Reduced platelet activation in triple-negative essential thrombocythemia compared with JAK2V617F-mutated essential thrombocythemia

Abstract Purpose: Triple-negative (TN) essential thrombocytopenia (ET) is characterized by the absence of driver mutations while retaining histological and phenotypic characteristics sufficient for an ET diagnosis. Our understanding of TN-ET and its platelet activation remains incomplete. We carried out a large-scale multi-center clinical analysis to analyze the clinical and molecular characteristics, thrombotic complications of TN-ET. We also related the above characteristics to platelet activation to further explore the thrombosis mechanism of TN-ET. Experimental Design:A retrospective multicenter study was conducted on 138 TN-ET and 759 ET patients with driver mutations from 1 March 2012 to 1 December 2021. The clinical and molecular characteristics of the TN-ET were summarized. Additionally, platelet activation, apoptosis, and reactive oxygen species (ROS) levels were analyzed in 73 TN-ET patients from this cohort and compared to 41 age- and sex-matched healthy donors.Results:Compared to patients with the JAK2V617F mutation, those with triple-negative mutation were younger (P < 0.001) and exhibited fewer thrombotic events before diagnosis (P < 0.001) and during follow-up (P = 0.039). Patients with triple-negative mutation also presented with significantly reduced CD62P expression in platelets (P = 0.031), slightly reduced calcium concentration in platelets (P = 0.063), increased mitochondrial membrane potential (P = 0.011), reduced phosphatidylserine exposure (P = 0.015), reduced levels of ROS (P = 0.043) and MitoSOX in platelets (P = 0.047).Conclusions: In comparison to JAK2V617F-mutated ET, TN-ET is associated with lower platelet ROS levels, which leads to reduced platelet activation and consequently a lower risk of thrombosis.