S5 Haemopoiesis Gone Wrong

Question 1

What can overproduction of cells be caused by?

Answer 1

• myeloproliferative disorders

* physiological reactions

Question 2

What are 4 examples of myeloproliferative disorders?

Answer 2

• essential thrombocythaemia
• polycythaemia vera
• myelofibrosis
• chronic myeloid leukaemia

Question 3

What mutation can cause myeloproliferative disorders?

Answer 3

Specific point mutation in one copy of the Janus kinase 2 gene (JAK2) - codes for a cytoplasmic tyrosine kinase which causes increased proliferation and survival of haemopoietic precursors

Question 4

What is Polycythaemia Vera?

Answer 4

High haematocrit or raised cell mass
(Some also have high platelet and neutrophil count)
JAK2 mutation is present in 95% of patients
Equal in men (haematocrit >0.52) and women (haematocrit >0.48), median age 60yrs

Question 5

What are the clinical features of Polycythaemia Vera?

Answer 5

• significant cause of arterial thrombosis
• venous thrombosis
• haemorrhage into skin/GI tract
• pruritis (blood in peripheries is thicker)
• splenic discomfort, splenomegaly
• gout
• can go onto myelofibrosis or acute leukaemia

Question 6

How do you manage Polycythaemia Vera?

Answer 6

• venesection to maintain the haematocrit below 0.45
• aspirin (75mg)
• manage the CVS risk factor
• sometimes consider drugs to reduce overproduction of cells

Question 7

What is polycythaemia?

Answer 7

An increase in circulating red cell concentration typified by a persistently raised haematocrit

Question 8

What can cause red cell concentration to increase?

Answer 8

• relative - normal red cell mass, but a reduced plasma volume
• absolute - increase in red cell mass - primary or secondary?

Question 9

What are primary and secondary increases in red cell mass (absolute) - Polycythaemia?

Answer 9

Primary - Polycythaemia Vera

Secondary - driven by erythropoietin (EPO) production (in response to hypoxia or due to an abnormally high affinity for Hb)

Question 10

What is essential thrombocythaemia?

Answer 10

High platelet count (excess platelets in blood)
(Also large and excess megakaryocytes in bone marrow)

Can lead to thrombosis

Question 11

How do you manage essential thrombocythaemia?

Answer 11

• manage CVS risk
• aspirin
• give hydroxycarbomide to high risk patients to return platelet count to normal

Question 12

What classes as a high risk patient with essential thrombocythaemia?

Answer 12

• over 60 yrs
• have a platelet count of over 1500
• have disease related thrombosis/haemorrhage

Question 13

If there is a high platelet count, what should you do before assume into essential thrombocythaemia?

Answer 13

Look for and excuse any reaction causes e.g.

• infection
• inflammation
• haemorrhage
• cancer
• redistribution of platelets after a splenectomy or in hyposplenism

Is it persistent rather than transient?

Question 14

What does myelofibrosis cause?

Answer 14

Causes massive splenomegaly with/without hepatomegaly due to extramedullary haemopoiesis

Question 15

What is myelofibrosis?

Answer 15

Fibrosis in bone marrow tissue so there is little space for haemopoiesis

Question 16

What do RBCs look like on a blood film for myelofibrosis?

Answer 16

Tear drop shaped as they’re squeezed out of the bone marrow

Question 17

How can myelofibrosis occur?

Answer 17

• as an end result of Polycythaemia Vera or essential thrombocythaemia
• as a primary disease

Question 18

What are the clinical features of myelofibrosis?

Answer 18

• if patient has advanced disease have severe symptoms - fatigue an sweats
• due to splenomegaly experience pain, early satiety (fill up quickly as speed is reducing stomach size) and splenic infarction
• can transform into leukaemia
• early death

Question 19

How do you manage chronic marrow failure?

Answer 19

Blood transfusions

Question 20

What does a patient with chronic myeloid leukaemia present with? Who is it more common in?

Answer 20

Presents with high WCC, symptomatic splenomegaly, hyperviscosity and bone pain

Disease in adults (rare in children)

Question 21

What can you see on the blood film (and marrow) for someone with chronic myeloid leukaemia?

Answer 21

Excess of all myeloid series from blast through to fully mature neutrophils

Question 22

What drug can be used to treat chronic myeloid leukaemia? What used to be used as treatment?

Answer 22

Imatinib - inhibits BCR-abl fusion from phosphorylating the substrate which switches on a receptor tyrosine kinase that drives proliferation

Previously standard treatment was bone marrow transplant (not very good treatment)

Question 23

What is pancytopenia?

Answer 23

Reduction in white blood cells, red blood cells and platelets

Question 24

How can pancytopenia arise?

Answer 24

• reduced production

* increased removal

Question 25

How can pancytopenia arise from reduced production?

Answer 25

* B12/folate deficiency * bone marrow infiltration by malignancy * marrow fibrosis * radiation * drugs * viruses * idiopathic aplastic anaemia * congenital bone marrow failure

Question 26

How can pancytopenia arise from increased removal?

Answer 26

* immune destruction (rare) * splenic pooling (leads to hypersplenism and splenomegaly) * haemophagocytosis (very rare)

Question 27

What is aplastic anaemia?

Answer 27

Pancytopenia with a hypocellular bone marrow - not caused by an abnormal infiltrate or an increase in reticulin (fibrosis) Autoimmune disease - bone marrow fails to produce RBC, WBC and platelets

Question 28

Is aplastic anaemia hard or easy to cure?

Answer 28

Hard (immune treatments and bone marrow transplant) but still a high mortality rate (deaths due to neutropenic infection or bleeding)

Question 29

What are the 3 stages in platelet action?

Answer 29

1. Adhesion - to damage endothelial wall (and do vWF - activated clotting) 2. Activation - change in shape from disc, release of granules 3. Aggregation - clumping together of more platelets to form a ‘plug’

Question 30

What are the two types of platelet disorders?

Answer 30

* quantitative - low number of platelets | * qualitative - normal number but defective function (thrombocythaemia)

Question 31

How can you get thrombocytopenia?

Answer 31

* acquired (common) - decreased platelet production, increased platelet consumption, increased platelet destruction * inherited (rare syndromes)

Question 32

How can platelet production be decreased?

Answer 32

* B12 or folate deficiency * acute leukaemia or aplastic anaemia * liver failure (reduced production of thrombopoietin) * sepsis * cytotoxic chemotherapy

Question 33

How can platelet consumption be increased?

Answer 33

* massive haemorrhage * disseminated intravascualar coagulation (DIT) in sepsis * thrombotic thrombocytopenic purpura (clotting in small blood vessels)

Question 34

How can platelet destruction be increased?

Answer 34

* autoimmune thrombocytopenic purpura (blood doesn’t clot normally) * drug induced e.g. heparin * hypersplenism - increased destruction and splenic pooling of platelets

Question 35

What are the consequences of severe thrombocytopenia?

Answer 35

* generally asymptomatic until platelet count is below 30 * easy bruising * petechiae and purpura * mucosal bleeding * severe bleeding after trauma * intracranial haemorrhage

Question 36

Why doesn’t a platelet transfusion work with immune thrombocytopenic purpura?

Answer 36

Transfused platelets are destroyed by spleen as well

Question 37

What can cause disorders of platelet function?

Answer 37

* hereditary (rare) * acquired (common) - aspirin, NSAIDS, clopidogrel (decrease) uraemia (blood in urine)(decrease), myeloma, myeloproliferative disorders (increase)