Haematology Flashcards
Process of receptor mediated apoptosis
Ligand binds FAS connected to death receptor Triggers intracellular cascade Activation of caspases DNA digestion Disintegration of cytoskeleton Apoptosis
Two mechanisms of apoptosis
Receptor mediated
Intrinsic mitochondrial
Mechanism of intrinsic mitochondrial apoptosis
Irreversible damage to cell constituents BCL family controls mitochondrial membrane permeability Release of cytochrome C React with members of apoptosis cascade Activation of caspases Apoptosis
How do gain of function mutations occur
Amplification of gene
Mutation of gene (product no longer sensitive to control mechanisms)
Mutation of regulator genes (oncogene now unopposed)
Translocation (production of fusion genes, transfer of gene to region that is actively transcribed)
How does loss of function mutation occur
Large deletions
Small deletions eg frame shift
Mutations causing 1. Stop codon 2. Disruption of promoter 3. Splice region - less active protein.
Why stem cells often origin of haemopoietic malignancy
Long lived - accumulate mutations
Capacity for self renewal - feed malignancy
Actively transcribe regulatory proteins
Phenotype of malignancy depends on…
Predominant cell lineage
Proliferation rate
Degree of differentiation
Amount of apoptosis
Why differentiate between ALL and AML
Very different treatment and prognosis. Therefore misdiagnosis = poorer prognosis
How to diagnose acute leukaemia
- FBC (differential and morphological review)
- Bone marrow aspirate and trephine biopsy
- Additional tests ( LP, DIC screen, HIV, electrolytes and renal Fx)
How do you manage a patient with leukaemia
Anaemia = exclude bleeding, give irradiated RBC Thrombocytopenia = transfuse platelets Prevent infection Prevent tumour lysis/ gout Prevent nausea Treat infections
What is induction therapy
Chemo to induce remission
What is consolidation therapy
Further chemo after remission that’s the same or more intense than induction which aims to eradicate disease
What is maintenance therapy
Less intense (often oral) helps to maintain remission.
Anti metabolites …
Metabolite of drug incorporated into DNA and inhibits DNA polymerase
Anrthracyclins
Bind DNA and prevent/ interfere with mitosis
Topiosomerase inhibitors
Induce DNA strands to break, inhibiting mitosis
Vinca alkaloids
Damage Mitotic spindle
Corticosteroids …
Lysis of RBC
Folate antagonists….
Deplete intracellular folate and block purine/pyrimidine synthesis by inhibiting dihydrofolate reductase
Purine analogues…
Inhibit purine synthesis
Incorporated into DNA
Uses of BM transplant
Eradicate aggressive cancers
Rescue patients treated with high dose chemo
Types of BM transplant
AUTOLOGOUS - persons own blood
ALLOGENIC - matched donor, more risk
Complications of chemo
Normal BM ‘‘killed’’
GIT cells affected - nausea, mucho sites
Immunosuppression - severe infection
Tumour lysis syndrome
Prognosis in AML dependent on..
Cytogenetics of cells Age Primary vs secondary AML WCC and diagnosis Response to induction therapy Performance status of patient
Poor risk factors in ALL
Age >35 High WCC at diagnosis CNS disease at presentation t(9:22) or t(4:11) More then four weeks to achieve remission
Wat info does family/patient need
Info RE diagnosis and therapy
First admission one month
Need to be close to transplant centre - 1 year
Adult/ kid miss a year or more of school
P53 raises the level of what to cause apoptosis
BAX
Three features of bone marrow failure and clinical consequences
Anaemia - fatigue, pallor
Neutropenia - susceptibility to infections
Thrombocytopenia - bleeding
Type of chromosomal abnormalities that may be found in acute leukaemia
Hyperdiploidy
Hypodiploidy
Deletions
Translocations
Define proto oncogenes
Normal genes
Code for proteins involved in regulation of cell growth, proliferation and differentiation.
