Is the neutrophil a ‘prima donna’ in the procoagulant process during sepsis?

Abstract

Activation of the coagulation system is a fundamental host defense mechanism. Microorganisms that have invaded the body are trapped and disposed of in clots. Monocytes/macrophages are widely accepted as the main players in the procoagulant process; however, recent evidence suggests that neutrophils also play important roles. Tissue factor, which initiates the extrinsic coagulation cascade, is reportedly expressed on the surface of neutrophils, as well as on microparticles derived from neutrophils. Neutrophil extracellular traps (NETs) are another source of tissue factor. The components of NETs, such as DNA, histones, and granule proteins, also provide procoagulant activities. For instance, DNA initiates the intrinsic pathway, histones are a strong generator of thrombin, and granule proteins such as neutrophil elastase, cathepsin G and myeloperoxidase contribute to the suppression of the anticoagulation systems. Although understanding of the mechanisms that are involved in coagulation/fibrinolysis in sepsis has gradually progressed, the impact of neutrophils on thrombogenicity during sepsis remains to be addressed. Since the importance of the connection between coagulation and inflammation is advocated nowadays, further research on neutrophils is required.

A Review of Radiation-Induced Coagulopathy and New Findings to Support Potential Prevention Strategies and Treatments

“…Circulating levels of microparticles also increase in patients with sepsis and DIC (59, 60). The role of microparticles in sepsis induced DIC has recently been reviewed (61). …”

Neutrophils, NETs, NETosis — old or new factors in sepsis and septic shock?

“…Thrombin, factor VIIa and factor Xa activate platelets and other cells through the activation of PARs . These receptors are also activated by trypsin and cathepsin G. PARs activation upregulates endothelial expression of TF and the release of von Willebrand factor [15]. Thrombin cleaves fibrinogen into fibrin and activates platelets.…”

“…Circulating levels of nucleosome and histone H3 were measured in patients with severe sepsis. Positive correlation was observed both between nucleosome and fibrin/fibrinogen degradation products (FDP; R 2 = 0.258), and between histone H3 and FDP (R 2 = 0.459), suggesting that neutrophil extracellular traps play some role in the activation of coagulation [15]. Neutrophils and NETs are inducers of immunothrombosis.…”

“…TF microparticles generated from platelets become procoagulant upon association with activated neutrophils while TF on monocyte-derived microparticles shows activity after fusion with phosphatidylserine-expressing platelets, but not resting platelets [27]. It is still a subject of debate if neutrophils synthesize TF or can acquire TF by binding monocyte/platelet-derived microparticles, while neutrophil-derived TF plays a role in septic immunothrombosis/ coagulopathy [15]. According to von Brühl and Fuchs' findings, TF can be produced by neutrophils and expulsed during NET formation.…”

The effect of plasma-derived activated protein C on leukocyte cell-death and vascular endothelial damage

“…The recent topic in this field is the tight link between coagulation and inflammation, and the fact that activated neutrophils play major roles in both phenomena is widely accepted [12]. Since anticoagulants are strong candidates for the management of a disrupted coagulation/ inflammation system and also for the regulation of the activated neutrophils, we attempted to evaluate the effect of pd-APC in an animal model of sepsis as well as in vitro study.…”