Increase of Neutrophil Activation Markers in Venous Thrombosis-Contribution of Circulating Activated Protein C

Autores de IIS La Fe

• Laura Martos Marin

  Autor

• Ana Julia Oto Martínez

  Autor

• Álvaro Fernández Pardo

  Autor

• Emma Plana Andani

  Autor

• Maria José Solmoirago

  Autor

• Fernando Cana Vidal

  Autor

• David Hervás Marín

  Autor

• Santiago Bonanad Boix

  Autor

• Fernando Ferrando Gosp

  Autor

• Francisco España Furio

  Autor

• Silvia Navarro Rosales

  Autor

• 

  Pilar Medina Badenes

  Autor

Grupos

• Hemostasia, Trombosis, Arteriosclerosis y Biología vascular

Abstract

Upon activation, neutrophils release their content through different mechanisms like degranulation and NETosis, thus prompting thrombosis. The natural anticoagulant activated protein C (APC) inhibits neutrophil NETosis and, consequently, this may lower the levels of neutrophil activation markers in plasma, further diminishing the thrombotic risk exerted by this anticoagulant. We aimed to describe the status of markers of neutrophil activation in plasma of patients with venous thrombosis, their association with the thrombotic risk and the potential contribution of APC. We quantified three markers of neutrophil activation (cell-free DNA, calprotectin, and myeloperoxidase) in 253 patients with venous thromboembolism (VTE) in a stable phase (192 lower extremity VTE and 61 splanchnic vein thrombosis) and in 249 healthy controls. In them, we also quantified plasma APC, soluble endothelial protein C receptor (EPCR), and soluble thrombomodulin (TM), and we genotyped two genetic regulators of APC: the EPCR gene (PROCR) haplotypes (H) and the TM gene (THBD) c.1418C>T polymorphism. We found a significant increase in plasma cell-free DNA (p< 0.0001), calprotectin (p= 0.0001) and myeloperoxidase (p= 0.005) in VTE patients compared to controls. Furthermore, all three neutrophil activation markers were associated with an increase in the thrombotic risk. Cell-free DNA and calprotectin plasma levels were significantly correlated (Spearmanr= 0.28;p< 0.0001). As expected, the natural anticoagulant APC was significantly decreased in VTE patients (p< 0.0001) compared to controls, what was mediated by its genetic regulatorsPROCR-H1,PROCR-H3, andTHBD-c.1418T, and inversely correlated with cell-free DNA levels. This is the largest case-control study that demonstrates the increase in markers of neutrophil activation in vivo in VTE patients and their association with an increased thrombotic risk. This increase could be mediated by low APC levels and its genetic regulators, which could also increase NETosis, further enhancing thrombosis and inflammation.

Keywords

• neutrophil; venous thrombosis; activated protein C; DNA; cell-free DNA; myeloperoxidase; calprotectin