Haemopoiesis Gone Wrong

Question 1

What can go wrong with haemopoiesis

Answer 1

Over production of cells

Either caused by myeloproliferative disorders or as a physiological reaction

Question 2

Myeloproliferative disorders

Answer 2

Now classified by WHO as Myeloproliferative neoplasms (MPN)

Essential Thrombocythaemia
Polycythaemia Vera
Myelofibrosis
Chronic Myeloid Leukaemia

All of these disorders involve dysregulation at the multipotent haematopoietic stem cell

Myeloproliferative disorders - clinical features
Overproduction of one or several blood elements with dominance
of a transformed clone.
Hypercellular marrow / marrow fibrosis.
Cytogenetic abnormalities.
Thrombotic and/or haemorrhagic diatheses.
Extramedullary haemopoiesis (liver/spleen).
Potential to transform to acute leukaemia.
Overlapping clinical features.

Many patients have a specific point mutation in one copy of the Janus kinase 2 gene (JAK2) - a cytoplasmic tyrosine kinase on chromosome 9, which causes increased proliferation and survival of haematopoietic precursors

We now have specific drugs targeting the aberrant protein

Question 3

Too many RBC - Polycythaemia Vera (PV)

Answer 3

Diagnostic criteria = High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass
JAK2 V617F mutation is present in approximately 95% PRV patients
No reactive cause found
Some patients also have high platelets & neutrophils
Median age 60 yrs + Male=Female - no discrimination

Clinical features - Significant cause of arterial thrombosis
Venous thrombosis
Haemorrhage into skin or GI tract
Pruritis
Splenic discomfort , splenomegaly
Gout
In some transformation to myelofibrosis or acute leukaemia

Management:
Venesection to maintain the Hct to <0.45
Aspirin 75 mg unless contraindicated
Manage CVS risk factors
Sometimes drugs to reduce the overproduction of cells should be considered

Question 4

Polycythaemia/ Erythrocytosis

Answer 4

Polycythaemia= an increase in circulating red cell concentration typified by a persistently raised haematocrit (Hct)

This increase can be: Relative = normal red cell mass with decreased

Question 5

Essential thrombocythaemia (ET)

Answer 5

Excess platelets in the blood - therefore need to screen for Jak2 and CALR mutations - can find large and excess number of megakaryocyes in bone marrow which leads to thrombotic events

Management:
Any cardiovascular risk factors should be aggressively
managed - Aspirin
High risk patients: - >60 years, platelet count >1500 or disease-related thrombosis/haemorrhage
Therefore need to return the platelet count into the normal range with drug such as hydroxycarbomide

once the High platelet count noted - 1st look for and exclude reactive causes - e.g. Infection
Inflammation (Inflammatory bowel disease, Rh arthritis)
Other tissue injury (e.g. surgery, trauma, burns)
Haemorrhage
Cancer
Redistribution of platelets - Post-splenectomy and hyposplenism

Ensure it is persistent rather than transient before investigating for ET

Question 6

Myelofibrosis

Answer 6

A cause of massive splenomegaly - +/- hepatomegaly due to extramedullary haematopoiesis

Heavily fibrotic marrow, little space for haemopoiesis, so this functions is then split between the spleen and the liver
Blood film shows red cells looking like tear drops

Clonal haemopoietic stem cell proliferation - May be end result of PV or ET, or Primary disease (PMF)
PMF starts with proliferative phase when all counts may be
high
Then in all cases progressive pancytopeniadue to bone marrow fibrosis and hypersplenism

Clinical features:
Patients with advanced disease experience severe constitutional symptoms – fatigue, sweats
The consequences of massive splenomegaly - pain, early satiety, splenic infarction
Progressive marrow failure requiring transfusions of blood products
Transformation to leukaemia
Early death

Question 7

Chronic myeloid leukaemia

Answer 7

Usually presents with very high WCC, this may be incidental finding

Patients may present with symptomatic splenomegaly, hyperviscosity (sticky blood) or bone pain

Disease of adults, v rare in children

Blood film and marrow will show excess of all myeloid series from blast through to fully mature neutrophils

The trail-blazing drug Imatinib developed due to the detailed work done over decades to understand this

Question 8

Imatinib is a Tyrosine kinase inhibitor

Answer 8

Before the introduction of this tablet, standard treatment was bone marrow transplantation from a donor with at the time ~20% mortality. Median survival increased from 5 years to beyond 20 years

Question 9

Pancytopenia and aplastic anaemia

Answer 9

Reduction in white cells, red cells and platelets
Is it due to reduced production or increased removal?

Pancytopenia - reduced production:
Could be due to -
-B12/folate deficiency
-Bone marrow infiltration by malignancy (blood cancers of other cancers)

Question 10

Platelets

Answer 10

Key role in Haemostasis to facilitate clot formation, initially via a platelet ‘plug’:

Question 11

Platelet disorders

Answer 11

Quantitative – low (thrombocytopenia)