Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia

Abstract

Thrombosis is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). The pathophysiology of thrombosis in these disorders remains unclear, and we hypothesized that upregulation of thrombotic, inflammatory, and hypoxia-inducible factor (HIF)–regulated genes may play a role in it. We performed unbiased RNA sequencing in granulocytes and platelets of PV patients and found differential expression of several thrombotic, inflammatory, and HIF-regulated genes. The expression of many of these genes positively correlated with JAK2 expression and JAK2V617F allelic burden. We then validated these findings by quantitative polymerase chain reaction analyses of selected gene transcripts in a larger number of PV and ET granulocytes and platelets (58 patients) and in 28 controls, and we compared these findings in patients with and without thrombosis. The study included 29 females and 29 males; of these, 28 had a history of thrombosis. We found that transcripts of several selected genes were upregulated in patients with PV or ET compared with controls. In granulocytes, the expression levels of F3, SELP, VEGFA, and SLC2A1 were significantly higher in patients with a history of thrombosis compared with those who did not have thrombosis. Patients with a history of thrombosis have significantly higher expression of IL1RAP (P < .05) in platelets compared with those without thrombosis. Our study confirms the presence of a thrombo-inflammatory state and augmented HIF activity in PV and ET and its role in thrombosis. These data may provide the background for targeted therapies in PV and ET.

Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques

“…Additional thrombosis-associated markers, coagulation factors, and HIF1α signaling pathway previously reported in patients with severe inflammatory disease ( Gangaraju et al., 2020 ) were upregulated in BAL, peripheral blood, and serum of infected macaques ( Figure S3 A). Moreover, markers of platelet activation and aggregation and extracellular matrix organization (COL1A1, COL1A2, FN1, PF4, IGF1, and ADAM15), which were increased in patients with severe-to-critical COVID-19 disease ( Ackermann et al., 2020 ), were also increased in BAL, peripheral blood, and serum of infected macaques ( Figure S3 B).…”

Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms

“…This suggests that peripheral blood monitoring may not accurately assess JAK2 mutant allele burden, particularly in megakaryocyte-erythroid lineage cells and HSCs. Finally, the JAK2- V617F mutation has been shown to have cell-intrinsic effects not only in leukocytes ( Rampal et al., 2014 ; Wolach et al., 2018 ) but also in erythroid cells ( Chen et al., 2010 ; De Grandis et al., 2013 ) and platelets ( Gangaraju et al., 2020 ; Guo et al., 2020 ). Our observation of high JAK2 -V617F allele fractions in megakaryocyte-erythroid lineage cells in individuals with low peripheral blood JAK2- V617F mutational burden may help explain the development of thrombosis in these people.…”

Reconstructing the lineage histories and differentiation trajectories of individual cancer cells inJAK2-mutant myeloproliferative neoplasms

“…Given that the JAK2-V617F mutation has been shown to have cell-intrinsic effects not only in leukocytes 46,47 , but also in erythroid cells 48,49 and in platelets 50,51 , the finding of a high JAK2-V617F allele fraction in megakaryocyte-erythroid lineage cells in patients with low peripheral blood JAK2-V617F mutational burden may help explain the development of thrombosis in these patients 52 .…”