- bleeding
71
Features of CML
- results from mutation in haemopoietic stem cell
- result of translocation t(9:22)
- results in abnormal fusion gene of BCR/ABL ON chromosome 22 (Philadelphia chromosome)
72
Effects of Philadelphia chromosome
Has enhanced tyrosine kinase activity leading to:
- increased prolif
- decreased apoptosis
- decreased adherence to BM to haemopoietic cells to stromal cells
73
Peripheral blood findings in CML
- many WCC
- all stages of maturation present with myeloctye hump
- neutrophils usually normal
- basophils increased
- normochromic normocytic anaemia
- platelet count usually increased
74
Bone marrow of CML
- hyper cellular
- predominantly granulocyte precursors
- myeloid:erythroid increased
75
3 phases of CML
- initial chronic stable phase (most diagnosed here)
- accelerated phase (unresponsive to treatment)
- blast phase (resembles AL)
76
Main causes if mortality and morbidity in Ph negative neoplasms
Arterial and venous thrombosis
77
Pathogenesis of Ph neg MPN
- JAK2 mutation underlies pathogenesis
| - results in unregulated prolif of granulocytes, erythroid series and megakaryocytes
78
Clinical and lab findings in essential thrombocythemia
- sustained increase in plt count due to megakaryocyte prolif
- bone marrow shows increased numbers of enlarged mature megakaryocytes
- other cell lines usually not increased
- abnormal platelet function may lead to bleeding
79
Clinical features of ET
- red, warm, painful fingers and toes
- thrombosis and haemorrhage
- splenomegaly
- very important to exclude reactive causes of thrombocytosis first
80
Reactive causes of thrombocytosis
- infection/inflammation
- chronic haemorrhage
- iron deficiency
- post surgery
- malignancy
81
Prognosis and treatment of ET
- indolent disorder (long symptoms free survival)
- median survival with therapy is 20 years
- principle of treatment is to control plt count
- cutler ductile agents and anti platelet drugs
82
Clinical and lab findings in polycythemia Vera
- increased red cell production
- prolif of granulocytes and megakaryocytes
- JAK2 mutation inmost cases
83
3 phases of PV
- prodromal prepolycythamic phase (mild erthtrocytosis)
- overt polycythemic phase
- post polycythemic myelofibrosis phase
84
Bone marrow in PV
- megakaryocytes have hyper lobated nuclei
85
Prognosis and treatment of PV
- most die from thrombosis or haemorrhage
- repeated venesection is mainstay
- cytoreductuve agents to control counts
- long term warfarin for cases with confirmed venous thrombosis
86
Clinical and lab features of primary myelofibrosis
- progressive generalized fibrosis of the bone marrow in association with extra medullary haematopoiesis in spleen and liver
- leads to anaemia and massive heparosplenomegaly
87
What causes the bone marrow fibrosis in PMF?
Cytokine release by abnormal megakaryocyte prolif
88
Two phases of PMF
- prefibrotic phase (hypercell marrow, large MK, minimal fibrosis)
- fibrotic phase (increased reticulin, red cells with teardrops)
89
Prognosis and treatment of PMF
- varying survival
- treatment is palliative (decrease splenomegaly and anaemia)
- cytoreductuve agents (hydroxuyrea)
- splenectomy/splenic radiation
- allogeneic BM transplant in young patients
90
Consequence of enhanced tyrosine kinase activity
- increased proliferation
- decreased apoptosis
- decreased adherence to BM
91
Acquired factors that can cause platelet inhibition
- asprin
| - uraemia
92
Function of Von willebrands factor
Facilitates plt vessel wall interaction
93
6 basic coag tests to perform
- VWB
- PTT
- INR
- FBG
- bleeding time
- plt count
94
Function of low weight heparin
- binds to anti thrombin
- inhibits FXa and thrombin
- little or no monitoring required
95
Common causes of acquired thrombophilia
- pregnancy
- COC
- obesity
- immobility
- surgery
- malignancy
96
How a genetic event leads to dysregulation of apoptosis and haematological malignancy
- t(14:18) translocation
- In follicular lymphoma
- over expression of bcl2
- reduces apoptosis
- accumulation if malignant cells
97
Investigations to confirm multiple myeloma
- SPEP (monoclonal peak)
- UBJ protein urea
- bone marrow clonal plasma cell
98
Causes of polycythemia
Primary
- inherited
- acquired (polycythemia Vera)
Secondary
- relative (dehydration)
- true
99
Exogenous factors known to predispose to acute leukemia
- viruses
- radiation
- chemicals
100
Factors that determine the phenotype of leukemia
- cell lineage
- rate of proliferation
- degree of differentiation
- degree of apoptosis
101
Molecular mechanisms whereby loss of function of oncogenes may occur
- large deletions
- small deletions leading to frame shift
- mutations resulting in stop codons
- mutations in promoter sequence of gene
- mutations in splice regions of genes
102
Mechanism of action of chemotherapeuric drugs
- damage to mitotic spindle
- bind to DNA and interfere with mitosis
- deprive cells of asparganine
- lysis of lymphoblasts
- induce DNA strand break
103
Allopurinol mechanism of action
Xanthine oxidase inhibitor
| Prevents production of Uric acid in the purine breakdown pathway
104
Properties of stem cells
- have the capacity for self-renewal and differentiation
| - capable of producing daughter cells which are either stem cells or more differentiated
