Novel Pathophysiological Mechanisms of Thrombosis in Myeloproliferative Neoplasms

Purpose of Review Thrombosis remains a leading cause of morbidity and mortality in BCR/ABL negative myeloproliferative neoplasms (MPN). Circulating blood cells are both increased in quantity and qualitatively abnormal in MPN, resulting in an increased thrombotic risk. Herein, we review recently elucidated mechanisms of MPN thrombosis and discuss implications of drugs currently under investigation for MPN. Recent Findings Recent studies highlight that in JAK2(V617F) granulocytes and platelets, thrombo-inflammatory genes are upregulated. Furthermore, in JAK2(V617F) granulocytes, protein expression of integrin CD11b, tissue factor, and leukocyte alkaline phosphatase are all increased. Overall, myeloid cells, namely neutrophils, may contribute in several ways, such as through increased adhesion via beta 1 integrin binding to VCAM1, increased infiltration, and enhanced inducibility to extrude neutrophil extracellular traps. Non-myeloid inflammatory cells may also contribute via secretion of cytokines. With regard to red blood cells, number, rigidity, adhesion, and generation of microvesicles may lead to increased vascular resistance as well as increased cell-cell interactions that promote rolling and adhesion. Platelets may also contribute in a similar fashion. Lastly, the vasculature is also increasingly appreciated, as several studies have demonstrated increased endothelial expression of pro-coagulant and pro-adhesive proteins, such as von Willebrand factor or P-selectin in JAK2(V617F) endothelial cells. With the advent of molecular diagnostics, MPN therapeutics are advancing beyond cytoreduction. Our increased understanding of pro-inflammatory and thrombotic pathophysiology in MPN provides a rational basis for evaluation of in-development MPN therapeutics to reduce thrombosis.

Automated summary

The main cause of thrombosis in MPN patients is the increased quantity and abnormal quality of circulating blood cells, leading to a higher thrombotic risk. Recent studies have shown that thrombo-inflammatory genes are upregulated in JAK2(V617F) granulocytes and platelets. Additionally, red blood cells, platelets, and the vasculature may also contribute to thrombosis through various mechanisms.