Platelets display immunophenotypic alterations and dysregulated transcriptomic signature in Philadelphia-negative...

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF) are Philadelphia-negative myeloproliferative neoplasms (MPN) associated with gain-of-function mutations in JAK2, CALR, and MPL genes. Chronic inflammation is a central hallmark of MPN, significantly contributing to disease pathogenesis and progression and severe complications such as thrombosis. Alterations in platelet immunophenotype and gene expression may influence the thromboinflammatory state observed in MPN patients. We aimed to characterize platelet immunophenotype, ex vivo activation, and transcriptomic signatures in MPN patients compared to healthy controls.

Inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), were assessed to determine the thromboinflammatory status. Platelet immunophenotyping was performed at baseline and following stimulation with calcium ionophore A23187 or thrombin. Control platelets were exposed to MPN plasma to evaluate inflammatory activation. Transcriptomic data were analyzed in silico to identify dysregulated platelet-related pathways.

MPN patients exhibited elevated NLR, PLR, and SII, consistent with systemic inflammation. Their platelets showed a pre-activated phenotype, with increased baseline expression of CD62P, CD36, CD63, and CD154. Compared to controls, MPN platelets were less responsive to thrombin stimulation, whereas control platelets exposed to MPN plasma acquired an activated phenotype. Transcriptomic profiling revealed downregulation of genes associated with cytoskeleton organization, integrin signaling, adhesion, metabolism, and trafficking.

MPN platelets are intrinsically activated and transcriptionally dysregulated, even in treated patients. These findings underscore the critical role of platelets in MPN-associated thromboinflammation, highlighting platelet contribution to hemostatic and thrombotic complications.