Dr. Joan Beckman

Myeloproliferative neoplasms (MPNs) are composed of three phenotypically distinct clonal disorders: polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). These diseases are characterized by excessive production of blood cellular components including red blood cells, platelets, and/or leukocytes. The JAK2^V617F mutation occurs in up to 95% of patients with MPNs and increases the risk of thrombosis six-fold, with a 40% mortality rate attributed to venous thromboembolism (VTE).

The scientific premise for this work is that activation of vascular endothelium is critical to the pathogenesis of MPN thrombosis. This premise is supported by studies evaluating JAK2V617F expression in vascular endothelial cells (ECs). For example, in PV patients with prior splanchnic thrombosis, at least three studies demonstrate endothelial JAK2V617F expression. Likewise, two recent studies directly assessed JAK2 ^V617F+ ECs and found increased expression of von Willebrand factor (VWF) and P-selectin. Additionally, in static adhesion assays, JAK2 V617F+ ECs exhibit increased leukocyte adhesion; concordantly, transcriptome analysis of JAK2 V617F+ inducible pluripotent stem cell derived ECs demonstrates increased cell adhesion, and coagulation gene expression profiles. Collectively, these data suggest that increased endothelial expression of pro-coagulant and pro-adhesive proteins, such as VWF or P-selectin, may account for increased JAK2V617F VTE risk. However, only a few studies have evaluated effects of shear or pressure, two variables that are unique to the splanchnic vasculature and cardiovascular system, vascular beds prone to MPN-related thrombotic complications. One study did observe that under venous flow rates, neutrophils exhibit increased adhesion to JAK2V617F ECs. A second demonstrated that in JAK2V617F cardiac ECs, E-selectin is upregulated. Collectively, these studies demonstrate evaluation of JAK2V617F ECs within the context of physiologic shear is needed to fully understand the development of thrombi in arterial and slow-flow venous vasculatures in MPN patients.