HAEM: Myeloproliferative disorders Flashcards
Summarise the normal haematopoiesis.
Common myeloid progenitor is where most disorders in relation to this topic arise.
Describe the function of growth factors in haematopoiesis. Which receptors play the most important role in normal/abnormal haematopoiesis?
Growth factors
GFs interact with receptors–> activation of kinases–> transfer of phosphate from ATP and phosphorylation of molecules in cells
Of these receptors, the tyrosine kinases play an important part in normal and abnormal haematopoiesis
What is the function of Janus Kinases (JAK)?
They are a family of 4 tyrosine kinases associated with haemopoeitic cell growth factor receptors
Conformational changes occur when growth factors/cytokines interact with their receptor–> phosphorylation of the kinases –> activation of the STAT pathway ultimately –> cell proliferation.
Briefly, what happens to this pathway when a JAK is mutated?
They act constitutively i.e. they do not require the presence of GF to be activated
JAK2 V617F mutation causes inactivation of the pseudokinase domain thereby removing an inhibition of activation
Which cell types is JAK most implicated in?
JAK 2 is mainly implicated in myeloid cells
What mutation is found in most MNPs?
Identical JAK2 kinase gene mutations seen in:
- Most PV cases
- About 50% of ET and less myelofibrosis cases
What two mutations of JAK2 are associated with MPNs?
- Exon 12 - associated with IE
- Exon 14 - PV
NB:
- BUT JAK2 mutation V617F is not found in all MNPs and some may be associated with mutations in thrombopoietic receptors in MF and ET cases.*
- MNPs are usually caused by intrinsic activation of tyrosine kinases so small inhibitory molecules are being developed to treat it.*
- The mutation can have variable penetrance (mainly homozygous in PV but less so in others)*
What is a chronic myeloproliferative neoplasm?
A group of neoplastic/clonal disorders of haemopoeitic stem cells
characterised by the overproduction of one or more of the mature myeloid cellular elements of the blood
What happens to the bone marrow in MPN?
Increased fibrosis in BM most extreme in idiopathic myelofibrosis
Often accompanied by various degrees of non-clonal reactive fibrosis in the bone marrow
What can MNPs progress to?
A proportion of cases progress to an acute leukaemia like picture (but usually after ~15 years)
What are some clinical features of MNPs?
Clinical presentations include greater preponderance to thrombosis (arterial) and sometimes splenomegaly and less frequency haemorrhage
Variability in clinical course
What happens to blood of MNP patients if you try to grow it without growth factors?
There is still spontaneous colony growth in cultures without added EPO or TPO
Give 4 examples of chronic MNPs.
- Polycythaemia vera (PV)
- Essential Thrombocythaemia (ET)
- Idiopathic Myelofibrosis
- Idiopathic erythrocytosis
- Chronic granulocytic leukaemia (discussed in a separate lecture)
Describe the differences between MPN, MDS and leukaemia in terms of proliferation and differentiation.
There is some overlap as you can get progression from MPN to leukaemia or sometimes MDS.
What are the laboratory features of PV?
- High haemoglobin
- High haematocrit
- Low serum of erythropoietin i.e. proliferation is independent of usual mechanisms
- WCC normal/high
- Increased RBC mass
- Increased plasma volume - compensatory increase in blood volume
- Usually increased platetets
- Slight to moderate reticulin fibrosis and megakaryocyte abnormalities
How common is PV?
More common in males 1.2:1
~2/100,000
Age ~60 at diagnosis
What is the clinical presentation of PV?
Incidental diagnosis on routine blood testing or
- Symptoms of increased hyper viscosity:
- Headaches, light-headedness, stroke
- Visual disturbances
- Fatigue, dyspnoea
- Increased histamine release:
- Aquagenic pruritus - itching after shower
- Peptic ulceration
Other:
- May have splenomeagaly
- Plethora
- Erythromelalgia: red painful extremeties
- Thrombosis
- Retinal vein engorgement -
- Gout - due to increased red cell turnover and overproduction of uric acid
+absence of other causes of increased haematocrit
What are the bone marrow features in PV?
Often increased cellularity mainly affecting erythroid cells but may also be seen in other series
Usually many fat spaces are present whereas here the spaces are occupied by cells; in contrast to other conditions, these cells are all mature.
What feature of PV is shown?
Erythromelalgia - painful and red extremities
What mutation is diagnostic in the presence of the clinical picture in PV?
JAK 2 V617F mutation present (diagnostic)
How is blood volume investigated in PV? Describe the differences in blood volume between PV, pseudopolycythaemia and normal.
In true PV there is increase in RBC mass and plasma volume with an increase in Hct too.
Measured by isotope dilution method: red cell mass measured by incubating patient’s RBC with radioactive chromium and plasma volume by incubating plasma with radioactive iodine
What if the patient has a raised haematocrit but no JAK2 mutation? What are the possibel diagnoses?
What is the current diagnostic criteria for PV?
Diagnostic criteria:
- Increased RBC production and usually also increased platelets and sometimes neuutrophils
- Most patients will have the JAK2 V617F mutation
Historical criteria shown below, but this was used before the JAK2 mutation was found in 2006.
What are the features of BM in ET?
Normal or slightly increased BM cellularity - usually only megakaryocytes increased
More fat spaces unlike PV, but some clustering of megakaryocytes seen some of which are less mature
What features of CIMF are shown here?
A - tear drop cells
B - nucleated RBC
C - basophilia
What feature of CIMF is shown here?
Increased platelet production
What features are seen in this BM biopsy in myelofibrosis/CIMF?
Collagen fibrosis
Reduced cellularity
