Myeloproliferative Disorders

Question 1

What is myeloproliferative neoplasms

Answer 1

Clonal HSCs disorder with increased production of RBCs &/ granulocytes &/ platelets (doesn’t affect lymphocytes)

Question 2

What are the sub-types of chronic myeloproliferative neoplasms

Answer 2

BCR-ABL1 positive
- Chronic myeloid leukaemia

BCR-AB1 negative
- Primary myelofibrosis (abnormal proliferation fibroblasts)
- Essential thrombocythaemia (over production platelets)
- Polycythaemia Vera (over production RBCs)

Question 3

What are 4 reactive causes of elevated RBCs (secondary polycythaemia)

Answer 3

• Chronic hypoxia (COPD, heart disease, OSA, smoking etc)
• Kidney disease
• Erythropoietin secreting tumour
• Medications (anabolic steroids, diuretics)

NOTE: diuretics/ dehydration cause pseudopolycthaemia (not a true elevation in RBCs)

Question 4

What are 3 reactive causes of elevated neutrophils

Answer 4

Bacterial infections
Acute inflammation & tissue damage
Corticosteroids

Question 5

What are 2 reactive causes of elevated eosinophils

Answer 5

Allergy
Parasitic infection

Question 6

What are 4 reactive causes of elevated platelets

Answer 6

Infection
Iron deficiency
Malignancy
Blood loss

Question 7

What would make you consider a myeloproliferative neoplasm

Answer 7

• High neutrophil +/- RBC +/- platelet +/- eosinophil/basophil
• With NO reactive explanation
• Splenomegaly or thrombosis in unusual place increases suspicion

Question 8

List features common to myeloproliferative neoplasm

Answer 8

• Asymtpomatic
• Increased cell turnover - gout, fatigue, weight loss, sweats
• Splenomegaly S&S - referred pain, early satiety
• Marrow failure (less likely in Polycythaemia Vera and ET)
• Thrombosis (TIA, MI, claudication etc)

Question 9

What is chronic myeloid leukaemia

Answer 9

A clonal stem cell disorder that affects the primitive compartment (HSCs & myeloid progenitors) & causes granulocytosis/ neutrophilia (+/- thrombocytosis)

Question 10

What translocation & chromosome is characteristic of CML (~90%)

Answer 10

Translocation of ABL gene on chromosome 9 to attach with the BCR gene on chromosome 22

This causes a BCR-ABL1 gene aka Philadelphia chromosome

Question 11

CML Pathophysiology

Answer 11

• BCR-ABL1 gene/translocation (Philadelphia chromosome)
• Increased transformation from HSCs to myeloid progenitors
• Subsequent excessive myeloid progenitor proliferation
• Then myeloid progenitor maturation (‘chronic’)
• Resultant excessive production of granulocytes & precursors (& occasionally thrombocytosis)

Question 12

What are the three phases of CML

Answer 12

• Chronic (3-5yrs) - granylocytosis & myelocytosis +/- thrombocytosis, no maturation defect
• Accelerated phase - genetics ‘hits’, increase in blasts, loss of maturation
• Blast crisis - reminiscent of acute leukaemia with maturation defect

Question 13

CML clinical features

Answer 13

• Common features of myeloproliferative neoplasms
• Hyperleucocytosis S&S
• Marrow failure similar to AML/ALL in blast crisis

Question 14

CML blood findings (chronic phase)

Answer 14

• Normal or low Hb
• Leukocytosis with neutrophilia
• Myeloid precursors (myelocytes)
• +/- Eosinophilia, basophilia, thrombocytosis

Question 15

CML investigations

Answer 15

Blood count & film
Cytogenetics using FISH to detect t(9;22) (of blood/ marrow)
Bone marrow biopsy not always necessary

Question 16

What is the gene product of the BCR-ABL1 gene

Answer 16

A tyrosine kinase - causes abnormal phosphorylation

Question 17

CML treatment

Answer 17

Tyrosine kinase inhibitors e.g. Imatinib

Question 18

What is characteristic of polycthaemia Vera

Answer 18

High Hb accompanied by a TRUE INCREASE IN RBC MASS
Note: can also have excessive production of other lineages

Question 19

Polycthaemia Vera vs secondary polycthaemia vs pseudopolycythaemia

Answer 19

Polycythaemia Vera - genetic mutation or defect in the bone marrow that produces a true increase in RBC mass

Secondary Polycythaemia - underlying condition that causes increased RBC production & hence increased RBC mass

Pseudopolycthaemia - High Hb without a true increase in RBC mass

Question 20

Is there an increased plasma viscosity in polycthaemia Vera

Answer 20

No - only a raised blood viscosity

Question 21

Polycthaemia Vera clinical features

Answer 21

Clinical features common to MPN
Clinical features of raised blood viscosity - headache, fatigue
Itch (aquagenic puritis)

Question 22

What gene is usually mutated in Polycythaemia Vera

Answer 22

JAK2 gene mutation (~95%)

Question 23

What is the impact of JAK2 mutation

Answer 23

Mutation (substitution) results in abnormal signalling =>
Activation of erythropoiesis in the absence of ligand

Question 24

Polycthaemia vera investigations

Answer 24

History to check for secondary/pseudo polycthaemia
Examination to check for e.g. splenomegaly
FBC & blood film
JAK2 mutation

Question 25

Polycthaemia Vera treatment

Answer 25

Venesection (immediate symptom control) Aspirin (thrombosis prevention) Cytotoxic oral chemotherapy e.g. hydroxycarbamide (definitive)

Question 26

What is essential thrombocythaemia

Answer 26

Uncontrolled production of abnormal platelets

Question 27

Why can essential thrombocythaemia cause both a thrombosis as well as bleeding

Answer 27

Increased platelets => thrombosis Increased use of vWF => acquired vWF disease => bleeding

Question 28

Essential thrombocythaemia clinical features

Answer 28

Common features of MPN Thrombosis & bleeding

Question 29

Essential thrombocythaemia investigations

Answer 29

- Exclude relative thrombocytosis!!! (B I M I) - Exclude CML by BCR-ABL1 testing - Blood genetics e.g. JAK2 mutations (diagnostic!) - Bone marrow biopsy (elevated megakaryocytes is characteristic of ET)

Question 30

Essential thrombocythaemia treatment

Answer 30

Usual treatment - anti-platelets (If very high risk of thrombosis) - hydroxycarbamide Other - anagrelide, interferon alpha

Question 31

What is myelofibrosis

Answer 31

Abnormal proliferation of marrow fibroblasts causing bone marrow fibrosis and lack of production of normal cells Can be primary - idiopathic Can be secondary - post-polycythaemia/ET

Question 32

Characteristic blood film of myelofibrosis

Answer 32

Leukoerythroblastic blood film +/- teardrop shaped RBCs

Question 33

Myelofirbosis clinical features

Answer 33

Marrow failure - anaemia, bleeding, infection Bone marrow fibrosis with no cause Extramedullary haematopoiesis (hepato/splenomegaly) Hypercatabolism - Night sweats & weight loss

Question 34

What are three causes of leucoerythroblastic haematopoiesis

Answer 34

Reactive e.g. sepsis Marrow infiltration e.g. malignancy Myelofibrosis

Question 35

Myelofibrosis investigations

Answer 35

Blood count & film - leukoerythroblastic & tear shaped RBCs Bone marrow - dry aspirate, firbosis on trephine biopsy Genetic testing - JAK2, CALR, MLP

Question 36

Myelofibrosis treatment supportive care

Answer 36

Blood transfusion, platelets, antibiotics

Question 37

Myelofibrosis gold standard treatment

Answer 37

JAK2 inhibitors (Or allergenic stem cell transplantation in select few)

Question 38

Essential thrombocythaemia diagnostic test

Answer 38

Blood genetics e.g. JAK2 mutation

Question 39

Essential thrombocythaemia characteristic bone marrow features

Answer 39

Increased megakaryocytes

Question 40

Hyperleukocytosis S&S

Answer 40

Abnormal aggregation & clumping of WBCs in blood vessels => impaired blood flow & oxygen delivery to tissues => e.g. headaches, confusion, SOB etc

Question 41

What are symptoms of splenomegaly

Answer 41

Early satiety Pain in LUQ & referred pain Pancytopenia Compression of nearby structures e.g. portal hypertension

Question 42

Why does myelofirbosis cause hypercatabolism

Answer 42

Increased production of inflammatory cytokines by abnormal marrow cells => chronic inflammation

Question 43

What are the three mutations in PV, ET & myelofirbosis (MPN)

Answer 43

JAK2 (main), CALR, MLP