Haematology Myeloproliferative Disorders

Question 1

Myeloproliferative disorders: Description

Answer 1

Clonal haematological disorders characterised by over-production of blood cells and a tendency to transformation to acute leukaemia.

Question 2

Myeloproliferative disorders: Epi

Answer 2

Generally diseases of middle or older age groups.

Incidence: 2 cases per 100,000

Question 3

Myeloproliferative disorders: Three related disorders with similar acquired genetic defects (e.g. Janus Kinase Jak-2 mutations)

Answer 3

1. Primary polycythaemia
2. Essential thrombocythaemia (increased platelets)
3. Idiopathic myelofibrosis

Question 4

Myeloproliferative disorders: Mixed myeloid progenitor

Answer 4

RBC/Platelets/ Neutophil/Monocyte/ Basophil/Eosinophil

Question 5

Myeloproliferative disorders: Similar disorders

Answer 5

Chronic myeloid leukaemia (CML)

Question 6

Myeloproliferative disorders: Essential thrombocythaemia

Answer 6

Increased platelet number

Question 7

Myeloproliferative disorders: Myelofibrosis

Answer 7

Affects stomal calsin BM – scarring and fibrosis in bone marrow

Question 8

Polycythaemia → Defined by

Answer 8

Defined by the packed cell volume (PCV): a raised PCV of >0.51 in males and >0.48 in females requires further investigation.

Question 9

Polycythaemia → Measure

Answer 9

The True red cell mass and the plasma volume can be measured.
Involves radionucelotide labelling of red cells and albumen, respectively (less common).

Question 10

Polycythaemia → The absolute measurements allows

Answer 10

“True” polycythaemia to be distinguished from an “apparent” polycythaemia (decreased plasma volume).

Question 11

Polycythaemia → Symptos and Signs of Primary Polycythaemia

Answer 11

Hyperviscosity:
Hypervolaemia:
Hypermetabolism:

Question 12

Hyperviscosity:

Answer 12

Haemostasis (thrombosis – stroke, transient ischaemic attacks, digital ischaemia), haemorrhage, headache

Question 13

Hypervolaemia:

Answer 13

Plethora, hypertension and splenomegaly

Question 14

Hypermetabolism:

Answer 14

Pruritis, weight loss, sweats, gout

Question 15

Polycythaemia → Packed cell volume >0.51 (males)

>0.48 (females) with a raised red cell mass (absolute) definition

Answer 15

Primary polycythaemia

Secondary polycythaemia

Question 16

Polycythaemia →Packed cell volume >0.51 (males)

>0.48 (females) Normal red cell mass diagnosis

Answer 16

Apparent polycythaemia

Question 17

Polycythaemia → True polycythaemia

Answer 17

Raised RBC

Plasma volume slightly reduced but overall volume higher

Question 18

Polycythaemia → Apparent polycythaemia

Answer 18

Overall blood volume is less. Red cell mass normal (Can occur burns, alcohol, smoking)

Question 19

Differential diagnosis of a true polycythaemia

Answer 19

Primary Polycythaemia

Secondary Polycythaemia

Question 20

Secondary Polycythaemia

Answer 20

Drive from EPO due to a stimulus.
• Hypoxaemia e.g. chronic lung disease, cyanotic congenital heart disease, sleep apnoea.
• Renal disease e.g. hypernephroma, polycystic kidney disease (cysts causes pressure on cells leading to increased EPO)
• Miscellaneous e.g. hepatomas, cerebellar haemangioma, massive fibroids, high oxygen affinity haemoglobins.

Question 21

Symptoms and Signs of Primary Polycythaemia

Answer 21

• Facial plethora
• Headache
• Mental clouding
• Pruritis
• Hypertension
• Splenomegaly
• Gout
• Occlusive vascular lesions e.g. stroke, transient ischaemic attacks, digital ischemia
• Bleeding
• Hyper viscosity

Question 22

Polycythaemia Specialist Investigations

Answer 22

1. Serum Erythropoietin → Low in primary polycythaemia
2. Jak 2 mutation
3. Bone marrow examination
4. Abdominnal ultrasound to assess spleen size

Question 23

Jak 2 mutation

Answer 23

Specific V617F mutation in Jak 2 signal transduction protein linked to erythropoietin receptor. This “activating” mutation promotes proliferation of stem cells.
Identified in 90% of patients with polycythaemia vera and 50% of patients with essential thrombocythaemia and myelofibrosis (30-50%) – permanently switched on – increased RBC.

Question 24

V617F

Answer 24

Found on cell surface involved in transfer of EPO binding signal to the cell

Question 25

Bone marrow examination for

Answer 25

Erythroid hyperplasia | Fibrosis (low levels)

Question 26

Treatment

Answer 26

1. Repeated venesections to maintain a PCV of <0.45 (aiming for (slightly lower than normal) 2. Hydroxyurea if there is also thrombocytosis (concern increase risk of leukaemia. 3. Low doe aspirin (if there are no bleeding manifestations) – prevent arterial clots (can’t tolerate other treatments) 4. Radioactive phosphorus

Question 27

Radioactive phosphorus

Answer 27

Single disease controls disorder for 12-18 months but associated with increased risk of leukaemia. Reserved for elderly frail patients.

Question 28

Progression and Prognosis

Answer 28

Untreated patients: survival 18 months (clots and myelofibrosis and leukaemia) Treated patents: survival 10-15 years In the longer term, 20% of patients transforms to myelofibrosis and about 5% to acute leukaemia (need monitoring)

Question 29

Essential Thrombocythaemia: Definition

Answer 29

A myeloproliferative disorder characterised by the presence of a persistent thrombocytosis (platelet count >450 x 109/L) increased + 600

Question 30

Essential Thrombocythaemia: JAk2 mutation

Answer 30

Positive in 50% of cases: useful for diagnosis (not as useful as in polycythaemia)

Question 31

Essential Thrombocythaemia: Diagnosis

Answer 31

Otherwise, this is a diagnosis of exclusion and other reactive causes of a raised platelet count first need to be considered: e.g. infection, inflammation, malignancy and bleeding (reactive picture).

Question 32

Essential Thrombocythaemia: Presentation

Answer 32

* 25-50% of patients present with microvascular occlusive events (e.g. burning pain in extremities or digital ischaemia), major vascular occlusive events or haemorrhage (interference with clotting cascade). * Erythromelalgia in essential – redness and burning the feet and hands * Livedo reticularis in essential thrombocythaemia.

Question 33

Essential Thrombocythaemia: Blood film in thrombocythaemia

Answer 33

* Large Platelets (variation in size) * Iron deficiency * Hypochrominc RBCs – Iron deficiency * CHECK THIS

Question 34

Essential Thrombocythaemia: Bone marrow morphology in essential thrombocytaemia

Answer 34

* Megakaryocytes and abnormal nucleation | * CHECK THIS

Question 35

Essential Thrombocythaemia: Treatment

Answer 35

1. Low dose aspirin (unless history of bleeding) 2. Hydroxyurea (carbomide(same thing)) 3. Anagrelide (younger patients) – chemoagents Transformatino to myelofibrosis or acute leukaemia may occur in a small minority of patients long term – Primary polycythaemia.

Question 36

Idiopathic Myelofibrosis: Main Clinical Features

Answer 36

* Bone marrow fibrosis (scar tissue leading to extramedullary) * Extramedullary haemopoiesis (blood cell production in the liver and spleen) * Splenomegaly – often massive * Anaemia with leucoerythroblastic blood picture (precursors to RBC/WBC which you wouldn’t expect to see * Weight loss, fatigue, bleeding

Question 37

Idiopathic Myelofibrosis: The Primary Malginant Process involves

Answer 37

Megakaryocytes: generate growth factors such as platelet-derived growth factor which stimulate fibroblast proliferation (stromal cell)

Question 38

Idiopathic Myelofibrosis:Fibroblast proliferation produce

Answer 38

Produce reticulin and scar bone marrow 1st – proliferation phase 2ndry – Splenomegaly and drop blood counts

Question 39

Idiopathic Myelofibrosis: X-ay changes

Answer 39

Myelosclerosis

Question 40

Idiopathic Myelofibrosis:Blood Picture

Answer 40

Leucoerythroblastic blood picture

Question 41

Idiopathic Myelofibrosis:Bone Marrow histology

Answer 41

Normally – fat cells and organised set of cells. ‘Starry night’ Stranding of cells into other areas – fat spaces

Question 42

Idiopathic Myelofibrosis: Determine severity of bone marrow histology

Answer 42

Fibrosis criteria to determine severity

Question 43

Idiopathic Myelofibrosis: Treatment

Answer 43

Blood Transfusions if symptomatic anaemia. Thrombocytopnaenia – symptomatic difficulty w/ splenomegaly therefore increased destruction and therefore not helpful. Splenectomy to correct anaemia or treat painful enlargement of the spleen.

Question 44

Idiopathic Myelofibrosis: | Prognosis

Answer 44

2-4 years with death due to haemorrhage, infection or transformation to acute leukaemia → poor Stem cell transplantation for younger patients (<65 years). Jak 2 inhibitors for recently licensed: early trials show reduction in splenomegaly and constituitional symptoms and improved survival.