The Role of Neutrophils in Venous Thrombosis in Primary Membranous Nephropathy
Qiuhan Wang, Benxia Bing1, Liang Xu2
1Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China, wqh7forever@163.com.
Introduction:
Patients with primary membranous nephropathy (PMN) are at high risk of developing venous thromboembolic events (VTEs), while 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 cell-free DNA (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 h 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. Four 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.
Insights
Neutrophils are linked to increased blood clot risk in primary membranous nephropathy (PMN). Inhibiting neutrophil extracellular trap formation (NETosis) reduced thrombosis in a rat model, suggesting new therapeutic targets for PMN patients.
Area of Science:
- Nephrology
- Hematology
- Immunology
Background:
- Patients with primary membranous nephropathy (PMN) face a high risk of venous thromboembolic events (VTEs).
- The specific role of neutrophils in VTE development within PMN remains incompletely understood.
Purpose of the Study:
- To investigate the association between neutrophils and VTEs in patients with PMN.
- To explore the potential role of neutrophil extracellular trap formation (NETosis) in thrombosis in a preclinical model.
Main Methods:
- Retrospective analysis of a large PMN patient cohort to assess neutrophil counts and VTE occurrence.
- Measurement of plasma cell-free DNA (cfDNA) levels in PMN patients.
- Establishment of a rat model of passive Heymann nephritis (PHN) with deep vein thrombosis induction.
- Evaluation of the effect of a NETosis inhibitor (GSK484) on thrombosis in the PHN rat model.
Main Results:
- Higher neutrophil counts were observed in PMN patients with VTEs compared to those without.
- Neutrophil counts correlated positively with coagulation factors and anticoagulation proteins.
- Neutrophils were identified as independent risk factors for VTEs in PMN patients.
- Elevated cfDNA levels were found in PMN patients, particularly those with VTEs.
- Inhibition of NETosis significantly reduced thrombus formation in the PHN rat model.
Conclusions:
- Neutrophils contribute to hypercoagulation and increased thrombosis risk in PMN.
- This study provides novel insights into the pathogenesis of thrombosis in PMN.
- Targeting neutrophils and NETosis may offer potential therapeutic strategies for managing thrombosis in PMN.
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