The role of neutrophils in venous thrombosis in primary membranous nephropathy.

Abstract

Introduction: Patients with primary membranous nephropathy (PMN) are at high risk of developing venous thromboembolic events (VTEs), while whether neutrophils are involved in the onset of VTEs in PMN remains unclear.

Methods: The association of neutrophils with VTEs was retrospectively analyzed in a large cohort of patients with PMN. Plasma cfDNA levels were evaluated in PMN patients with and without VTEs. In addition, we established a rat model of passive Heymann nephritis (PHN) by immunization with sheep anti-rat Fx1A serum. The inferior vena cava (IVC) was ligated to establish the deep vein thrombosis model. Thrombus weight and length were evaluated at 4 hours after IVC stenosis in rats. GSK484 was administered via intraperitoneal injection to assess the role of NETosis inhibition in thrombosis formation in PHN rats.

Results: Circulating neutrophils in PMN patients with VTEs were significantly higher than in patients without VTEs. Neutrophil counts were positively correlated with the activity of factor IX, factor XI, protein C, protein S, and AT-III (r=0.328, p=0.002; r=0.378, p<0.001; r=0.380, p<0.001; r=0.243, p=0.029; r=0.254, p=0.020). In multivariate logistic regression, neutrophils were the independent risk factors for VTEs in PMN patients (OR=1.608, 95%CI: 1.293-2.000; p<0.05). Significantly increased plasma levels of cfDNA were detected in PMN patients, especially in PMN patients with VTEs, relative to controls. In animal experiments, the plasma cfDNA levels elevated significantly after IVC stenosis in PHN rats, and GSK484 decreased the plasma cfDNA levels in PHN rats with IVC stenosis. 4 hours after IVC stenosis surgery, thrombi formed in PHN rats were both longer and heavier compared to those observed in control rats, and GSK484 administration significantly inhibits the thrombus formation in PHN rats.

Conclusion: This study preliminarily indicated that neutrophils were involved in the hypercoagulation state and increased thrombosis propensity in PMN, offering novel insights into the pathogenesis of thrombosis formation in PMN and potential therapeutic targets for its management.