How ruxolitinib reduces thrombosis in MPNs

^{Image courtesy of AFIP}

Polycythemia vera

Preclinical research helps explain how the JAK1/2 inhibitor ruxolitinib can reduce thrombosis in patients with myeloproliferative neoplasms (MPNs).

Experiments revealed a link between JAK2^V617F and the formation of neutrophil extracellular traps (NETs), which have been implicated in thrombosis.

Researchers found that ruxolitinib reduced NET formation and decreased thrombosis in JAK2-mutant mice.

Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues reported these findings in Science Translational Medicine.

The researchers noted that patients with MPNs have an increased risk of thrombosis, and previous research linked thrombosis to the formation of NETs. NETs are structures that help trap pathogens but may also promote autoimmune responses and excessive blood clotting.

With the current study, Dr Ebert and his colleagues examined whether NET formation could promote thrombosis in patients with MPNs.

The team found that neutrophils from MPN patients were more likely to form NETs than neutrophils from healthy individuals. However, incubating neutrophils with ruxolitinib reduced NET formation.

The researchers also found that mice with JAK2^V617F were more likely to form NETs and develop thrombosis when compared to wild-type mice. However, treatment with ruxolitinib reduced rates of thrombosis and prevented NET formation in the mice.

The researchers noted that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils. And the team found that PAD4 is required for JAK2^V617F-driven NET formation and thrombosis in mouse models of MPNs.

Lastly, the researchers looked at data from 10,893 human subjects. None of these subjects had MPNs, but some had JAK2^V617F.

Subjects who were JAK2^V617F-positive had a significantly higher risk of thrombotic events than subjects without the mutation (P=0.0003).

Taken together, these findings suggest that JAK2 inhibition can reduce NET formation and ameliorate thrombosis in patients with MPNs or the JAK2^V617F mutation.

The researchers noted that, in the phase 3 RESPONSE trial, patients with polycythemia vera had a lower rate of thromboembolic events if they received ruxolitinib rather than standard therapy.