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MEH > Lecture 10 > Flashcards

Lecture 10 Flashcards

1
Q

What does myeloproliferative disorders (cancer)/physiological reactions (to stimulus) cause?

A

Overproduction of cells

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2
Q

Give some examples of myeloproliferative disorders:

A
  • polycythaemia Vera (overproduction of RBC’s)
  • myelofibrosis (hardening process in bone marrow)
  • essential thrombocythaemia (overproduction of platelets)
  • chronic myeloid leukaemia (overproduction of myeloid series)
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3
Q

What are myeloproliferative disorders now called?

A

Myeloproliferative neoplasms

They are now classed as cancers

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4
Q

What causes myeloproliferative disorders?

A

Disregulation of multipotent haematopoietic stem cells

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5
Q

What are some clinical features of myeloproliferative disorders?

A
  • 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 )
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6
Q

What causes myeloproliferative disorders often?

A

Point mutation in one copy of the Janus Kinase 2 gene (JAK2)

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7
Q

What does the mutated JAK2 gene do?

A

The abnormal cytoplasmic tyrosine kinase on chromosome 9, causes an increase in proliferation and survival of haematopoietic precursors

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8
Q

When do you see cytogenetic abnormalities in myeloproliferative disorders?

A
  • at the beginning of disorder
  • secondary cytogenetic abnormalities due to increased proliferation (so these conditions can lead to other conditions such as acute leukaemia)
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9
Q

Why is it good that we have identified the specific JAK2 gene?

A

So we can make specific drugs that target the mutated protein

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10
Q

What is polycythaemia Vera?

A

Too many RBC’s

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11
Q

What does a normal blood sample look like + compare this to PV?

A

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%

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12
Q

What is the diagnostic criteria for PV?

A

High haematocrit (% of RBC’s in blood)
Women: >0.52
Men: >0.48

Some patients will also have high platelets and neutrophils

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13
Q

At what age are you usually affected by PV?

A

60 yo (Equal in men and women)

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14
Q

What are the clinical features of PV?

A
  • 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
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15
Q

How do you treat PV?

A
  • 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
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16
Q

What else could cause high Hb or high haematocrit, other than PV?

A

-dehydration (less plasma so overall percentage of RBC’s will appear higher) e.g. diuretics

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17
Q

What is polycythaemia?

A

Increased in circulating red cell concentration with a persistently raised Hct

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18
Q

What is relative polycythaemia?

A

Where RBC mass is normal, but there is less plasma volume

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19
Q

Once you have ensured it is not relative polycythaemia, what is absolute polycythaemia?

A

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

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20
Q

What are the classes of secondary polycythaemia?

A
  • physiologically appropriate EPO production (high altitude, chronic lung disease, hypoxia)
  • pathological EPO production
  • other causes of EPO in blood
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21
Q

What causes central/renal hypoxia? (Physiological appropriate high EPO level)

A

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)
22
Q

What are some physiologically inappropriate EPO production causes?

A 
Produce ectopic EPO
(Cancers of liver and kidney, because EPO are made there)
-hepatocellular carcinoma
-renal cell cancer
-uterine tumours
-endocrine tumour
23
Q

What does ectopic mean?

A

Abnormal

24
Q

What are some other causes of high EPO?

A

Doping- exogenous EPO (better performance)

25
Q

What is essential thrombocythaemia?

A

Too many platelets in blood (small dark purple stained)

  • more + larger megakaryocytes (precursor) in marrow
  • due to JAK2/ CALR mutations
  • thrombotic events
26
Q

How do you treat essential thrombocythaemia?

A
  • CVS risk factors should be aggressively managed
  • aspirin to reduce thrombosis formation
  • return platelet count back to normal with hydroxycarbomine
27
Q

When you see someone with high platelet count what do you look for first?

A

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
28
Q

What is myelofibrosis?

A

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)
29
Q

What does myelofibrosis cause?

A

-splenomegaly
-hepatomegaly
Due to extramedullary haemopoiesis

30
Q

What do the RBC’s look like in myelofibrosis?

A

Tear drop cells

Red cells trying to squeeze out of marrow, so get deformed

31
Q

When does myelofibrosis develop?

A

De novo- as primary disease

End results of PV/ET

32
Q

What happens to blood cells during myelofibrosis?

A
  • starts with high proliferation so all counts will be high

- gradually blood counts fall> pancytopenia (all cells low)

33
Q

What are some clinical features of myelofibrosis?

A

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
34
Q

What is chronic myeloid leukaemia?

A

Picked up as an incidental finding (very high white cell count)
-myeloid cells in blood

35
Q

What are the symptoms of chronic myeloid leukaemia?

A
  • 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
36
Q

What age group is susceptible to chronic myeloid leukaemia?

A

Adults

Very rare in children

37
Q

What causes chronic myeloid leukaemia?

A
  • 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
38
Q

What drug stops chronic myeloid leukaemia?

A

Imatinib

-binds to BCR/ABL kinase domain stopping substrate entering kinase site, so tumour can’t proliferate

39
Q

What is pancytopenia and what causes it generally?

A

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)
40
Q

What causes pancytopenia via reduced production?

A
  • 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
41
Q

What is aplastic anaemia?

A

Pancytopenia with hypocellular bone marrow with no increase in fibrosis/ intrusion of other cells
-low platelets and Hb, low neutrophil count

42
Q

How do you treat aplastic anaemia?

A

-isolate them so aren’t exposed to any infection
-replace immune system by bone marrow transplant
Mortality is very high

43
Q

What are the role of platelets?

A

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
44
Q

What are the types of disorders of platelets?

A
  • quantative (number of platelets: e.g. thrombocytopenia)

- qualitative (normal number but defective function)

45
Q

What are the types of thrombocytopenia?

A

-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)

46
Q

What happens when you have thrombocytopenia?

A
  • 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
47
Q

What is the normal platelet range?

A

150-400

-not symptomatic until <30

48
Q

What is the most common cause of thrombocytopenia after the acquired causes?

A

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

49
Q

How do you treat ITP?

A

Reduce immune system with steroids

Platelet transfusions don’t work as those get destroyed too

50
Q

What are some disorders of platelet function?

A

Hereditary (rare)
Acquired (common)
-drugs (aspirin, NSAIDS, clopidogrel- all destined to inhibit normal function of platelets)

MEH (22 decks)

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