Patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and
primary myelofibrosis (PMF) are at increased risk of arterial and
venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates
erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that
heparanase protein forms a complex and enhances the activity of the blood coagulation initiator
tissue factor (TF) which leads to increased
factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate
heparanase procoagulant activity in myeloproliferative
neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to
heparanase, TF and TF pathway inhibitor (
TFPI).
Erythropoietin receptor positive cell lines U87 human
glioma and MCF-7 human
breast carcinoma were studied.
Heparanase and
TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies.
Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (
Ruxolitinib, VZ3) and
hydroxyurea, although the latter
drug did not inhibit JAK-2 phosphorylation.
Erythropoietin increased while JAK-2 inhibitors decreased the
heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in
heparanase up-regulation via the
erythropoietin receptor. The present findings may potentially point to a new mechanism of
thrombosis in JAK-2 positive ET patients.