Genetic insights into myeloproliferative neoplasms and unusual sites thrombosis

Myeloproliferative neoplasms (MPNs) are associated with an elevated risk of thrombosis in unusual sites such as the splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT). In patients with unusual site thrombosis, screening for MPNs is routine, but diagnosis is often difficult due to the absence of clear clinical signs or elevated blood counts-frequently leading to an MPN-U classification-while the thrombotic event itself is often the first clue. Furthermore, there is no consensus on treatments beyond anticoagulation, leading to variability across centers. This study investigates the molecular characteristics of MPNs associated with SVT and CVT. We conducted a retrospective, multicenter analysis of 44 patients with MPN and unusual site thrombosis from Italian hematology units, using next-generation sequencing. (NGS) to identify driver and passengers mutations. Our findings confirm a high prevalence of unclassifiable MPN (MPN-U) among SVT patients. JAK2 p.V617F was found in 86.4% of cases, and patients with additional mutations had higher median JAK2 variant allele frequencies. JAK2 p.V617F is known to promote thrombosis by inducing a pro-inflammatory endothelial environment, particularly relevant in low-flow venous sites such as cerebral sinuses and splanchnic veins, supporting MPN screening in these patients. In contrast, data on JAK2-unmutated cases are more limited, but our cohort suggests a possible association between unusual site thrombosis and a more complex mutational profile involving multiple genetic alterations. TET2 mutations were more frequent in patients with MPN-CVT compared to the rest of the cohort (66.6% vs. 15.7%). Absence of KIT mutations was associated with poorer thrombotic recurrence-free survival, suggesting a negative prognostic role of KIT mutation. Brief report.