Proteomic profiling links complement activation to thrombosis in JAK2V617F myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are associated with a high risk of thrombotic complications, particularly splanchnic vein thrombosis (SVT). This study aimed to elucidate the proteomic signature of JAK2V617F-mutated MPN patients with and without SVT, focusing on dysregulated pathways contributing to thrombotic risk.

We conducted a comprehensive proteomic analysis of plasma samples from 28 JAK2V617F-mutated MPN patients (22 with SVT, 6 without thrombosis) and 6 healthy controls. Proteins were quantified using TMT labeling and nanoLC-MS/MS, followed by multivariate and univariate statistical analyses.

A total of 275 high-confidence proteins were identified. Compared to controls, MPN patients exhibited significant dysregulation of complement and coagulation pathways, with upregulation of complement components (C1QA, C1QB, C1QC, C7) and endothelial adhesion molecules (VCAM1, ICAM1), along with downregulation of anticoagulant proteins (PROS1, SERPINA10). SVT patients showed heightened complement activation, markedly increased C7, VCAM1, and von Willebrand factor, and reduced levels of coagulation factors (F9, F10, F11). Hierarchical clustering and pathway enrichment analyses highlighted the central role of complement activation, platelet activation, and endothelial dysfunction in SVT pathogenesis. Serum validation confirmed elevated alternative pathway markers (Ba, Bb) and terminal complement products (C5a, sC5b-9) in SVT, implicating complement activation as a key driver of thrombosis.

This study identifies complement activation as a potential key contributor to thrombosis in JAK2V617F MPN patients, particularly those with SVT. The interplay between complement, coagulation, and endothelial dysfunction suggests potential therapeutic targets for reducing thrombotic complications in this high-risk population.

This work was supported by AGAUR, ISCIII, and Novartis.