LB 02.4 - Platelets as Versatile Effectors of Thromboinflammation in Chronic Myeloproliferative Neoplasms

Patients with Philadelphia (Ph)-negative myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), often elicit unique clinical features, such as a tendency toward both thrombosis and hemorrhage, splenomegaly (at times massive) and clinical manifestations of microcirculatory disturbances such as ocular migraine, Raynaud phenomenon, and erythromelalgia. Although an increase in one or more blood cell lineages contributes to these morbid sequelae, the qualitative abnormalities of myeloid cells that increase vascular risk or disease progression are not well understood.

Aims:

Considering the critical role of inflammation in the vascular risk; and considering emerging evidence for platelet functional interplay between thrombosis, inflammation, and cancer, we study the platelet transcriptome in a large clinical cohort of the three chronic progressive MPN phenotypes, ET, PV and MF.

Methods: MPN patient blood samples were obtained with informed consent and approval by the Stanford Institutional Review Board. Established high-quality reproducible methods were followed for platelet isolation, purification, RNA isolation, high-throughput sequencing, and bioinformatic analyses

Results: Using platelet RNA-sequencing (RNA-seq), we quantify how gene expression, alternative splicing and the associated molecular pathways are altered in each of ET (n=24), PV (n=33) and MF (n=42) with respect to healthy controls (n=11). Differential markers in each of ET, PV and MF highlight candidate genes as potential mediators of the pro-thrombotic and pro-fibrotic phenotypes in MPNs

Conclusion(s):

In summary, we present comprehensive platelet RNA profiling of a large (100+) clinical cohort of hematologic disorders (across all three chronic progressive subtypes), that includes both expression and splicing changes as a function of disease. Our findings indicate that the platelet transcriptome offers a unique window into cross-functional molecular mechanisms of thromboinflammation in myeloproliferative neoplasms, thus expanding our classical understanding of platelet function in hemostasis and thrombosis. MPN platelets reveal a chronic proinflammatory state that likely contributes to disease pathogenesis.