Haem 6 Flashcards
Differentiate normal and malignant haemopoiesis
Normal:
Polyclonal healthy/reactive
Malignant
Abnormal/clonal
Leukaemia (lymphoid,myeloid), myelodysplasia , myeloproliferative
Outline precursors to T cell, b cell, RBC, megakaryocyte/platelt, neutrophils, basophils, eosinophils and monocytes
Pre T, pre B, BFU-E, Meg-CFC, GM-CFC (granulocytes and monocytes),
- CFC= colonony forming cells
- BFU- E = erythroid burst-forming units
How to differntiate myeloblast and lymphoblast
Myeloblast small granues, nothing in lymphoblast
Outline the differentiaton of myeloblast into a neutrophil
Myeloblast –> promyelocyte –> myelocyte –> metamyelocyte –>band cell –> neutrophil
When would you see any myeloid precurosrs, not just neutrophils
In a myeloproliferative disease, e.g. chronic myeloid leukaemia incl. myeloblast
After chemotherapy when G-CSF given to increase formation of new granulocytes so lots of blasts in peripohery)
Sepsis (up to promyelocyte)
How is cell number controlled in productin of erythroid, lymphoid and myeloid cells
Haemopoiesis regulated by cytokines, chemokines and hormone…..
(so in infection, cytokines released could message the bone marrow that more neturophils required)
Erythroid- erythropoietin
Lymphoid- IL2
Myeloid- G-CSF and M-CSF (just monocyte)
Influence DIFFERENTIATION and PROLIFERATION
DNA directed differentiation and proliferation
Cell types found in bone marrow
Lymphoblasts
Myelpblast,promyeloblast,melocyte, metamyelocyte
How could WBC increase
Increase cell production:
Reactive (infection or inflammation)
Malignant (leukaemia or myeloproliferative)
Increase cell survival (failure of apoptosis –> acquired cancer causing mutations in lymphomas)
How could WBC decrease
Decreased cell production (impaired BM function, due to b12/folate deficiency OR BM failure- apalstic anaemia, post chemo, metastatic cancer, haematological cancer)
Or
Decreased cell survival (immune breakdown e.g. HIV)
Examples of normal (or reactive) with primary (malignant) haemopoiesis
Normal haemopoiesis:
- Inflammation,
- infection (parasitic),
- increased cytokine production from distant tumour, (haemopoietc or non haemopoietic)
Abnormal haemopoiesis:
- cancer of haemopoietic cells,
- leukaemia (myeloid/lymphoid, chronic or acute)
- myeloproliferative disorder
Genetic basis of CML
Fusion gene called BCR-ABL due to translocation of chromosome 9 and 22…
DNA damage occurs at early stage of differenation (at GM-CFC) so it leads to proliferation of many myeloid cell types (platelets, all white cells, etc)
How is a raised WCC investigated
CHECK
BASICALLY: History and examination Haemoglobin and platelet count Automated differential Examine blood film
History and examination
Haemoglobin and platelet count (if low, could be because the immature cells produced in acute lymphoid leukaemia, for example, are suppressing platelet and red cell production because there are so many)
Automated differential (machine tells you about each type of blood cell….could be no differential if there are lots of blasts….. there could be lots of blasts because of malignancy OR because patient has been treated with G-CSF following chemotherapy to increase white cell count)
Examine blood film
Abnormality White cells only, or all 3 lineages (red cells/platelets/white cells)…. in malignancy usually only increase in ONE cell lineage, in reactivity increase in all the white cells (apart from CML, which also has all cells prolferating)
White cells 1 cell type only, or all white cell lineages? (e.g. neuts/eos/monocytes/lymphocytes)
Mature cells only or mature and immature cells?
Causes of elevated WCC with:
increased by mature cells
increased mature +immature
Immatuure
Mature:
- all lineages or only 1 of neutrophil, eos or baso –> reactive/infection
- lymphocytes –> reactive (viral) or primary (chronic lymphocytic leukaemia)
Mature and immature: Neutrophils+ myelocytes+ basophils ?Chronic myeloid leukaemia
Immature: Blasts + low Hb low platelets ? Acute leukaemia
Neutrophil life span
2-3 days
T/F: neutrophils that are marginated are included in FBC
False
Cuase of neutrophilia which develops in minutes, hours, and days
mins: demargination (i.e. neutrophils stop going into tissues)
hours: early release from BM
days: increased production (X3 in inection)
How do neutrophils change in infection and CML
infectin: Neutrophilia >7.5x109/l
toxic granulation
vacuoles
CML: Neutrophilia (mature) and precursor cells (myelocytes), increase in monotcytes too… neutrophils don’t have toxic granules
Common causes of neutrophilia
- Tissue inflammation (e.g.colitis, pancreatitis)
- Physical stress, adrenaline, CORTICOSTEROIDS
- Underlying neoplasia
ie. Malignant neutrophilia:
- myeloproliferative disorders like CML
SIN: Stress, inflammation, neoplasia
Cuases of neutrophilia in infection
in localised and systemic acute bacterial, fungal, certain viral infections (less so)
Which infections will not have neutrophilia
brucella, typhoid, many viral infections.
Causes of eosinophilia
- -Reactive (parasitic infection; allergic disease e.g. asthma, rheumatoid, polyartertitis, pulmonary eosinopholia);
- neoplasms inc. Hodgkin’s or T cell NHL;
- hypereosinopshilic syndrome
Malignant:
Only one cause involing clonal process= Malignant chrnoic eosinopholic leukaemia (PDGFR fusion gene… fusion between FIP1L1 and PDGFR-a)
When is monocytosis seen
Chronic infections and primary haematological disorders.
- TB, brucella, typhoid
- Viral; CMV, varicella zoster
- Sarcoidosis
- Chronic myelomonocytic leukaemia
Causes of mature lymphocytosis
Mature
- reactive to infection (EBV, CMV, toxoplasma),
- autoimmune or inflammatory, sarcoidosis
- underlying malignancy
primary disorder (CLL)
What is glandular fever
- EBV infection of B-lymphocytes via CD21 receptor
- Infected B-cell proliferates and expresses EBV associated antigens
- Cytotoxic T-lymphocyte response
- acute infection resolved resulting in lifelong sub-clinical infection.
Infectious mononucleosis, atypical cells
What is more dangeorus monomorphic or pleomorphic lymphoytosis
monomorphic –> malignancy (clonal)
Pleomorphic –> reactive
How can you distinguish between polyclonal and monoclonal lymphotcytosis
Immunophenotye (the antigens on the b cell surface)… in CLL they are CD5+
State the cells in the myeloid lineage
Monocyte Erythrocyte Dendritic cell Megakaryocyte Eosinophil Basophil Neutrophil Macrophage
How can there be a loss of regulation of haemopoiesis
Normally controlled by homones etc and is DNA directed after this.
If DNA mutation at any point during differentiation, cells get survival advantage, stops being regulated by cytokines, replicates uncontrollable –> cancer.
Define leukaemia
Malignant disease, when bone marrow produce increased number of immature (in the case of proliferative disorders) /abnormal (in the case of dysplastic disorders) leuocytes, leading to suppression of production of other blood cells like erythrocytes, granulocytes and platelets.
Can be myeloid or lymphoid
Define lymphoma
Lymphoma typically more solid and found in lymph nodes etc
Leukaemia more often resulting in the increase of white cell count in the blood
Differentiate reactive increase in whicte cell production vs malignant one with regard to the bone marrow
Normal infection (IE. reactive) –> differentiating cells in bone marrow stimulated and mature cells released into ciructilation
Hamatopoietic cancer (i.e. malignant), immature and mature cells released from the bone marrow
Difference in white cell count with malignancy and reactive haemopoiesis
In maliginacy, usually just one white cell type increased as clonal process, whereas reactive usually all cell types increased (exception is CML, in which all granulocytes increased and monocytes too)
Why is it important to see whether the increased WCC has mature white cells only or mature and immature cells
Mature and immature –> CML
Immature only- AML
When might basophils be increased
Pox virus
How would CLL vs ALL look on microscope
CLL- mature cells…. all have characteristic large nucleus and small cytoplasm as in typical lymphocytes.. all look same. Remember, may also look like this in autoimmune
ALL- much bigger, may contain nucleolus
What type of infections could cause reactive lymphocytosis
EBV, CMV, toxoplasma
Infectious hep, rubella or herpes
How to distinguish cause of lymphocytosis (e.g. is it reactive to underlying autoimmune disorder or CLL?)
- Morphology (i.e. do they all look the same, if so CLL)
- Immunophenotype (i.e. what surface molecules are they expressing, CLL ar CD5+)
- Gene re-arrangement (if they are all derived from the same mother cell, they will have same TCR/immunoglobulin gene rearrangement, if they are different they will have different rearragnements…. use southern blot)….
also use light chain (if all they are polyclonal, there will be a mixture of kappa only and lamda only lymphocytes….. in monoclonal, thus CLL, they will all be kappa or all be lamda)
What is aplastic anaemia
When there is damage to HSC so reduction in all cell types
Differentiate myelodysplastic and myeloproliferative disease
Myelodysplastic is when cells cannot mature PROPERLY… instead they mature into something weird. Therefore you get a lot of dysfunctional cells. More symptoms arise as the number of dysfunctional cells increases compared to functional. If there is a mutation in these cells which stops them from maturing at all, then they cannot be released from the bone marrow, and it is now called acute myeloid leukaemia. (You would see a mixture of weird and normal cells in the peripheral circulation)
The difference between AML and myelodysplasia is that in AML the cells cannot mature at all (so you get lots of blasts) and in myelodysplasia they mature into something weird.
Myeloproliferative diseases occur when the normal cell type is produced, but just too much of it. So the maturation is normal, but the rate of proliferation is too high. There are 4 types…. 2 of which are chronic myeloid leukaemia and polycythaemia vera. (you would see immature cells in the peripheral circulation because rate of production is so high)
https://www.youtube.com/watch?v=hcuTspQc99s
This is a fantastic vid.
What types of phagocyte would respond to the following types of lymphoma:
- Responds to all types of lymphoma
- Hodkin’s/Non Hodgkin’s
- neutrophil
- eosinophil (particularly hodgkins, and T-cell NHL). NB…. IL5 stimulates the production of eosinophils (can use antibody against this in treatment of these cancers)
Causes of immature lymphocytosis
ALL
