Page 217 - Essential Haematology

Chapter 15 Myeloproliferative neoplasms / 203

in a highly conserved region of the pseudokinase Once established, absolute polycythaemia can
domain, which is believed to negatively regulate then be subdivided into primary polycythaemia
JAK2 signalling. JAK2 has a major role in normal (in which the erythroid progenitor cell shows an
myeloid development by transducing signals from enhanced response to cytokines) or secondary
diverse cytokines and growth factors including polycythaemia (driven by factors outside the eryth-
interleukin - 3 (IL - 3), erythropoietin, granulocyte – roid compartment) (Table 15.3 ).
macrophage colony - stimulating factor (GM - CSF),
granulocyte colony - stimulating factor (G - CSF) and

thrombopoietin (see Fig. 1.8 ). Why the same muta- Primary p olycythaemia
tion is associated with diff erent myeloproliferative ( e rythrocytosis)

diseases is unclear. The exact cell in which the muta-
tion arises, the number of stem cells involved, the Congenital
genetic background of individual subjects including
(See below.)
polymorphism of the JAK2 gene, and other factors
may be relevant.
Acquired
Polycythaemia This is caused by the acquisition of mutations in the

JAK2 gene leading to PV.
Polycythaemia is defined as an increase in the hae-

moglobin concentration above the upper limit of
’
normal for the patient s age and sex.
Polycythaemia v era
In PV, the increase in red cell volume is caused by

Classification of p olycythaemia
a clonal malignancy of a marrow stem cell. Th e

Polycythaemia is classified according to its patho- disease results from somatic mutation of a single
physiology but the major subdivision is into abso- haemopoietic stem cell which gives its progeny a
lute polycythaemia or erythrocytosis, in which the proliferative advantage. Th e Val617Phe JAK2 muta-
red cell mass (volume) is raised to greater than tion is present in haemopoietic cells in over 95% of
125% of that expected for body mass and gender, patients and a mutation in exon 12 is seen in some
and relative or pseudopolycythaemia in which the of the remainder. Although the increase in red cells

red cell volume is normal but the plasma volume is is the diagnostic finding, in many patients there is
reduced. If the haematocrit is > 0.60 then there will also an overproduction of granulocytes and plate-
always be a raised red cell mass. Hb > 18.5 g/dL or lets. Some families have an inherited predisposition
haematocrit > 0.52 in men, and Hb > 16.5 g/dL or to myeloproliferative disease and, interestingly,
haematocrit > 0.48 in women, indicate that eryth- although affected individuals acquire JAK2 muta-

rocytosis is likely but isotope studies may be required tions in the marrow, these are not present in the
(Table 15.2 ). germline.

Table 15.2 Radiodilution methods for measuring red cell and plasma volume.
Primary or secondary Relative
Normal polycythaemia polycythaemia
51
Total red cell volume ( Cr) Men 25 – 35 mL/kg Increased Normal
Women 22 – 32 mL/kg
Total plasma volume 40 – 50 mL/kg Normal Decreased
125
( I - albumin)