HAEMATOLOGY - MYELOPROLIFERATIVE NEOPLASMS

Question 1

What are myeloproliferative neoplasms?

Answer 1

Proliferation of bone marrow cells from the myeloid lineage (RBC, Plt, neutrophils, basophils, mast cells and eosinophils)

Question 2

What are the different myeloproliferative neoplasms?

Answer 2

Polycthemia Vera - RBC
Essential thrombocythemia - Plt
CML - granulocytes
Primary myelofibrosis - bone marrow fibrosis
Chronic eosinophilia leukaemia
Systemic mastocytosis

Question 3

What is polycythemia?

Answer 3

A myeloproliferative disorder where there is excess proliferation of RBCs

Question 4

What are the different types of secondary polycythaemia?

Answer 4

A relative polycythemia results from decreased plasma volume but normal RBC mass e.g. dehydration, diuretics

Appropriate absolute polycythaemia - physiological response to any cause of chronic hypoxia where we get low O2 sats causing increased EPO production so RBC mass increases but plasma volume remains the same

Inappropriate absolute polycythaemia - pathological overproduction of EPO e.g. renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma etc . EPO levels and RBC mass are increased but plasma volume is normal

Question 5

What is polycythemia Vera

Answer 5

Primary polycythaemia
The malignant proliferation of a clone derived from a single pluripotent stem cell.
Caused by a mutation in JAK2 in 95% of cases
There is excess proliferation in RBCs, WBCs and platelets leading to hyperviscocity and thrombosis

Question 6

Outline the pathophysiology of polycythemia Vera

Answer 6

JAK2 is found on haematopoietic stem cells and, when activated by EPO, causes the cell to divide and produce blood cells
In polycythemia Vera, JAK2 is always on due to a mutation so the cell binds even in the absence of EPO
= massive RBC production
As these keep proliferating they will eventually become the predominant haematopoeitic stem cells in the bone marrow
In time these cells start to die out and cause fibrosis of the bone marrow. Eventually it can’t produce blood cells leading to anaemia, thrombocytopenia and leukopenia. = spent phase (now its secondary myelofibrosis)

Question 7

How is polycythemia treated?

Answer 7

Venesection
Chemotherapy with hydroxyurea in those who don’t tolerate Venepuncture
JAK2 inhibitor ruxolitinib
Low dose aspirin
Anagrelide - inhibits megakaryocyte differentiation
Avoiding very hot baths to prevent pruritis
Allopurinol to block uric acid production

Question 8

Why is uric acid high in polycythemia Vera?

Answer 8

occur due to the high turnover of red blood cells, which results in higher-than-normal uric acid production

Question 9

What proportion of polycythemia Vera cases progress to myelofibrosis?

Answer 9

12-21% of cases

Question 10

What proportion of polycythemia Vera cases progress into AML?

Answer 10

5%

Question 11

What can polycythemia Vera develop into?

Answer 11

Myelofibrosis and AML

Question 12

What is essential thrombocythemia?

Answer 12

A myeloproliferative neoplasm characterised by a persistently raised platelet count. Patients usually have normal Hb levels, but mild anaemia may occur

Question 13

Whats the pathophysiology of essential thrombocythemia?

Answer 13

A mutation in JAK2 gene so that its always on and cases haematopoetic cells to divide even in the absence TPO stimulation (50%)
There can also be a mutation in the thrombopoetin receptor (25%) or chaperone protein calreticulin too (25%)

Question 14

What can essential thrombocythemia develop into?

Answer 14

Myelofibrosis and acute leukaemia

Question 15

How does essential thrombocythaemia present?

Answer 15

Thrombotic complications
Erythromelalgia
Splenomegaly

Also:
Fatigue, headache, dizziness, nausea, tinnitus. Numbness in hands and feet
Predisposed to bleeding

Question 16

How is essential thrombocythaemia diagnosed?

Answer 16

Increased Plt count
Bone marrow biopsy - increased megakaryocytes and genetic mutations e.g. JAK2 or CalR
There must also be no alternative diagnosis and the absence of any indicator of reactive thrombocytosis

Question 17

What is thrombocytosis? What are the 2 subtypes?

Answer 17

a disorder in which your body produces too many platelets.
It’s called reactive thrombocytosis or secondary thrombocytosis when the cause is an underlying condition, such as an infection

Question 18

How is essential thrombocythaemia managed?

Answer 18

Low dose aspirin to rescue thrombotic risk
Hydroxyurea for cytoreduction
Interferon-Alfa is also effective used for young patients or pregnancy women

Question 19

What can cause secondary thrombocytosis?

Answer 19

Those who have had splenectomy’s
Autoimmune rheumatic disorders
Malignancy
Acute bleeding and blood loss
Infections
Iron deficiency
Haemolytic anaemia

Question 20

What is myelofibrosis?

Answer 20

A debilitating myeloproliferative neoplasm characterised by clonal proliferation of stem cells and abnormal myeloid cells in the bone, liver, spleen etc

Question 21

What are the 2 types of myelofibrosis?

Answer 21

Primary - idiopathic (myeloproliferative neoplasm)
Secondary - arises secondary to other things e.g. leukaemia, autoimmune diseases, toxins, glycogen storage disease

Question 22

Whats the pathophysiology of myelofibrosis?

Answer 22

50% had a JAK2 mutation and 25% have CalR mutation
These both lead to hyperplasia of abnormal megakaryocytes which release fibroblast stimulating factors such as platelet derived growth factors. This increases fibrosis in the bone marrow by excessive collagen deposition which replaces haematopoetic stem cells leading to anaemia

Question 23

What are WBC and Plt counts like in myelofibrosis?

Answer 23

Variable from normal to low depending on the extent of bone marrow fibrosis

Question 24

What are the symptoms of myelofibrosis?

Answer 24

Cytokines released into the blood cause fever, weight loss and decreased appetite
Fatigue and SOB - anaemia
Bleeding and bruising - thrombocytopenia
Fullness or pain in upper abdomen because of hepatosplenomegaly - can cause Loss of appetite and weight loss - extramedullary haematopoeisis
Gout
Pruritis
Severe pain related to respiration may indicate perisplenitis secondary to splenic infarction

Question 25

How do you investigate myelofibrosis?

Answer 25

FBC - anaemia, low Hb, WCC may be high and PLt may be high
Blood film - teardrop cells (dacrocytes)
Bone marrow aspiration - bone marrow trephine can show markedly increased fibrosis
Cytogenic and molculear analysis shows absence of Philadelphia chromosome which helps differentiate between MF and CML. Look for JAK2 mutation or CALR mutation

Question 26

How do you manage myelofibrosis?

Answer 26

Blood transfusions
Allopurinol
Ruxolotinib - JAK2 inhibitor for splenomegaly
Allergenic stem cell transplants may be curative in young people but carries a high risk of mortality

Question 27

Whats the prognosis of polycythemia vera?

Answer 27

average life expectancy after diagnosis with polycythemia vera to be about 15 years.
The most common cause of death is complications from blood clots (about 33%)

Question 28

Whats the prognosis of essential thrombocythaemia?

Answer 28

an expected survival of 18 years

Question 29

Whats the prognosis of myelofibrosis?

Answer 29

4-5 years

Question 30

What are the symptoms of polycythemia vera?

Answer 30

Depending on where blood clots form: Blurred vision, headaches, stroke, angina, MI, peptic ulceration, Budd-chiari syndrome
Plethoric face - constant blush
Pruritis after warm showers
Erythromelalgia
Gout
Early satiety and weight loss

Question 31

Why can polycthemia vera cause pruritis?

Answer 31

Mast cells are increased and cause increased histamine release in response to heat

Question 32

What is erythromelalgia and why does polycythemia vera cause it?

Answer 32

Episodes of redness, intense warmth and pain in palms and soles

Small blood clots from in the distal extremities due to hyperviscocity or increase platelet count

Question 33

Why can polycythemia vera cause gout?

Answer 33

Increased RBC production means increased DNA synthesis = increased purine metabolism = hyperuricaemia

Question 34

Why can polycythemia vera cause early satiety and weight loss?

Answer 34

The spleen gets filled up with old blood cells
This pushes against the stomach causing early satiety and eventually weight loss

Question 35

How can you differentiate between essential thrombocythaemia and polycythemia vera based on symptoms?

Answer 35

Pruritis is unlikely in essential thrombocythemia
ET also has other symptoms like fatigue, headache, dizziness, nausea, tinnitus, numbness in hands and feet

Question 36

What is extramedullary haematopoesis?

Answer 36

the formation and activation of blood cells outside the bone marrow, as a response to hematopoietic stress when the proper functioning of the marrow is deteriorated

Question 37

How is polycythemia vera diagnosed?

Answer 37

It’s a diagnosis of exclusion - you have to think through all other causes before considering it
**Hb >16.5g/dL in men or >16 in women
**HCT >49% in women or 48% in women
RBC mass increased
Uric acid can be increased
Bone marrow biopsy can show JAK2 mutation
Low EPO

Question 38

What is a symptom specific to myelodysplastic syndromes?

Answer 38

Aquagenic pruritus - skin itching when wet

Question 39

How do we diagnose myelodysplastic syndromes?

Answer 39

Look for JAK2 mutations

Question 40

Why can COPD cause polycthemia?

Answer 40

Impaired oxygen exchange in the lungs can result in a low PaO2 which results in stimulation of EPO release from the kidneys. EPO stimulates erythropoiesis and increases red cell mass, thereby resulting in polycythaemia.