The proteolytic inactivation of protein Z-dependent protease inhibitor by neutrophil elastase might promote the procoagulant activity of NETs

Septic shock is the archetypal clinical setting in which extensive cross talk between inflammation and coagulation dysregulates the latter. The main anticoagulant systems are systematically impaired, depleted and/or downregulated. Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that not only targets coagulation factors Xa and XIa but also acts as an acute phase reactant whose plasma concentration rises in inflammatory settings. The objective of the present study was to assess the plasma ZPI antigen level in a cohort of patients suffering from septic shock with or without overt-disseminated intravascular coagulation (DIC). The plasma ZPI antigen level was approximately 2.5-fold higher in the patient group (n=100; 38 with DIC and 62 without) than in healthy controls (n=31). The elevation’s magnitude did not appear to depend on the presence/absence of DIC. Furthermore, Western blots revealed the presence of cleaved ZPI in plasma from patients with severe sepsis, independently of the DIC status. In vitro, ZPI was proteolytically inactivated by purified neutrophil elastase (NE) and by NE on the surface of neutrophil extracellular traps (NETs). The electrophoretic pattern of ZPI after NE-catalyzed proteolysis was very similar to that resulting from the clotting process - suggesting that the cleaved ZPI observed in severe sepsis plasma is devoid of anticoagulant activity. Taken as a whole, our results (i) suggest that NE is involved in ZPI inactivation during sepsis, and (ii) reveal a novel putative mechanism for the procoagulant activity of NETs in immunothrombosis.

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A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis

Blood ◽

10.1182/blood-2005-08-3249 ◽

2006 ◽

Vol 108 (1) ◽

pp. 177-183 ◽

Cited By ~ 43

Author(s):

Javier Corral ◽

Rocio González-Conejero ◽

Jose Manuel Soria ◽

Jose Ramón González-Porras ◽

Elena Pérez-Ceballos ◽

...

Keyword(s):

Protease Inhibitor ◽

Venous Thrombosis ◽

Stop Codon ◽

Anticoagulant Activity ◽

Low Frequency ◽

Protein Z ◽

Antithrombin Deficiency ◽

Thrombotic Risk ◽

Genetic Modifications ◽

History Of

The protein Z-dependent protease inhibitor (ZPI) is a hemostatic serpin with anticoagulant activity. As for antithrombin, deficiency of ZPI could have relevant thrombotic consequences. We have studied 6 genetic modifications affecting the ZPI gene, identifying 5 haplotypes. Haplotype H5 is featured by a stop codon at position 67. The relevance of these genetic modifications and haplotypes in venous thrombosis was evaluated in a case-control study including 1018 patients and 1018 age- and sex-matched controls. Surprisingly, the H5 haplotype was found in 0.9% of controls, supporting that the Arg67Stop change is a low frequency nonsense polymorphism. The prevalence of this haplotype increased significantly in patients (3.0%), one of whom was in a homozygous state. Multivariate analysis confirms that carriers have a 3.3-fold risk of developing venous thrombosis (P = .002; 95% CI: 1.5-7.1). Moreover, we observed a significant association of this polymorphism with familial history of thrombosis (P < .001). Our study supports that the ZPI Arg67Stop nonsense polymorphism might be an independent genetic risk factor for venous thrombosis. This polymorphism has slightly lower prevalence but similar thrombotic risk than the FV Leiden or prothrombin 20210A. Although further studies are required, all available data support that the ZPI is a candidate to play a significant role in thrombosis and should be evaluated in thrombophilic studies. (Blood. 2006;108:177-183)

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Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor

TH Open ◽

10.1055/s-0041-1730037 ◽

2021 ◽

Vol 05 (02) ◽

pp. e220-e229

Author(s):

Mahita Razanakolona ◽

Frédéric Adam ◽

Elsa Bianchini ◽

François Saller ◽

Allan de Carvalho ◽

...

Keyword(s):

Protease Inhibitor ◽

Whole Blood ◽

Anticoagulant Activity ◽

Inhibitory Effect ◽

Inflammatory Activity ◽

Protein Z ◽

Tnf Α ◽

Factor Xia ◽

Anti Inflammatory ◽

Factor Α

AbstractThe protein Z (PZ)-dependent plasma protease inhibitor (ZPI) is a glycoprotein that inhibits factor XIa and, in the presence of PZ, FXa. Recently, ZPI has been shown to be an acute-phase protein (APP). As usually APPs downregulate the harmful effects of inflammation, we tested whether ZPI could modulate the increase of cytokines observed in inflammatory states. We observed that recombinant human ZPI (rhZPI) significantly decreases the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor- α (TNF-α) induced by lipopolysaccharide (LPS) in a whole blood model. This inhibitory effect was unaffected by the presence of PZ or heparin. A ZPI mutant within the reactive loop center ZPI (Y387A), lacking anticoagulant activity, still had an anti-inflammatory activity. Surprisingly, rhZPI did not inhibit the synthesis of IL-6 or TNF-α when purified monocytes were stimulated by LPS, whereas the inhibitory effect was evidenced when lymphocytes were added to monocytes. The requirement of lymphocytes could be due to the synthesis of CCL5 (RANTES), a chemokine mainly produced by activated lymphocytes which is induced by rhZPI, and which can reduce the production of proinflammatory cytokines in whole blood. Lastly, we observed that the intraperitoneal injection of rhZPI significantly decreased LPS-induced IL-6 and TNF-α production in mouse plasma.

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Effect of fluid bolus triggers and their combination on fluid responsiveness in optimization phase of severe sepsis and septic shock resuscitation

MedPharmRes ◽

10.32895/ump.mpr.2.3.27 ◽

2018 ◽

Vol 2 (3) ◽

pp. 27-32

Author(s):

Bien Le ◽

Dai Huynh ◽

Mai Tuan ◽

Minh Phan ◽

Thao Pham ◽

...

Keyword(s):

Blood Pressure ◽

Septic Shock ◽

Severe Sepsis ◽

Fluid Responsiveness ◽

Statistical Significance ◽

Venous Pressure ◽

Fluid Bolus ◽

Low Blood Pressure ◽

Low Central Venous Pressure ◽

Sepsis And Septic Shock

Objectives: to evaluate the fluid responsiveness according to fluid bolus triggers and their combination in severe sepsis and septic shock. Design: observational study. Patients and Methods: patients with severe sepsis and septic shock who already received fluid after rescue phase of resuscitation. Fluid bolus (FB) was prescribed upon perceived hypovolemic manifestations: low central venous pressure (CVP), low blood pressure, tachycardia, low urine output (UOP), hyperlactatemia. FB was performed by Ringer lactate 500 ml/30 min and responsiveness was defined by increasing in stroke volume (SV) ≥15%. Results: 84 patients were enrolled, among them 30 responded to FB (35.7%). Demographic and hemodynamic profile before fluid bolus were similar between responders and non-responders, except CVP was lower in responders (7.3 ± 3.4 mmHg vs 9.2 ± 3.6 mmHg) (p 0.018). Fluid response in low CVP, low blood pressure, tachycardia, low UOP, hyperlactatemia were 48.6%, 47.4%, 38.5%, 37.0%, 36.8% making the odd ratio (OR) of these triggers were 2.81 (1.09-7.27), 1.60 (0.54-4.78), 1.89 (0.58-6.18), 1.15 (0.41-3.27) and 1.27 (0.46-3.53) respectively. Although CVP < 8 mmHg had a higher response rate, the association was not consistent at lower cut-offs. The combination of these triggers appeared to raise fluid response but did not reach statistical significance: 26.7% (1 trigger), 31.0% (2 triggers), 35.7% (3 triggers), 55.6% (4 triggers), 100% (5 triggers). Conclusions: fluid responsiveness was low in optimization phase of resuscitation. No fluid bolus trigger was superior to the others in term of providing a higher responsiveness, their combination did not improve fluid responsiveness as well.

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