Lecture 10 Flashcards
What does myeloproliferative disorders (cancer)/physiological reactions (to stimulus) cause?
Overproduction of cells
Give some examples of myeloproliferative disorders:
- polycythaemia Vera (overproduction of RBC’s)
- myelofibrosis (hardening process in bone marrow)
- essential thrombocythaemia (overproduction of platelets)
- chronic myeloid leukaemia (overproduction of myeloid series)
What are myeloproliferative disorders now called?
Myeloproliferative neoplasms
They are now classed as cancers
What causes myeloproliferative disorders?
Disregulation of multipotent haematopoietic stem cells
What are some clinical features of myeloproliferative disorders?
- overproduction of 1/more blood elements with dominance of a transformed clone causing other cells to be underproduced (e.g. myeloid series increased, so more WBC’s, you may get less RBC’s being produced/platelets due to lack of space)
- hypercellular marrow (packed marrow)> leads to marrow fibrosis
- extramedullary haemopoiesis
- cytogenetic abnormalities (chromosomal defect)
- thrombotic/haemorrhagic (tendency to clot/bleeding )
What causes myeloproliferative disorders often?
Point mutation in one copy of the Janus Kinase 2 gene (JAK2)
What does the mutated JAK2 gene do?
The abnormal cytoplasmic tyrosine kinase on chromosome 9, causes an increase in proliferation and survival of haematopoietic precursors
When do you see cytogenetic abnormalities in myeloproliferative disorders?
- at the beginning of disorder
- secondary cytogenetic abnormalities due to increased proliferation (so these conditions can lead to other conditions such as acute leukaemia)
Why is it good that we have identified the specific JAK2 gene?
So we can make specific drugs that target the mutated protein
What is polycythaemia Vera?
Too many RBC’s
What does a normal blood sample look like + compare this to PV?
Test tube to sit
- RBC’s settle to bottom
- buffy coat (white cells + platelets)
- plasma (55% of total sample)
In PV the RBC layer is much larger than 45%
What is the diagnostic criteria for PV?
High haematocrit (% of RBC’s in blood)
Women: >0.52
Men: >0.48
Some patients will also have high platelets and neutrophils
At what age are you usually affected by PV?
60 yo (Equal in men and women)
What are the clinical features of PV?
- less dilute blood= more likely to form arterial thrombosis
- venous thrombosis/pulmonary emboli
- haemorrhage into skin/GI
- Pruritis (blood dilated is thicker- itchy especially after the shower)
- splenomegaly
- gout
- may transform into acute leukaemia/myelofibrosis
How do you treat PV?
- venesection (remove units of blood to maintain haematocrit below 0.45)
- aspirin (reduce risk of arterial thrombosis)
- manage CVS risk factors (check BP/cholesterol)
- sometimes use of drugs to reduce overproduction of cells
What else could cause high Hb or high haematocrit, other than PV?
-dehydration (less plasma so overall percentage of RBC’s will appear higher) e.g. diuretics
What is polycythaemia?
Increased in circulating red cell concentration with a persistently raised Hct
What is relative polycythaemia?
Where RBC mass is normal, but there is less plasma volume
Once you have ensured it is not relative polycythaemia, what is absolute polycythaemia?
Primary- PV (blood cancer causing body to make too many RBC’s)
Secondary- driven by increased EPO production
Physiologically appropriate: in response to tissue hypoxia
Physiologically inappropriate
What are the classes of secondary polycythaemia?
- physiologically appropriate EPO production (high altitude, chronic lung disease, hypoxia)
- pathological EPO production
- other causes of EPO in blood
What causes central/renal hypoxia? (Physiological appropriate high EPO level)
Central
- chronic lung disease
- R-L shunts
- training at high altitude
- CO poisoning
Renal (reduced oxygen levels within the kidney)
- renal artery stenosis
- polycystic disease (cysts in kidney)
What are some physiologically inappropriate EPO production causes?
Produce ectopic EPO (Cancers of liver and kidney, because EPO are made there) -hepatocellular carcinoma -renal cell cancer -uterine tumours -endocrine tumour
What does ectopic mean?
Abnormal
What are some other causes of high EPO?
Doping- exogenous EPO (better performance)
What is essential thrombocythaemia?
Too many platelets in blood (small dark purple stained)
- more + larger megakaryocytes (precursor) in marrow
- due to JAK2/ CALR mutations
- thrombotic events
How do you treat essential thrombocythaemia?
- CVS risk factors should be aggressively managed
- aspirin to reduce thrombosis formation
- return platelet count back to normal with hydroxycarbomine
When you see someone with high platelet count what do you look for first?
Reactive causes so these can be excluded before esssential thrombocythaemia is diagnosed (ensure it is persistent rather than transient before investigating for ET)
- infection
- inflammation
- tissue injury (burns, surgery, trauma)
- haemorrhage
- cancer
- redistribution of platelets after splenectomy/hyposplenism
What is myelofibrosis?
RARE
- clonal haemopoietic stem cell proliferation
- large easy to feel spleen
- heavily fibrotic marrow, little space for haemopoiesis (strands of fibrotic tissue which ossifies as bone)
What does myelofibrosis cause?
-splenomegaly
-hepatomegaly
Due to extramedullary haemopoiesis
What do the RBC’s look like in myelofibrosis?
Tear drop cells
Red cells trying to squeeze out of marrow, so get deformed
When does myelofibrosis develop?
De novo- as primary disease
End results of PV/ET
What happens to blood cells during myelofibrosis?
- starts with high proliferation so all counts will be high
- gradually blood counts fall> pancytopenia (all cells low)
What are some clinical features of myelofibrosis?
Features due to bone marrow failure
- low blood counts (require blood transfusions)
- consequences of splenomegaly (pain, early satiety-fill up quicker as large spleen stops stomach expanding, splenic infarction)
- lose weight
- fatigue
- can lead to leukaemia
- sweats
What is chronic myeloid leukaemia?
Picked up as an incidental finding (very high white cell count)
-myeloid cells in blood
What are the symptoms of chronic myeloid leukaemia?
- symptomatic splenomegaly
- hyperviscosity (sticky blood)- Buffy layer would be much larger
- breathless (as blood gets stuck in lungs/headaches/blurred vision-retinal/cerebral vessels, kidney failure)
- bone pain
What age group is susceptible to chronic myeloid leukaemia?
Adults
Very rare in children
What causes chronic myeloid leukaemia?
- reciprocal switch between chromosome 9 and 22 between ABL(on chromosome 9) and bit below BCR (on chromosome 22)
- forming BCR/ABL fusion on 22= PHILADELPHIA CHROMOSOME
- forms BCR/ABL protein to which substrate binds to kinase domain on it, causing substrate to become phosphorylated = tumour proliferation
- switches on a tyrosine kinase > proliferation of the cells
What drug stops chronic myeloid leukaemia?
Imatinib
-binds to BCR/ABL kinase domain stopping substrate entering kinase site, so tumour can’t proliferate
What is pancytopenia and what causes it generally?
Reduction in all cell lines (WBC’s, RBC’s and platelets)
- reduced production of cells (most common)
- increased removal of cells (immune destruction-rare to cause pancytopenia as targets all cell lines /splenic pooling-hypersplenism as more cels taken out of bloodstream/haemophagocytosis-chewing up of cells in bone marrow)
What causes pancytopenia via reduced production?
- b12/folate deficiency
- drugs (chemotherapy/antibiotics etc- look through drugs and see if any are related to causing pancytopenia)
- viruses (hepatitis B/C, EBV-causes glandular fever, HIV)
- bone marrow infiltrated by malignancy
- marrow fibrosis
- radiation
- idiopathic aplastic anaemia (occurs with no reason)
- congenital bone marrow failure
What is aplastic anaemia?
Pancytopenia with hypocellular bone marrow with no increase in fibrosis/ intrusion of other cells
-low platelets and Hb, low neutrophil count
How do you treat aplastic anaemia?
-isolate them so aren’t exposed to any infection
-replace immune system by bone marrow transplant
Mortality is very high
What are the role of platelets?
Facilitate clot formation
(Low count= bruise and bleed)
- forms platelet plug
- adhesion of platelets to damages endothelial wall and as vWF moves past them they bind activating clotting
- activate (change from disc shape to 3D shape + release granules to encourage blood clotting)
- aggregate to form plug
What are the types of disorders of platelets?
- quantative (number of platelets: e.g. thrombocytopenia)
- qualitative (normal number but defective function)
What are the types of thrombocytopenia?
-inherited (rare: autoimmune, drug, splenic destruction/pooling)
Acquired (common)
-decreased platelet production (B12/folate deficiency, aplastic anaemia, liver failure-decreased production of thrombopoietin, sepsis-overwhelming infection leads to reduced platelet formation, chemo)
-increased platelet consumption (disseminated intravascular coagulation from sepsis-clotting cascade set up and you consume all platelets, haemorrhage)
What happens when you have thrombocytopenia?
- fine dotty rash on arms, shins, hands= PURPURA
- easy bruising
- bleed from puncture sites
- mucosal bleeding (blood blisters in mouth)
- bleeding on retina (back of eye-blindness)
- intercranial haemorrhage
- severe bleeding after trauma
What is the normal platelet range?
150-400
-not symptomatic until <30
What is the most common cause of thrombocytopenia after the acquired causes?
Immune thrombocytopenic purpura (ITP)
-autoantibodies against platelet glycoproteins
-spleen gets rid of those platelets with the antibodies bound
Occur out of blue in adults/ driven by infection in children
How do you treat ITP?
Reduce immune system with steroids
Platelet transfusions don’t work as those get destroyed too
What are some disorders of platelet function?
Hereditary (rare)
Acquired (common)
-drugs (aspirin, NSAIDS, clopidogrel- all destined to inhibit normal function of platelets)
