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 (Spearman r = 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 regulators PROCR-H1, PROCR-H3, and THBD-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.
Highlights
Blood coagulation is a process that starts quickly after vascular damage in order to repair damaged tissue and maintain blood homeostasis
activated protein C (APC) levels are genetically determined [16] and, we have previously demonstrated that mutations in the proteins that comprise the quaternary complex needed for protein C activation modulate the risk of thrombosis [17,18]
The association of the main markers of neutrophil activation and the thrombotic risk was not evaluated. This is the largest case-control study that demonstrates the increase in markers of neutrophil activation in vivo in venous thromboembolism (VTE) patients and where an increase in the thrombotic risk was demonstrated
Summary
Blood coagulation is a process that starts quickly after vascular damage in order to repair damaged tissue and maintain blood homeostasis. In NETs, released DNA is associated with citrullinated histone 3 along with enzymes such as myeloperoxidase (MPO), calprotectin, and elastase contained within neutrophils [5]. The polyanionic surface of NETs activates the contact phase proteins such as FXII [7], and can bind and induce the expression of tissue factor to initiate the intrinsic and extrinsic pathways of coagulation, respectively [1,8]. NETs activate coagulation and inhibit the natural anticoagulants. NET-associated elastase and MPO are capable of degrading the tissue factor pathway inhibitor and thrombomodulin (TM) [9,10], limiting their anticoagulant function. APC displays anti-inflammatory and cytoprotective functions [13], which may be diminished in the presence of NETs, further enhancing the inflammatory scenario
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