Neutrophils: back in the thrombosis spotlight

Abstract

Reactive and clonal neutrophil expansion has been associated with thrombosis, suggesting that neutrophils play a role in this process. However, although there is no doubt that activated monocytes trigger coagulation in a tissue factor-dependent manner, it remains uncertain whether stimulated neutrophils can also directly activate coagulation. After more than a decade of debate, it is now largely accepted that normal human neutrophils do not synthetize tissue factor, the initiator of the extrinsic pathway of coagulation. However, neutrophils may passively acquire tissue factor from monocytes. Recently, the contact system, which initiates coagulation via the intrinsic pathway, has been implicated in the pathogenesis of thrombosis. After the recent description of neutrophil extracellular trap (NET) release by activated neutrophils, some animal models of thrombosis have demonstrated that coagulation may be enhanced by direct NET-dependent activation of the contact system. However, there is currently no consensus on how to assess or quantify NETosis in vivo, and other experimental animal models have failed to demonstrate a role for neutrophils in thrombogenesis. Nevertheless, it is likely that NETs can serve to localize other circulating coagulation components and can also promote vessel occlusion independent of fibrin formation. This article provides a critical appraisal of the possible roles of neutrophils in thrombosis and highlights some existing knowledge gaps regarding the procoagulant activities of neutrophil-derived extracellular chromatin and its molecular components. A better understanding of these mechanisms could guide future approaches to prevent and/or treat thrombosis.

Figure 1.

Most common mechanisms of chromatin release by neutrophils during cell death.

Figure 2.

Proposed mechanisms by which NETs/chromatin components activate coagulation in vitro. Intact NETs (1), extracellular chromatin (2), nucleosomes (3), or histone octamers (4) do not directly activate coagulation. (5) Free DNA activates coagulation through the contact pathway. (6) Free histones promote coagulation activation mainly by inducing a procoagulant phenotype on blood and endothelial cells (ECs). FVa, activated factor V; Kal, kallikrein; PolyP, polyphosphate; PS, phosphatidylserine; RBC, red blood cell; TLR, tool-like receptor.

Figure 3.

Proposed mechanism of NET-dependent thrombosis in vivo. (1) Neutrophils adhere to the endothelium by interaction between E-selectin and neutrophil P-selectin glycoprotein ligand (PSGL) and CXCR2. Platelets (PLTs) adhere by binding to von Willebrand factor (VWF) attached to the endothelium. (2) PSGL-1 and CXCR2 signaling in neutrophils (PMNs), as well as interactions between adherent neutrophils and platelets mediated by platelet HMGB1 or P-selectin, promote NET release. (3) NETs adhere and damage the vascular wall, impair flow, trap circulating procoagulant actors, impair physiologic anticoagulants, (4) ultimately leading to enhanced coagulation and thrombosis. aPTL, activated platelet; E-SEL, endothelial selectin; NE, neutrophil elastase; PMV, procoagulant microvesicle; TFPI, TF pathway inhibitor.