Abnormal WBC count Flashcards
what term defines the reduction of all three blood cell lineages?
pancytopenia
in which two situations that normal haemopoiesis occur?
normally and in reaction
to malignancy for example in leukaemia, myelodysplasia and myeloproliferative conditions
where should the neutrophil usually be found?
where should precursors be found?
in the peripheral blood
precursors should be found within the bone marrow, as maturation occurs here
what changes occur in the differentiation and maturation of neutrophils in pathological conditions?
cells become smaller
cytoplasm become clearer
multi-lobed nucleus
precursors found in the periphery
which cytokine controls the differentiation of RBCs?
EPO
which cytokine controls the differentiation of lymphoid cells?
IL-2
which cytokine controls the differentiation of myeloid cells?
Colony Stimulating Factors
G-CSF
GM-CSF
what affects the regulatory role of these cytokines?
what is the consequence of this?
DNA damage in cancer affects their regulating signals
this leads to cancer proliferation
where is malignant process occurring in leukaemia?
bone marrow
what is found in the blood in lymphoma/leukaemia?
lymphatic cell tumours
what is myeloma the disease of?
disease of the bone marrow
what are the two main umbrella reasons for increased WBCC?
1) increased cell production
- reactive e.g. infection
- malignant e..g leukaemia
2) increased cell survival
- failure of apoptosis
what are the two main umbrella reasons for decreased WBCC?
1) decreased cell production
- Bone marrow function impaired
- b12 or folate deficiency
2) decreased cell survival
- immune breakdown of cells
what is the difference in cell release in normal infection and heamo. cancers?
in normal infection: mature cells are released in reaction
in cancer: immature AND mature cells are released
two types of causes of eosinophilia
1) reactive- infection/inflammation
2) primary- malignancy
like with lymphocytosis
where does the mutation occur to cause CML?
GM-CSF
how would you go about investigating a raised WBCC?
- history and examination
- Hb and platelet count
- automated differential
- blood film
- pancytopenia? (all cell linages)
- one WC type or more?
- immature or mature cells?
what is eosinophilia characteristic of?
myeloproliferative disorders
parasitic infection (metazoan)
allergy
neoplasm e.g. Hodgkins (lymphatics)
what is the presence of immature cells indicative of?
malignancy like leukaemia
if mature cells are also present–> chronic leukaemia
acute leukaemia will present with low Hb and platelets
what cell types are present in the chronic leukaemia?
neutrophils and myelocytes
what cells add to the abnormal WBCC?
phagocytes- neutrophils, eosinophils, monocytes
immune cells- lymphocytes
which sites are neutrophils present in?
Bone marrow
blood
tissues
life span of neutrophils in varying locations
tissues: 2-3 days
peripheral blood: hours
why is the FBC for neutrophils not strictly accurate?
50% of neutrophils are marginated i.e. stuck onto the wall of a damaged vessel
time scale of development of neutrophils
minutes- demargination
hours- early release from BM i.e. sepsis
days- increased production i.e. x3 in infection
what can be seen in infection in the peripheral blood?
neutrophilia
toxic granulation
vacuoles
what can be seen in leukaemia in the peripheral blood?
neutrophilia
lymphocytosis (primary)
myelocytes (precursor)
absence of granules (no toxic granulation)
what are the main causes of neutrophilia?
- infection
- tissue inflammation
- physical stress
- adrenaline
- corticosteroid
- neoplasia
- malignancy e.g. CML
what is the normal cause for neutrophilia?
infection (local and systemic) : bacterial, fungal and certain viral infections
some infections do not produce neutrophilia e.g. Brucella, typhoid and many viral infections
what are the reactive causes of eosinophilia?
- parasitic infection
- allergic disease
- neoplasm e.g. HL
- hypereosinophillic syndrome
Hodgkins Lymphoma presentation on X ray
increased mediastinal mass
with increased IL-5 secretion
what are the causes of monocytosis (rare)?
- TB, Brucella, typhoid
- viral
- sarcoidosis
- CML
when are immature cells seen?
only in primary disorders (malignant)
disease of the bone marrow e.g. leukaemia
i.e. not in reaction
when are mature cells seen?
reactive to infection
what do immature lymphoblasts looks like?
larger than usual
nucleolus can be seen indicating immaturity
what are the reactive (secondary) causes of lymphocytosis?
- polyclonal response to infection: EBV, toxoplasma, hep, rubella, herpes
- chronic inflammation
- underlying malignancy, neoplasia
- autoimmune
- sarcoidosis
primary cause of lymphocytosis
malignant cause e.g. CLL
–>MONOclonal lymphoid proliferation
what causes mononeuclosis?
infection by the EBV of B lymphocytes via the CD21 receptor
common in the young
what happens in the mononucleosis?
glandular fever caused
infective B cells proliferates and expressed EBV associated antigens causing cytotoxic T-cell response
what is the most likely cause of lymphocytosis in the elderly?
CLL or an autoimmune disorder
what is the difference between polyclonal and monoclonal expansion?
(light chain restriction)
polyclonal involves more than one mother cells so light chains express kappa and lambda
monoclonal has all antibodies come from one mother cell therefore express either kappa or lambda
what are polyclonal and monoclonal expansion indicative of?
polyclonal: infection (reactive)
monoclonal: cancer (primary)
gene recombination in lymphocytosis
Ig genes and TCR genes undergo recombination in antigen stimulated B or T cells.
With primary monoclonal proliferation, ALL daughter cells carry the IDENTICAL TCR gene arrangement which isn’t normal for infection – indicative of cancer.
Detected by southern blot analysis.
i.e. if recombination has taken place, it means reactive lymphocytosis
upon investigation of raised WBCC, what is a lack of automated differential indicative of?
either they have had an G-CSF injection or there is an underlying malignant condition
what is the difference in immunophenotype between between primary (immature) lymphocytosis and secondary/reactive (mature) lymphocytosis?
primary–> monoclonal B cell expansion therefore express kappa OR lambda
secondary/reactive –> polyclonal B cell expansion therefore express either kappa AND lambda
what can lymphocytosis be split into?
- release of mature cells (primary or reactive)
- release of immature cells (primary–> lymphoproliferative disorder (ALL)
what are the 3 stimuli for leucocytosis (of various leucocytes)?
- infection (bacterial, viral, parasitic)
- inflammation (autoimmune, allergic)
- neoplastic
what are the leucocytes involved in the different types of infection?
- bacterial
- viral
- parasitic
- chronic infections
bacterial–> neutrophils
viral–> basophils
parasitic–> eosinophils
chronic infections–> monocytosis
what are the leucocytes involved in the different types of inflammation?
- autoimmune
- allergic
autoimmune–> neutrophils
allergic–> eosinophils
what is normal in terms of neutrophils behaviour during pregnancy?
toxic/heavy granulation
what is left shift neutrophilia?
increased in non-segmented neutrophils known as band cells (immature neutrophils/neutrophils precursors)
how many lobes do hypersegmented neutrophils have?
5+
what kinds of neoplasm do eosinophils reacts to?
Hodgkins and Non-Hodgkins Lymphoma
what kinds of neoplasms do neutrophils react to ?
most neoplasms
what are neoplasms?
cells that don’t respond to normal growth mechanisms
what are the triggers for toxic granulation?
- tissue necrosis
- pregnancy
- infection
what are the causes of the release of hypersegmented neutrophils?
low folate or B12
in megaloblastic anaemia
what may cause atypical lymphocyte production?
glandular fever (EBV infection)
how can you differentiate between primary and secondary mature lymphocytosis?
- Clinical context e.g. age
- Morphology
- Immunophenotype (just kappa or just lambda or both)
- Gene rearrangement (evidence of Ig gene recombination indicative of secondary/reactive)
what infection causes glandular fever?
EBV (infectious mononucleosis)
what are the features of glandular fever?
- RBCS: mildy hypochromic and microcytic
- WBCs: atypical (look like monocytes)
what are the features of acute myeloid leukaemia?
- RBCs are normal
- WBCs: lots of blast cells, may stick together, unable to differentiate between myeloid or lymphoid until granules appear
investigating leucocytosis
- is it one cell type that is elevated? or multiple cell types?
- is it mature cell? or immature cells?
- morphological changes? reactive changes? e.g. toxic granulation of neutrophils
this is useful for further investigations:
e.g. I see high number of eosinophils only –> underlying parasitic infection
e.g. I see high number of immature blast cells–> underlying leukaemia
what is the significance of seeing immature white cells like myeloblasts and lymphoblasts in the peripheral blood?
immature cells shouldn’t be seen in the periphery, they are usually confined to the bone marrow
increase in immature cells in the periphery is seen in bone marrow disease like leukaemia
what are the common explanations for neutrophilia in clinical practice?
- bacterial infection
- inflammation and tissue necrosis
- underlying neoplastic disease
- myeloproliferative disorder
- demmargination
bacterial infection as a cause of neutrophilia
- most common of neutrophilia
- toxic granulation
- cytoplasmic granules and vacuoles increased
inflammation and tissue necrosis as a cause of neutrophilia
appendicitis
MI
autoimmune tissue damage
underlying neoplastic disease as a cause of neutrophilia
carcinoma or lymphoma may cause reactive neutrophilia due to aberrant production of stimulatory cytokines
myeloproliferative disorders as a cause of neutrophilia
e.g. CML where less mature (not completely immature) cells are seen
demargination as a cause of neutrophilia
physical stress increases the circulating neutrophil number by moving them from the endothelial surface of small vessels into the flowing blood
corticosteroids raise neutrophil count
what are the common causes of eosinophilia?
- parasitic infection e.g. schistosomiasis
- atopic allergic condition e.g. eczema
- pulmonary eosionphilia
- Hodgkin’s disease (lymphatic system cancer causing reactive eosinophilia)
what causes monocytosis?
CHRONIC BACTERIAL infections which don’t produce a neutrophil response
e.g. TB, brucellosis, typhoid, chronic myelomonocytic leukaemia
how does pyogenic bacterial infection increase white cell count?
- cause the production of G-CSF and GM-CSF (inflammatory cytokines- colony stimulating factors)
- they lead to increased granulocytes and monocytes production by the BM
- in acute response, there is a release of less mature cells
- this gives a left shifted appearance in peripheral blood
chemotaxis
the phagocytes will circulate in the peripheral blood, at the site of infection they will move out of the circulation and into the tissues moving to the site of inflammation in response to chemotactic factors.
phagocytosis
The neutrophils and monocytes will encounter foreign material that has been opsonised by immunoglobulin or complement.
Using their Fc and C3b receptors they are able to recognise and phagocytose the foreign material.
what are the 2 types of lymphocytosis?
reaction to cancer:
- primary (malignant monoclonal proliferation) e.g. lymphoma
reaction to infection:
- secondary reactive (polyclonal reactive proliferation)
e. g. infection and autoimmune disease
infections that cause reactive lymphocytosis
Epstein-Barr virus (EBV), cytomegalovirus (CMV), toxoplasmosis, rubella, adenovirus infection, varicellazoster, infectious hepatitis, pertussis, tuberculosis, brucellosis.
glandular fever due to atypical lymphocytes
infectious mononucleosis
reactive lymphocytosis
how would you distinguish between someone with primary or secondary (reactive) lymphocytosis when both release mature cells?
NB primary lymphocytosis can release mature cells OR immature cells, Reactive releases only mature cells
- age
- clinical features
- lab investigations (maturity)
how would you know someone has primary lymphocytosis?
immature cells (blasts) abnormal cells (smears)
suggests lymphoproliferative disorder like leukaemia or lymphoma
how can the proliferation of the two types of lymphocytosis be distinguished?
primary–> monoclonal
secondary–> polyclonal (oh shit!)
how can the two types of lymphocytosis be distinguished by the receptors on the B lymphocytes produced?
primary–> either kappa or lambda light chains (mono)
secondary–> both kappa and lambda light chains (poly) mixed population
