Evaluation of JAK-STAT inhibition in JAK2V617F myeloproliferative leukocytes and endothelium

Vascular activation is characterized by increased proinflammatory,
prothrombotic, and proadhesive signaling. Several chronic and acute
conditions, including Bcr-abl-negative myeloproliferative neoplasms
(MPNs), graft-vs-host disease, and COVID-19, have been noted to have
increased activation of the Janus kinase (JAK)-signal transducer and
downstream activator of transcription (STAT) pathways. Two notable
inhibitors of the JAK-STAT pathway are ruxolitinib (JAK1/2 inhibitor) and
fedratinib (JAK2 inhibitor), which are currently used to treat MPN
patients. However, in some conditions, it has been noted that JAK
inhibitors can increase the risk of thromboembolic complications. We
sought to define the anti-inflammatory and antithrombotic effects of
JAK-STAT inhibitors in vascular endothelial cells and leukocytes. By using
endothelialized microfluidics perfused with whole blood samples, we
demonstrated that endothelial treatment with JAK-STAT inhibitors prevented
rolling of both healthy control and JAK2V617F MPN leukocytes. Together,
these findings demonstrate that JAK-STAT inhibitors reduce the
upregulation of critical prothrombotic pathways and prevent increased
leukocyte–endothelial adhesion.